Systemic Juvenile Idiopathic Arthritis

Polyarticular Juvenile Idiopathic Arthritis (Polyarthritis)

Pauciarticular Juvenile Idiopathic Arthritis (Oligoarthritis)

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].

Neurological Manifestations

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.

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].

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].

Fig. 86-1 Brain imaging in systemic lupus erythematosus.

A, Computed tomographic scan of a 14-year-old female with systemic lupus erythematosus, isolated seizures, depressed affect, and intellectual impairment. Cortical atrophy is prominent. B, T1-weighted magnetic resonance image in the sagittal plane of the same patient, demonstrating mild enlargement of the frontoparietal sulci, indicative of atrophy.

(A, Courtesy of Dr. Joseph Thompson, Department of Neuroradiology, Loma Linda University Children’s Hospital. B, Courtesy of Dr. David B Hinshaw, Jr., Department of Neuroradiology, Loma Linda University Children’s Hospital.)

Fig. 86-2 Magnetic resonance image of a 15-year-old female with systemic lupus erythematosus, who developed seizures, depression, generalized weakness, and severe membranous nephritis.

Proton density-weighted axial MRI through the high frontal region shows multiple bright cortical lesions (arrows; more lesions are visible than those marked). The lesions represent acute microinfarctions that result from small segmental leptomeningeal and parenchymal artery thromboses. With gadolinium, these microinfarctions tend to enhance in the subacute phase.

(Courtesy of Dr. Joseph Thompson, Department of Neuroradiology, Loma Linda University Children’s Hospital.)

Fig. 86-3 Magnetic resonance image of a 9-year-old female with systemic lupus erythematosus, who had fever, leukopenia, abdominal pain, worsening headache, and cardiomyopathy.

A T2-weighted axial image through the centrum semiovale above the lateral ventricles shows multiple bright white-matter foci (largest labeled with black arrow) and intrafalcial hemorrhage (arrowheads). No cortical lesions are discerned. Focal T2 lengthening is somewhat nonspecific as to whether it results from demyelination, microvascular infarction, edema, or more probably a combination of these. Cerebral falx hemorrhage is characterized by a black appearance on T2-weighted images of deoxyhemoglobin and bright adjacent methemoglobin or serum.

(Courtesy of Dr. Joseph Thompson, Department of Neuroradiology, Loma Linda University Children’s Hospital.)

Fig. 86-4 Representative single-photon emission computed tomographic study of a 14-year-old male with systemic lupus erythematosus and acute onset of optic neuritis and transverse myelitis.

The study was done immediately after the onset of central nervous system symptoms and shows bilateral cerebral hemisphere decreased perfusion defects in the right frontal region (white arrow) and in the right basal ganglia (black arrow) compatible with antecedent ischemia.

(Courtesy of Dr. MT Parisi, Department of Radiology, Children’s Hospital of Los Angeles.)

Treatment of Neurologic Manifestations

Treatment of the neurologic complications seen in children with SLE can be categorized as follows.

Treatment of generalized symptoms, where the nervous system is involved as a bystander, requires controlling the underlying inflammatory disorder, correcting metabolic or systemic abnormalities such as hypertension, and administering specific symptom-directed medications, such as antiepileptic drugs for the treatment of seizures; analgesic medications for headache; antidepressants, sedatives or tranquilizers, or antipsychotic agents for specific psychiatric symptoms; and dopamine-blocking agents for the treatment of chorea. Commonly used antiepileptic drugs in children with seizures associated with SLE include phenobarbital, phenytoin, diazepam, lorazepam, valproate, and carbamazepine. Antiepileptic drug use should not be prolonged unnecessarily; discontinuation should be considered when the primary disease is well controlled. In moderate doses, corticosteroids do seem to have beneficial effects in studies of adults with mood or cognitive disorders, suggesting that these are often secondary to neuropsychiatric disease [Carbotte et al., 1995]. However, corticosteroids have also been associated with a variety of behavioral and mood disorders and with psychosis, although the mechanism of this toxic response is unknown. Treatment of lupus chorea with haloperidol, chlorpromazine, valproate, or corticosteroids is usually successful in conjunction with treatment of the underlying disorder.

Treatment of CNS infection depends on the infectious agent causing the CNS disease. The infection will necessitate a diminution of the immunosuppressive therapy until the infection is controlled. Evaluation for CNS infection may be indicated in patients in whom the history or clinical examination suggests systemic infection that may have spread to the CNS or in patients in whom no definite explanation for their CNS symptoms can be determined. A high index of suspicion for fungal infection must be maintained. MRI and cerebrospinal fluid examination provide the most accurate and sensitive methods for such an evaluation.

Anticoagulation may be considered in patients with ischemic cerebrovascular insults who have antiphospholipid antibodies, because there is a significant risk of recurrent thrombotic episodes [Bruyn, 1995; Khamashta et al., 1995]. Agents used in adults have included acetylsalicylic acid, heparin, and warfarin. In adults, prevention of recurrent venous thrombosis may require doses of warfarin with an international normalized ratio of 2 to 3 [Meroni et al., 2003]. It is unclear, even in studies of adults with arterial thromboembolic disease, if anticoagulation is effective, even with a higher international normalized ratio [Brey et al., 2003]. Because of the small number of children with SLE who have such events, it is unlikely that controlled clinical studies will be completed. Given the nature of children’s activities and the reports of hemorrhage in children without SLE but with a lupus-type anticoagulant [Becton and Stine, 1997], it might be suspected that the risk of serious or life-threatening hemorrhage would be greater than in adults. Various alternative regimens have been recommended in children [Ravelli and Martini, 1997; Silverman, 1996]. Steroids have not been found to alter the pathology of antiphospholipid manifestations. It is imperative that patients with hypertension and thrombocytopenia do not receive anticoagulants because of the potential risk of CNS hemorrhage. Patients on long-term steroid therapy for SLE who also require anticoagulation must be monitored for the increased risk of gastrointestinal bleeding. Although strategies to prevent thrombosis occurrence should be part of the management of patients with SLE, to date, no laboratory test can predict recurrent thrombotic events and no pharmacogenomics studies that could help with anticoagulation monitoring have been carried out in SLE patients [Burgos and Alarcon, 2009].

Immunosuppressive therapy with corticosteroids has proved to be the mainstay of treatment for patients with neuropsychiatric symptoms or symptoms associated with vasculitis [Hanmer and Saltissi, 1986; Sanna et al., 2003]. High-dose steroids have also been used for the treatment of coma, seizures, chorea, and transverse myelitis [Chan and Boey, 1996; Eyanson et al., 1980; Harisdangkul et al., 1995; West, 1994]. Adverse neuropsychiatric effects, such as psychosis or vacuolar myopathy, seen with high doses or chronic administration of corticosteroids, are unusual [Wysenbeek et al., 1990].

Cytotoxic agents, such as mycophenolate [Buratti et al., 2001; Contreras et al., 2004; Kapitsinou et al., 2004] or cyclophosphamide, are used in patients with serious renal or neurologic disease. Candidates for such treatment include those who have evidence of diffuse proliferative glomerulonephritis, and those with CNS lupus or myelopathy who are refractory to corticosteroids. As there are no prospective controlled trials comparing different immunosuppressive and cytotoxic modalities in the various CNS lupus disorders, it is difficult to feel confident about a specific therapeutic regimen [Berlanga et al., 1992; Neuwelt et al., 1995; Propper and Bucknall, 1989]. Whereas mycophenolate is being used increasingly in steroid-resistant major organ disease and diffuse proliferative lupus nephritis, there are no data about the effectiveness of azathioprine or mycophenolate in CNS lupus.

Neuropathology

Neuropathologic studies of childhood and adult SLE are rare, and available reports document a variety of abnormalities. Foci of acute cortical and cerebellar encephalomalacia with neuronal loss and demyelination have been described [Gold and Yahr, 1960; Smith et al., 1994]. Postmortem examination reports of adults who have died from CNS lupus have documented diffuse microthrombi and demyelination [Hanly et al., 1992]. Vascular changes have also included vasculitis. Proliferative intimal changes, fibrinoid degeneration, and perivascular inflammation in cerebral arterial vessels have been reported in older studies, but have rarely been observed in recent investigations, suggesting that therapy may have altered the pathologic findings. These vascular changes are seen less frequently in children than in adults [Walravens and Chase, 1976].

Segmental small artery involvement with leptomeningeal and parenchymal thrombosis may occur, as well as venous sinus thrombosis [Falko et al., 1979; Steinlin et al., 1995]. These individuals have both occlusion and recanalization of vessels without changes in the media and adventitia, suggesting that the cerebrovascular lesions in SLE may result from processes acting at the endothelial-blood interface [Smith et al., 1994]. Intravascular coagulation and occlusion may be the primary mechanisms responsible for microinfarction [Falko et al., 1979]. More recent neuropathologic studies in adults implicate platelet thrombi, possibly mediated by antiphospholipid antibodies [Ellison et al., 1993]. Other studies, which do not document vascular involvement, suggest a role for antineuronal antibody-mediated damage in adults with SLE [Kuroe et al., 1994; Bluestein, 1997].

A review of the histopathologic studies of lupus patients with chorea rarely indicated abnormalities of the basal ganglia [Kuroe et al., 1994], but there were other CNS changes in these patients, such as microinfarction [Penn and Rowan, 1968; Kovacs et al., 1993; Scolding and Joseph, 2002].

Some neuropathologic studies of patients with peripheral neuropathies have revealed, although rarely, focal areas of necrosis in small arteries supplying nerve bundles, as well as perivascular inflammatory changes, fibrinous exudates, and thrombus formation. Adult patients with myelopathy exhibited large spinal cord infarcts, spinal cord subdural hematoma, and subpial leukomyelopathy [Provenzale and Bouldin, 1992].

Neurologic Manifestations

Children with the coup-de-sabre form of localized scleroderma are at risk for CNS involvement [Appenzeller et al., 2004]. Coup-de-sabre lesions have been associated with intractable partial seizures, although the causality of the association has been questioned [Rigante et al., 2008; Chiang et al., 2009]. Other associated neurological abnormalities have included pseudopapilledema, strabismus, hemiparesis contralateral to the facial lesions, and developmental regression [Zannin et al., 2007; Verhelst et al., 2008]. Vasculitis of small and medium-sized cerebral vessels ipsilateral to the skin lesions has been documented by angiography. A case study with neuropathology has suggested that this may not be a form of CNS vasculitis but rather a neurocutaneous syndrome with vascular dysgenesis [Chung et al., 1995].

Periarticular muscle atrophy, common in children with systemic scleroderma, may be attributed to both disuse and subtle myopathic involvement. Muscle biopsy demonstrates findings of a mixed neuromyopathy with group atrophy, suggesting vascular neuropathic involvement as one of the mechanisms associated with the primary disease [Clements et al., 1978]. Despite elevation of creatine kinase activity in 33 percent of patients with scleroderma, muscle atrophy is rare [Dabich et al., 1974], but clinical weakness is frequent, particularly during the early inflammatory phase of the illness. MRI may be useful in the localization of suspected muscle disease in patients with scleroderma [Olsen et al., 1996].

Children with progressive systemic sclerosis generally do not have primary CNS involvement, although cerebral hemorrhage secondary to thrombocytopenia has been reported [Gordon and Silverstein, 1970; Kornreich et al., 1977].

Although neurologic manifestations have been reported rarely in adults with scleroderma, some reviewers [Cerinic et al., 1996; Hietaharju et al., 1993] have argued that these manifestations may be more common than originally believed and include neuropsychiatric symptoms, bulbar palsy, optic neuritis, trigeminal neuropathy, mononeuritis multiplex, and polyneuropathy. There is no consensus regarding treatment of these complications. Of interest is a recent study that demonstrated cerebral hypoperfusion on SPECT scans in half of the neurologically asymptomatic adults with progressive systemic sclerosis [Nobili et al., 2002]. This hypoperfusion is hypothesized to be the result of a noninflammatory microangiopathy that has its origins in endothelial cell damage and dysfunction.

Laboratory Findings

Laboratory evaluation should include determination of antinuclear antibody titers, immunoglobulins, erythrocyte sedimentation rate, rheumatoid factor, and creatine kinase activity. A mild elevation of serum immunoglobulins may be present, and there may be markers of inflammation. Patients with progressive systemic sclerosis may have antibodies to DNA topoisomerase 1 (Scl-70) or RNA polymerase I, II, or III (RNAPs). Patients with the CREST syndrome may have an anticentromere antibody. Approximately 27 percent of children with progressive systemic sclerosis have Scl-70 antibodies [Vancheeswaran et al., 1996], compared with 14–77 percent of adults, whereas an uncertain number of children with the CREST syndrome have anticentromere antibody, compared with 44–98 percent of adults [Okano, 1996].

Treatment

Treatment of progressive systemic scleroderma is largely supportive, and management of the underlying disease is often not successful. Initial management includes a course of corticosteroids to improve weakness associated with myopathy. d-Penicillamine was initially reported as beneficial for skin fibrosis but generally has not been associated with improvement [Murray and Laxer, 2002]. There has been anecdotal support for the use of steroids and methotrexate in combination for the treatment of linear scleroderma [Uziel et al., 2000]. Raynaud’s phenomenon should be treated with calcium channel blockers, such as nifedipine or amlodipine. Gastrointestinal symptoms may be relieved by bethanechol chloride, metoclopramide, or cisapride [Pope, 1996]. Occupational and physical therapy is the mainstay of treatment, and is aimed at maintaining and improving joint mobility that is impaired secondary to scarring.

Recent efforts have shown promising results with mechanistic therapeutic strategies aimed at newly identified targets, including signal transduction effectors, effector T cells, and vascular endothelial cells [Ong and Denton, 2010].

Neurologic Manifestations

Proximal muscle weakness, increased creatine kinase activity, myopathic electromyograms, and muscle biopsy are consistent with inflammatory myositis. In one study, asymptomatic children with mixed connective tissue disease had abnormalities detectable on electromyography and biopsy of proximal muscles [Singsen et al., 1980]. A more recent study revealed myositis in 58 percent of patients [Rayes et al., 2002].

Seizures, headache, increased cerebrospinal fluid protein content, and aseptic meningitis have been reported in children with mixed connective tissue disease [Oetgen et al., 1981]. In the original 1972 description of 25 patients, of whom at least 4 were children, none had neurologic symptoms [Sharp et al., 1972]. A follow-up study of 14 of the original cohort indicated myositis as the only neurologic finding in 5 adults. The only surviving child was asymptomatic; the other three died of non-neurologic causes [Nimelstein et al., 1980]. Two additional children have been described with neurologic manifestations [Graf et al., 1993]. The first had an internal carotid artery occlusion and stroke, eventually recovered without evidence of antiphospholipid antibody. The second child had a large intracerebral hematoma and died. Postmortem examination found fibrinoid necrosis of intracerebral capillaries. Trigeminal neuralgia has been observed in adults but has not been reported in children [Sharp, 1975]. Studies of adults have indicated a significant incidence of neuropsychiatric symptoms [Bennett and O’Connell, 1980]. Additionally, adults with recurrent optic neuropathy and/or transverse myelopathy have been reported [Flechtner and Baum, 1994; Mok and Lau, 1995; Bhinder et al., 2007].

Treatment

Treatment of mixed connective tissue disease depends on disease manifestations. For disease with mild organ involvement, hydroxychloroquine may be adequate. For more severe organ system involvement or significant myositis, corticosteroids may be necessary. As there are few long-term studies that clarify the prognosis and best therapy, treatment is empirical [Mier et al., 1996; Tiddens et al., 1993]. Methotrexate, azathioprine, and cyclophosphamide have been used, similar to therapy for SLE.

Neurologic Manifestations

Several children with primary Sjögren’s syndrome and neurologic involvement have been reported. A 10-year-old female with optic neuritis and severe CNS disease has been described [Berman et al., 1990], as well as an 18-year-old female with aseptic meningitis and small infarctions in both temporal regions and in the right posterior parietal region [Gerraty et al., 1993]. In addition, a 17-year-old female has been described with bilateral carotid and vertebral artery occlusions, who was treated with surgical bypass [Nagahiro et al., 1996]. A 9-year-old female who was eventually diagnosed with Sjögren’s syndrome developed recurrent paresis with associated nonenhancing lucencies of the left internal capsule and subcortical white matter in the right temporo-occipital regions on CT. MRI confirmed the CT findings and exhibited multiple regions of increased signal intensity on T2-weighted images in the internal capsule and subcortical and periventricular white matter [Ohtsuka et al., 1995]. She developed a rapidly increasing paresis that resulted in quadriplegia but responded fairly well to corticosteroids. T2-weighted images on MRI indicated diffuse swelling of the cervical cord and increased signal intensity from the first cervical to the seventh thoracic vertebrae [Ohtsuka et al., 1995]. In adult patients with Sjögren’s syndrome and biopsy-documented inflammatory vascular disease, both CNS and peripheral nervous system involvement have been reported in 25–66 percent of patients [Alexander, 1992]. Neurologic manifestations in these patients consisted of focal and diffuse brain disease, including seizures, cognitive and behavioral disorders, acute encephalopathy, aseptic meningitis, and forms of progressive myelopathies. Peripheral nervous system involvement included motor and sensory neuropathies and carpal tunnel syndrome [Malinow et al., 1985; Molina et al., 1985]. Further study of these patients revealed one or more cerebrospinal fluid abnormalities in 16 of 21 patients, including increased protein content, pleocytosis, elevated IgG levels, elevated IgG index, increased oligoclonal bands, and abnormal cerebrospinal fluid/serum glucose ratios [Malinow et al., 1985]. Because classification criteria for Sjögren’s syndrome vary, it is difficult to interpret the frequency of neurologic symptoms in adults [Alexander, 1992]. MRI may indicate subcortical or periventricular lesions in the white matter in up to 80 percent of adult patients [Alexander, 1992]. Although the pathogenesis of Sjögren’s syndrome is unknown, it has been suggested that the anti-Ro (anti-SSA) antibody may play an immunopathologic role in CNS disease [Alexander, 1992].

Laboratory Findings

Characteristic laboratory findings include hypergammaglobulinemia, positive antinuclear antibody, anti-SSA, anti-SSB, and classic rheumatoid factor [Anaya et al., 1995]. Confirmation of the diagnosis is obtained by labial salivary gland biopsy, demonstrating periductal lymphocytic infiltration [Cassidy and Petty, 2001]. The Schirmer test, sialogram, and salivary scintiphotography support the diagnosis [Chudwin et al., 1981].

Treatment

Hydroxychloroquine and supportive care are the mainstays of treatment of non-neurologic manifestations of Sjögren’s syndrome [Fox, 1992]. Immunosuppressive management with corticosteroids is needed for significant neurologic manifestations [Anaya et al., 1995; Ostuni et al., 1996]. If there is progressive neurologic disease, cyclophosphamide in addition to corticosteroids has been used successfully [Alexander, 1992]. Long-term prognosis in children with and without neurologic disease is unclear [Anaya et al., 1995; Ostuni et al., 1996].

Polyarteritis Nodosa

Polyarteritis nodosa occurs principally in older children and adolescents. Classic polyarteritis nodosa is characterized by unexplained fever, arthralgias, calf discomfort, abdominal pain, recurrent pulmonary infection, renal disease with hypertension, fatigability, weight loss, malar rash, and purpura. Severe kidney impairment and marked hypertension occur early in the course of the disease. Diffuse glomerulonephritis or necrotizing arteritis is found in renal biopsy material. Mesenteric arteritis and resultant bowel wall infarction may lead to gastrointestinal hemorrhage [Bakkaloglu et al., 2001; Maeda et al., 1997].

Before corticosteroid therapy, progressive neurologic, renal, and cardiovascular involvement led to a mortality rate of 80–90 percent. Currently, the use of corticosteroids and cytotoxic agents has dramatically reduced the mortality rate to as low as 5 percent [Bakkaloglu et al., 2001; Maeda et al., 1997]. Unfortunately, polyarteritis nodosa often follows a chronic course, characterized by periods of exacerbations despite aggressive immune suppression [Maeda et al., 1997].

Neurologic manifestations

Approximately one-quarter of patients with polyarteritis nodosa demonstrate neurologic manifestations during their lifetimes [Dillon, 1997]. Seizures frequently accompany polyarteritis nodosa and generally appear early in the illness, become more difficult to control as the disease becomes chronic, and may culminate in episodes of status epilepticus in terminally ill patients. Headache, disturbances of higher cortical function, and affective disorders commonly precede the onset of seizures. This finding suggests CNS vasculitis in addition to vasculitis of the internal organs and skin. Cerebrospinal fluid is usually normal, and the presence of blood strongly suggests a ruptured cerebral microaneurysm [Peal et al., 1946]. Commonly reported EEG abnormalities include diffuse and focal paroxysmal activity and background slowing. Cerebral angiography may indicate segmental narrowing of small and medium-sized vessels, and occasional microaneurysmal dilatation. Biopsy of the superficial temporal artery is not recommended because only 11 percent of patients have demonstrable arteritis in the external carotid circulation [Goder, 1956].

Polyarteritis nodosa may manifest with sudden onset of visual field defects, hemiparesis, or increased intracranial pressure. These symptoms tend to occur only in patients with a protracted course. Visual loss, associated with proliferative retinitis and fundal hemorrhages, may occur independently or accompanying increased intracranial pressure [Fager et al., 1951; Magilavy et al., 1977]. Nystagmus, ophthalmoplegia, diminished corneal reflexes, and ataxia are reported rarely [Ford and Siekert, 1965].

The sudden onset of stroke in a patient with polyarteritis nodosa requires complete assessment of the cerebral circulation, initially with MRI and MR angiography, followed by cerebral angiography in selected patients. Although angiography may initially be normal, evidence of segmental arterial narrowing may be demonstrated within several weeks of the CNS event (Figure 86-5B). Pathology indicates necrotizing angiitis, ruptured microaneurysms of the superficial and deep arteries, subarachnoid hemorrhage, and encephalomalacia caused by ischemia or infarction.

Fig. 86-5 Angiography in polyarteritis nodosa.

A, Renal arteriogram of a child with polyarteritis nodosa demonstrating segmental vasculitis, microaneurysmal dilatation, and focal hypoperfusion. B, Cerebral angiogram demonstrating segmental narrowing of posterior communicating and posterior cerebral arteries, and small branch occlusions in the middle cerebral artery distribution.

(Courtesy of Dr. Joseph Thompson, Department of Neuroradiology, Loma Linda University Children’s Hospital.)

Aseptic meningitis with spinal fluid lymphocytosis and normal protein concentration also has been reported in childhood forms of polyarteritis nodosa. Bacterial meningitis is an uncommon complication in children, despite the use of immunosuppressive agents.

Neuropsychiatric symptoms are uncommon in polyarteritis nodosa, despite the diffuse cerebral arteritis [Ford and Siekert, 1965]. Extremely ill patients may develop organic psychosis, a progressive confusional state, and variable states of consciousness that are associated with renal insufficiency. Depression is unusual in the stable patient.

Children with polyarteritis nodosa often experience diffuse myalgia; however, myositis is rarely diagnosed clinically, although it is demonstrated in approximately 11 percent of postmortem studies. There may be an accompanying increase of creatine kinase activity or evidence of myopathy indicated by electromyography [Blau et al., 1977; Magilavy et al., 1977]. Muscle biopsy may reveal necrotizing arteritis with fibrinoid necrosis and perivascular inflammation. A myopathic pattern is demonstrated in approximately 50 percent of children with polyarteritis nodosa who undergo electromyography.

Peripheral neuropathy responds well to corticosteroids. Mononeuritis multiplex is the most common and typically early neurologic feature of adult polyarteritis nodosa [Nadeau, 2002]. Sensory and motor nerve conduction velocities are decreased in childhood polyarteritis nodosa. Pathologic studies of the peripheral nervous system reveal fulminant arteritis with thrombotic occlusion of small and medium-sized arteries, and accompanying profound nerve infarction and demyelination. Myelopathy occurs rarely and usually only in patients who suffer from chronic disease [Carr and Bryer, 1993].

Microscopic polyangiitis is a subgroup of polyarteritis nodosa and is seen rarely in children [Ozen, 2004]. There is frequent pulmonary hemorrhage, and all patients have glomerulonephritis. They are frequently positive for perinuclear staining antineutrophil cytoplasmic antibody (p-ANCA) due to myeloperoxidase antibody. Peripheral neuropathy is less common than in polyarteritis nodosa.

Kawasaki’s Disease

Kawasaki’s disease is characterized by aneurysms that are largely limited to the coronary arteries, although aneurysms have been reported in multiple vessels as well [Burns and Glodé, 2004]. Kawasaki’s disease is diagnosed by the presence of fever of at least 5 days’ duration and by 4 of the following 5 criteria:

Prognosis has been excellent since the use of intravenous immunoglobulin and acetylsalicylic acid, with immediate clinical improvement in the majority of children and a decreased rate of coronary artery aneurysmal formation from 20–25 percent to less than 8 percent. However, myocardial infarction, dysrhythmias, and sudden death were reported in 1 percent of patients [Melish, 1996].

Cogan’s Syndrome

Cogan’s syndrome has been reported rarely in children [Ndiaye et al., 2002]. Although vasculitis may be diffuse, the characteristic features are vertigo, deafness, photophobia, and interstitial keratitis. Eye and ear involvement may precede other systemic symptoms by years. Aortitis and aortic valve insufficiency may also be present [Cassidy and Petty, 2001], along with arthralgia, myalgia, anorexia, episcleritis and/or uveitis, and fever. The noncardiac features generally respond well to corticosteroid therapy, but the aortic valve disease may require surgical replacement of the valve [Olfat and Al-Mayouf, 2001]. Neurologic symptoms have been described in adults [Bicknell and Holland, 1978].

Henoch–Schönlein Purpura

Henoch–Schönlein purpura is characterized by palpable purpura, petechiae, or ecchymotic rash, typically found over the buttocks and the lower extremities. It is often associated with large-joint arthritis, cramping abdominal pain, fever, peripheral edema, and renal involvement, with a median age of onset of about 6 years [Cassidy and Petty, 2001; Szer, 1996]. Henoch–Schönlein purpura is a common, self-limited illness lasting from about 1 to 3 months. Recurrences may occur over 1–2 years. Laboratory tests are usually normal, except for microscopic hematuria and guaiac-positive stools. Approximately 50 percent of patients have elevated IgA levels. Skin, renal, and gastrointestinal biopsies demonstrate leukocytoclastic vasculitis with polymorphonuclear cells within the vessel walls and deposition of IgA, complement, and properdin.

Hypersensitivity Angiitis

Hypersensitivity, or allergic, angiitis is an acute necrotizing inflammation of blood vessels similar to Henoch–Schönlein purpura. Unlike in the latter, however, recurrent attacks are uncommon. The disorder may be acute and rapidly fatal, and may be caused by a hypersensitivity reaction to various drugs, infections, or serums [Cassidy and Petty, 2001; Farooki et al., 1974]. Among adults manifesting similar clinical symptoms, decreased serum complement and cryoglobulinemia have been reported [Cassidy and Petty, 2001]. The occurrence of neurologic complications in the various forms of hypersensitivity angiitis appears to be rare because the cerebral vessels tend to be spared.

Churg–Strauss Syndrome

Churg–Strauss syndrome, also known as allergic granulomatosis, is associated clinically with asthma, fever, eosinophilia, cardiac failure, renal damage, and peripheral neuropathy [Sehgal et al., 1995]. Criteria established by the American College of Rheumatology require the presence of four of the following seven findings:

Approximately 21 percent of patients are children [Farooki et al., 1974]. The vasculitis is manifested by fibrinoid necrosis of the media of small arteries and veins, with arterial and capillary involvement.

Wegener’s Granulomatosis

A necrotizing granulomatous vasculitis of the small vessels in the upper and lower respiratory tract and the kidneys characterizes Wegener’s granulomatosis. Symptoms frequently include fever, malaise, rhinorrhea, epistaxis, chronic sinusitis, nasal obstruction, pharyngeal ulcers, parenchymal pulmonary lesions, and chronic glomerulonephritis. The most common laboratory abnormality is a cytoplasmic staining antineutrophil cytoplasmic antibody due to anti-PR3 antibodies found in about 90 percent of patients [Cassidy and Petty, 2001]. Children are rarely affected. The cause of this disorder is unknown.

Primary Angiitis of the Central Nervous System

Primary angiitis of the CNS, also called granulomatous angiitis, is characterized by granulomas in 80 percent of cases. Numerous case reports have been published in the last decade. Clinical criteria require a history or finding of an acquired neurologic deficit associated with angiographic or histopathologic demonstration of vasculitic changes, exclusion of other etiologies, and no evidence of systemic disease [Calabrese, 1995]. It is increasingly recognized as the cause of otherwise unexplained cerebral ischemic episodes in the young [Dillon, 1997] and has been mistaken on occasion for Rasmussen’s encephalitis [Derry et al., 2002]. Clinical features include headache, confusion, nausea, altered mental status, focal neurologic deficits, and progressive intellectual deterioration. Primary angiitis of the CNS may occur in children as young as 2 years of age and has an equal sex distribution [Barron et al., 1993; Matsell et al., 1990].

Laboratory findings

Laboratory studies reveal elevated erythrocyte sedimentation rate, elevated cerebrospinal fluid protein concentration, and moderately increased monocytosis with increased pressure [Calabrese et al., 1992; Sabharwal et al., 1982]. However, normal acute phase reactants and spinal fluid have been reported in children [Benseler and Schneider, 2004]. Cerebral angiography documents small and medium-sized vessel occlusion, or segmental narrowing with saccular aneurysms and areas of infarction. Neuropathologic studies indicate segmental necrotizing granulomatous vasculitis diffusely affecting the parenchymal and leptomeningeal vessels of the cortex but not the subcortical areas of the brain [Hankey, 1991; Sabharwal et al., 1982]. Patients with small-vessel disease are more likely to demonstrate multifocal, hyperintense lesions on T2-weighted MRI, with normal cerebrospinal fluid, erythrocyte sedimentation rate, and cerebral angiograms. Those with medium-sized or large-vessel disease often demonstrate infarcts on CT and MRI, and are more likely than those with small-vessel disease to have abnormal cerebrospinal fluid studies, erythrocyte sedimentation rates, and angiograms (Figure 86-6) [Lanthier et al., 2001].

Fig. 86-6 A 4-year-old male with primary angiitis of the central nervous system who had a 2-month history of seizures, chorea, left hemiparesis, and dysarthria.

The patient improved significantly with intravenous immunoglobulin and corticosteroids. A, Time-of-flight magnetic resonance angiogram, partitioned for the right distal internal carotid artery, shows prominent segmental supraclinoid internal carotid artery narrowing (arrowheads). B, Lateral right internal carotid digital subtraction arteriogram shows residual segmental narrowing (arrow), significantly improved after 2 days of steroid therapy.

(Courtesy of Dr. Joseph Thompson, Department of Neuroradiology, Loma Linda University Children’s Hospital, Loma Linda, CA.)

Necrotizing Sarcoid Granulomatosis

Necrotizing sarcoid granulomatosis, first described in 1973, is clinically and pathologically intermediate between sarcoidosis and Wegener’s granulomatosis [Kwong et al., 1994]. It consists of a necrotizing granulomatosis and vasculitis similar to that found in Wegener’s granulomatosis, with noncaseating granulomas resembling those of sarcoidosis. The condition has been reported in children with multifocal neurologic disease and retinal angiitis. In one child, progressive asymmetric lower limb weakness associated with urinary retention, and diagnosed as an acute myelitis and polyneuritis, responded to treatment with corticosteroids [Beach et al., 1980]. A more recent review discussed the previous reported cases, defined the vasculitic features, and differentiated childhood sarcoidosis from familial granulomatous arteritis with arthritis, uveitis, and fever [Kwong et al., 1994]. Findings reported in this disease are similar to those in sarcoidosis and include disc edema and retinal periphlebitis responsive to corticosteroid therapy. Necrotizing sarcoid granulomatosis usually responds to corticosteroids and does not require cytotoxic therapy. No significant reports of neurologic involvement have been made [Heinrich et al., 2003]. The extent of this disorder in children and the degree of neurologic involvement are unknown.

Sarcoidosis

Sarcoidosis is a chronic, multisystem granulomatous disease of unknown etiology that is rare in children. Interestingly, sarcoidosis in older children is indistinguishable from adult sarcoidosis, but younger children (younger than 4 years) tend to have different clinical manifestations. In the early-onset form, the children tend to present in infancy to preschool years [Fink and Cimaz, 1997]. This form is characterized by relatively painless, boggy polyarthritis with well-preserved range of motion. Uveitis and cutaneous sarcoid lesions are usually present, but pulmonary involvement is rare. Older children tend to present with pulmonary symptoms, hilar adenopathy, fatigue, weight loss, anorexia, headache, fever, and parotid enlargement [Kwong et al., 1994; Pattishall and Kendig, 1996]. This form of sarcoidosis is characterized by hilar and paratracheal adenopathy with interstitial infiltrates, hypercalciuria, leukopenia, and eosinophilia. An elevated erythrocyte sedimentation rate and the presence of elevated serum immunoglobulins further support the diagnosis. Pulmonary function study results are abnormal in most older patients. Noncaseating granulomas obtained from mediastinal or peripheral lymph node biopsies are found in 90 percent of patients.

Musculoskeletal findings in several children with sarcoidosis have included joint pain with effusions and palpable muscle masses; on biopsy, these muscle masses consist of noncaseating granulomas.

Temporal Arteritis

Classic giant cell arteritis (temporal arteritis) most often affects men older than 50 years of age [Nordborg et al., 1995]. A recent report of temporal arteritis in a 9-year-old Haitian female with a past medical history remarkable for sensorineural hearing loss; an initial presentation with monocular blindness and a tortuous superficial temporal artery, with a temporal artery biopsy study consistent with giant cell arteritis; and a disease course that included a systemic illness with encephalopathy most consistent with polyarteritis nodosa make it clear that this disorder can occur in childhood [Bert et al., 1999]. Headache, scalp tenderness, visual disturbances, and jaw claudication appearing in association with an elevated sedimentation rate suggest the diagnosis. Biopsy of the superficial temporal artery reveals giant cell perivascular inflammatory infiltrates [Small, 1984]. Hemiparesis, vertigo, hearing loss, brainstem strokes, seizures, oculomotor disorders, and peripheral neuropathies have been reported. Optic neuritis is the most common problem. The superficial temporal, vertebral, ophthalmic, and posterior ciliary arteries are frequently involved. The internal and external carotid and central retinal arteries are less commonly affected, but occlusion of the ophthalmic or central retinal artery can lead to blindness. Intracranial arterial involvement has been documented, although it is rare [Small, 1984]. Myelopathy, transient ischemic attacks, and cerebral infarctions have been reported in adults with temporal arteritis. It is unclear whether the latter two disorders are due to the underlying condition or the patient’s age [Caselli and Hunder, 1993].

Before the case report of Bert et al. [1999], juvenile temporal arteritis was regarded as a different and even uncommon clinical entity than adult-type temporal arteritis. Two children, 7 and 8 years of age, initially developed unilateral nodules of the temporal arteries without systemic or neurologic symptoms [Lie et al., 1975]. Studies of these lesions failed to demonstrate the classic giant cells but instead revealed perivascular lymphoid hyperplasia with eosinophilia. Occlusion of the temporal artery lumen with thrombus formation and diffuse intimal thickening and focal disruption of the internal elastic lamina and media were observed. This disorder demonstrates a form of non-giant cell granulomatous inflammation of the temporal artery; it is distinct from classic temporal arteritis of adults [Lie et al., 1975]. A more recent review included an additional case report of this syndrome [Lie, 1995].

Takayasu’s Arteritis

Takayasu’s arteritis, a form of arteritis involving the aorta and its branches, has been reported in children as young as 5 months of age. Onset occurs before 16 years of age in 25–30 percent of patients [Morales et al., 1991], and a recent postmortem study from India demonstrated a mean age at death of 22.6 ± 10.2 years [Sharma et al., 1998]. In children, the abdominal aorta and its branches are more commonly affected than the aortic arch. The clinical course is variable. Most patients come to medical attention in the pre-pulseless stage with nonspecific symptoms of fever, fatigue, dyspnea, anorexia, and arthralgia. The obstructive phase of the illness is characterized by aneurysmal dilatation and stenosis of the aorta or pulmonary arteries. As the abdominal aorta is involved in young children, initial symptoms may include abdominal pain or mass, congestive heart failure, and occlusive vascular disease of the abdominal organs or lower extremities [Gronemeyer and Demello, 1982].

Symptoms of claudication, pulselessness, carotid hypersensitivity, and cerebrovascular involvement have been reported in children [Pantell and Goodman, 1981]. Hypertension caused by renal artery stenosis occurs in approximately 70 percent of patients. Hypertensive encephalopathy has been reported in two children with renal artery stenosis [Millar et al., 1996]. One review noted that neurologic symptoms in childhood are quite rare, but that adults may develop carotid thromboembolic disease, cerebral hypertension, subclavian steal syndrome, or hypersensitivity of the carotid sinus [Tervaert and Kallenberg, 1993]. A review of 26 children emphasized that hypertension, constitutional symptoms, gastrointestinal pain, and heart failure were fairly common. In addition, 50 percent of patients had significant headache, 12 percent had convulsions, and 8 percent developed hemiplegia [Morales et al., 1991]. Another review of 24 patients found similar findings, except for a lack of neurologic symptoms [Jain et al., 2000]. In one small study of patients who succumbed to Takayasu’s arteritis, 20 percent had seizures and 10 percent had hemiplegia [Sharma et al., 1998]. All of these patients had hypertension as the presenting feature of their disease.

A lymphocytic and plasma cell inflammatory infiltrate in the media and adventitial large vessels occurs in the presence of few giant cells during the active phase of the disease. Subsequently, necrosis and thrombosis occur with accompanying fibrosis, and then narrowing of the arterial lumen.

Treatment with corticosteroids and other immunosuppressive agents improves the long-term prognosis, but most immunosuppressive drugs provide little improvement over corticosteroids [Hoffman, 1996]. Significant improvement has been made with the use of bypass grafts and angioplasty [Hoffman, 1995; Kohrman and Huttenlocher, 1986].

Behçet’s Disease

Behçet’s disease is rare in children [Cassidy and Petty, 2001; Rakover et al., 1989], usually having its onset in the second decade of life. This rarity has led some authors to postulate that juvenile Behçet’s disease may differ from adult Behçet’s disease in pathogenesis [Koné-Paut et al., 1998]. One study of juvenile Behçet’s disease placed the onset of this disorder at or around age 7 [Krause et al., 1999]. The classic clinical triad of Behçet’s disease consists of recurrent oral and genital ulcerations and recurrent uveitis [Schor, 2000]. The uveitis tends to be a panuveitis with retinal vasculitis [Tugal-Tutkun and Urgancioglu, 2003]. The following criteria have been proposed for the diagnosis of Behçet’s disease: the presence of recurrent aphthous stomatitis and two of the following:

Thrombotic Thrombocytopenic Purpura

Rapid onset of thrombocytopenia, severe microangiopathic hemolytic anemia, renal disease, neurologic symptoms, and fever characterizes thrombotic thrombocytopenic purpura [Amorosi and Ultmann, 1966].

Erythromelalgia and Erythermalgia

Erythromelalgia, a rare disorder, consists of intense, asymmetric burning sensations with associated erythema and elevated temperature in the extremities [Mandell et al., 1977]. The transient episodes may last for minutes, hours, or even days. Due to the intense pain and discomfort, patients often do not walk or use their hands. Patients find relief by immersing their hands or feet in ice water. One form of the disorder is associated with thrombocythemia (a fixed increase in the number of platelets). Blood pressure and peripheral pulses are normal during the symptomatic phase. In older patients, this condition has been associated with hypertension, SLE, diabetes mellitus, and myeloproliferative diseases. A defect in prostaglandin metabolism was postulated after many patients reported relief of symptoms after using acetylsalicylic acid [Jorgensen and Sondergaard, 1978]. This so-called secondary erythromelalgia has no parallel in childhood [Drenth et al., 1994].

Primary erythromelalgia or “erythermalgia” is a more rare, chronic, symmetric, burning sensation that occurs in children and adults. It is not reliably responsive to medication [Davis et al., 2000], although some patients have responded well to amitriptyline, sodium nitroprusside, regional anesthetic blockade, and gabapentin [Chan et al., 2002; Harrison et al., 2003; McGraw and Kosek, 1997; Rauck et al., 1996]. Regional nerve block has also been used to control pain [Harrison et al., 2003]. Histopathology reveals no consistent vasculitic changes, and erythermalgia is not associated with thrombocythemia [Drenth et al., 1994]. Some studies have demonstrated autonomic and small sensory fiber axonal neuropathy in patients with this disorder [Chan et al., 2002; Davis et al., 2000; Harrison et al., 2003].

The differential for this disorder includes Raynaud’s phenomenon and reflex sympathetic dystrophy, but it can usually be distinguished from these conditions by its unique clinical appearance and the relief provided by ice water immersion. In one report, a child with a syndrome resembling erythermalgia was found to have growth hormone deficiency and remission of symptoms with growth hormone replacement therapy; this has raised the question of whether a disorder involving the insulin-like growth factor family of trophic factors and receptors is involved [Cimaz et al., 2001]. Familial instances of erythermalgia have facilitated localization of the gene for susceptibility to this condition to chromosome 2q31–32 [Drenth et al., 2001].

Antiphospholipid Antibody Syndrome

Antiphospholipid antibody syndrome is a multisystem, autoimmune disorder characterized by the clinical features of recurrent thrombosis, pregnancy loss, or thrombocytopenia, and the laboratory feature of antiphospholipid antibodies (aPL) directed against negatively charged phospholipids [Wilson et al., 1999]. Numerous aPL have been described, including lupus anticoagulants (LAC), anticardiolipin antibodies (aCL), antibodies to β₂ glycoprotein-I (β₂GPI), and antibodies directed against prothrombin, annexin V, phosphatidylserine, and phosphatidylinositol [Passam and Krillis, 2004]. LAC are a group of antibodies directed against plasma proteins such as β₂GPI, prothrombin, and annexin V, which are bound to anionic phospholipids. They are detected by functional clotting tests, such as the activated partial thromboplastin time, dilute Russell viper venom time, kaolin clotting time, and, infrequently, prothrombin time. In clotting factor deficiencies such as hemophilia, diluting a patient’s plasma 1:1 with normal plasma can correct the observed prolonged clotting, but this does not occur in the presence of a LAC. Criteria for the diagnosis of a LAC include both the absence of correction in a 1:1 mixing reaction with a healthy person’s plasma, and confirmation of phospholipid dependence with the addition of a phospholipid-containing substrate [Brandt et al., 1995]. aCL can be detected in enzyme-linked immunosorbent assays, or indirectly in the VDRL assay. Although initially developed as a serologic test for syphilis, this latter assay detects agglutination of lipid particles that contain cholesterol and cardiolipin, thus resulting in a false-positive result in patients with antibodies against cardiolipin. Although the significance of the isotype is controversial, elevated levels of IgG aCL likely have a greater association with thrombotic risk than IgM and IgA isotypes. In addition to cardiolipin, aPL may react with other phospholipids, such as phosphatidyl serine and phosphatidyl inositol; however, the clinical significance of these antibodies is less clear. Beta₂GPI is the most common target of aPL; it becomes antigenic upon binding to a negatively charged surface, thereby inhibiting clotting. Antibodies to β₂GPI are likely critical to the pathogenesis of clinical manifestations of antiphospholipid antibody syndrome, particularly stroke, although many patients with antiphospholipid antibody syndrome do not test positive on these assays.

The diagnosis of antiphospholipid antibody syndrome requires specific clinical manifestations in addition to detection of antibodies. Antiphospholipid antibody syndrome is a heterogeneous syndrome, and thus strict diagnostic criteria for “definite” antiphospholipid antibody syndrome have been developed. The most recent international Sapporo criteria for antiphospholipid antibody syndrome require that individuals meet at least one of the clinical criteria and one of the laboratory criteria [Miyakis et al., 2006]. Clinical criteria include either:

One of the following three laboratory criteria must be met:

In order to meet the laboratory criteria, these antibodies must be detected on two or more occasions at least 12 weeks apart.

Patients with antiphospholipid antibody syndrome are usually classified as having “primary antiphospholipid antibody syndrome” if there is no evidence for another underlying autoimmune disorder, or “secondary antiphospholipid antibody syndrome” if another autoimmune disorder, such as SLE, Wegener’s granulomatosus, scleroderma, or psoriatic arthritis, is present [Falcini et al., 1991]. When seen in the setting of a lupus-like disorder that does not meet the strict American College of Rheumatology criteria for SLE, the disease is referred to as SLE-like antiphospholipid antibody syndrome [Weber et al., 1999]. These syndromes are seen in both children and adults; in some children, primary antiphospholipid antibody syndrome is a precursor of secondary antiphospholipid antibody syndrome.