Inflammatory, vascular, and infectious myelopathies in children

Handbook of Clinical Neurology, Vol. 112 (3rd series) Pediatric Neurology Part II O. Dulac, M. Lassonde, and H.B. Sarnat, Editors © 2013 Elsevier B.V. All rights reserved

Chapter 104

Inflammatory, vascular, and infectious myelopathies in children LEONARD H. VERHEY1 AND BRENDA L. BANWELL2* Paediatric Demyelinating Disease Program, Hospital for Sick Children, University of Toronto, Toronto, Canada

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Division of Neurology, Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA

INTRODUCTION Acute inflammation, vascular compromise, and infection of the spinal cord represent serious life-altering disorders of childhood. Prompt recognition and initiation of therapy may improve outcome, and thus clinicians must be aware of the clinical, laboratory, and radiographic features of these disorders. Management of chronic spinal cord dysfunction is also a key aspect of care, as residual spinal cord compromise occurs in many children. Acute inflammation or infarction of the spinal cord may herald an underlying chronic autoimmune disorder such as neuromyelitis optica (NMO), multiple sclerosis (MS), or systemic lupus erythematosus (SLE), a vascular malformation of the spinal vasculature, or a genetically defined or acquired risk for aberrant coagulation (antiphospholipid syndrome). Preventative strategies to reduce further episodes of spinal cord compromise are essential. Table 104.1 categorizes the inflammatory, vascular, and infectious spinal cord disorders occurring in childhood. The clinical and neuroimaging features, pathophysiology, and specific management will be presented for each of the major etiologies, and clinical vignettes will be used to illustrate key facets of the conditions presented. Traumatic, malignant, and compressive disorders of the spine are discussed elsewhere in Chapters 100, 102, and 103. The chapter will conclude with commentary on important aspects of care that apply irrespective of specific etiology, and with evolving scientific concepts and potential future therapeutic strategies for spinal cord repair.

INFLAMMATORY DISORDERS OF THE SPINAL CORD Primary inflammatory myelopathies include idiopathic acute transverse myelitis (TM), NMO, spinal cord

relapses in multiple sclerosis (MS), and inflammatory myelopathies that occur in the context of autoimmune disease (SLE and connective tissue disorders). While infectious myelopathies are discussed separately below, postinfectious inflammation occurring following resolution of active infection may be an important triggering event in patients with inflammatory TM.

Idiopathic acute transverse myelitis Idiopathic TM is a rapid-onset inflammatory disease, with approximately 20% of all cases of TM occurring in childhood. In a study of 47 cases of pediatric-onset TM, peak age at onset appears bimodal, with a cluster of cases occurring in very young children (less than age 2 years) and another cluster in adolescence (Pidcock et al., 2007). The Transverse Myelitis Consortium Working Group developed a classification scheme and diagnostic criteria for idiopathic TM that require: (1) bilateral impairment of sensory, motor, or autonomic function; (2) demonstration of a clearly defined sensory level; (3) no evidence of a compressive etiology; (4) evidence of inflammation (cerebrospinal fluid (CSF) pleocytosis, elevated immunoglobulin (Ig) G index, or magnetic resonance imaging (MRI) lesion enhancement); and (5) progression to nadir within 4 hours to 21 days of symptom onset (Transverse Myelitis Consortium Working Group, 2002). Idiopathic TM also requires exclusion of a prior history of spinal radiation, anterior spinal artery thrombosis, arteriovenous malformation, clinical or serological evidence of a connective tissue disease, central nervous system (CNS) manifestations of an infectious process (see Table 104.4), or a confirmed diagnosis of MS or NMO. However, exclusion of MS or

*Correspondence to: Brenda L. Banwell, M.D., F.R.C.P.C., The Children’s Hospital of Philadelphia, University of Pennsylvania, 3501 Civic Center Boulevard, Philadelphia, PA, USA 19104. E-mail: [email protected]

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Table 104.1 Nontraumatic disorders of the spinal cord in children Inflammatory/autoimmune ● Transverse myelitis ● Idiopathic isolated transverse myelitis ● Neuromyelitis optica ● Multiple sclerosis ● Vasculitis/vasculopathy ● Systemic lupus erythematosus ● Connective tissue disease ● Small vessel vasculitis ● Other vasculopathies Vascular ● Infarction ● Fibrocartilaginous embolism ● Hypercoagulable disorders/thrombosis ● Anterior spinal artery infarct ● Vascular malformation ● Arteriovenous fistula ● Arteriovenous malformation Infectious ● Bacterial ● Viral (HTLV1, West Nile virus, enteroviruses – including poliovirus) ● Other (Lyme disease)

NMO may not be possible at the time of acute spinal inflammation, as TM may be the first manifestation of these conditions. Observation over time is required to determine whether an episode of TM represents an acute monophasic event or the heralding sign of a chronic disease. TM may also be a manifestation of SLE (Katramados et al., 2008) or of an underlying connective ogren syndrome, Behc¸et’s distissue disorder such as Sj€ ease, and systemic sclerosis (Cikes et al., 2008), although these latter disorders are rare in children. The clinical features of TM are often preceded by a prodromal event, such as fever, vaccination, or minor trauma (Pidcock et al., 2007). Although no specific gene has been linked with TM incidence, TM appears to be more common in children with Asian ancestry (Nakashima et al., 2006). Clinical manifestations may include a complete cord syndrome with sensory, motor, and autonomic impairment or a partial cord syndrome with deficits in one or more of motor, sensory, or autonomic tracts. TM, whether partial or complete, is typically severe with over 85% of children having marked motor deficits (typically paraplegia) and bladder impairment at disease nadir (Defresne et al., 2003; Pidcock et al., 2007). Evolution of deficits occurs over time, with improvements slowly achieved even more than 1 year following the acute illness. MRI features of TM include focal or extensive regions of increased signal on T2-weighted or fluid-attenuated

inversion recovery (FLAIR) images. Both high-quality sagittal and axial planes are required to document lesion extent. Severe lesions may be associated with hemorrhage, best seen on gradient-echo sequences. Longitudinally extensive lesions (LETM) are defined as lesions extending more than the rostral–caudal length of three spinal vertebral bodies. Lesions that are longitudinally extensive typically also occupy the complete transverse diameter of the spinal cord, at least in the spinal cord region of maximal edema. All patients with TM should also undergo MRI of the brain. Multiple foci of clinically silent increased T2-weighted signal within the brain are strongly suggestive of MS, and evidence for accrual of clinically silent lesions over time may be confirmatory (discussed further below). Lesions in the diencephalon, brainstem, and optic nerve could also implicate a diagnosis of NMO (Cabrera-Go´mez et al., 2008). Serum antibodies directed against aquaporin-4 (NMO IgG), especially in patients with LETM, predicts a high likelihood of relapsing NMO (Wingerchuk et al., 2007). CSF white blood cell (WBC) count is typically increased, and a correlation between total CSF WBC count and longitudinal lesion length on MRI has been noted by the authors. CSF oligoclonal bands (OCBs) are typically absent in children with monophasic TM. However, a recent publication describing the outcome of 58 adults with TM (all of whom had normal brain imaging at onset) found that while 100% of the 17 patients diagnosed with MS over the 5-year observation period had positive CSF OCBs, OCBs were also detected in 15 patients who remained monophasic (Perumal et al., 2008). Treatment of TM is empirical. Proposed management involves high-dose intravenous methylprednisolone (20–30 mg/kg daily for 3–5 days) (Dale et al., 2009). As most children will not experience full clinical recovery within 5 days, oral prednisone (starting at a daily dose of 1 mg/kg/day) followed by a tapering schedule over 14–21 days is suggested. Children with severe TM (brainstem involvement, profound quadriplegia), those with positive NMO IgG, or patients not responding to corticosteroids may benefit from plasma exchange or intravenous immunoglobulin (Dale et al., 2009). The tendency for clinicians to treat all children with TM promptly limits the ability to evaluate the importance of acute therapy. Nonetheless, the marked edema and CSF evidence of inflammation noted in most children strongly supports a rationale for anti-inflammatory treatments. Chronic therapy for children with NMO or MS is discussed below. The clinical outcome of TM is variable, although several clinical, biological, and MRI variables have predictive significance. Recovery from maximal deficit, which as stated above includes severe neurological impairment in over 85% of children at clinical nadir, occurs rapidly, and children destined for recovery typically begin

INFLAMMATORY, VASCULAR, AND INFECTIOUS MYELOPATHIES IN CHILDREN ambulating (often with aides) by 2 weeks postonset. However, approximately 20% of children with TM do not recover independent ambulation (Pidcock et al., 2007). Children with complete cord syndromes, young children (age less than 3 years), children whose deficits reached maximal severity in less than 24 hours of onset, and those with persistent upper motor neuron signs are less likely to regain full ambulatory ability (Defresne et al., 2003; Miyazawa et al., 2003; Pidcock et al., 2007). The presence of hemosiderin on gradient-echo MRI sequences, indicative of intralesional hemorrhage, is also predictive of poor functional outcome (Pidcock et al., 2007).

CLINICALVIGNETTE A previously healthy 14-year-old girl developed a mild upper respiratory illness characterized by rhinorrhea, cough, and malaise. She was afebrile throughout the illness. Four days after the onset of her symptoms, she developed a band of hyperesthesia across the mid-thoracic region. Within 6 hours, she noted progressive weakness of her legs. The following morning, she was unable to move her legs, and noted weakness involving her upper limbs. She was unable to void, and complained of abdominal pain. On arrival to hospital, she was alert and afebrile. She had flaccid paraplegia, grade 3/5 strength in the proximal and distal muscles of the upper limbs, and was areflexic. A spinal sensory level was detected at T4. MRI of the spine demonstrated LETM (Fig. 104.1A). Treatment with intravenous methylprednisolone did not yield any functional improvement. Treatment with plasma exchange was associated with clear improvement in upper limb and truncal strength, and she regained the ability to perform activities with her arms and to sit independently. Four years after her illness, she has experienced no further relapses. She is wheelchair-dependent and requires intermittent catheterization for bladder hygiene. Spinal cord atrophy is evident on subsequent MRI (Fig. 104.1B). Despite extensive investigation at onset, no infectious pathogen was implicated as contributing to her severe TM.

Neuromyelitis optica Apart from MS, NMO is probably the most common inflammatory demyelinating disease of the CNS (Jacob et al., 2007). The defining features of NMO include monophasic or recurrent inflammatory demyelination of the optic nerves and spinal cord (Wingerchuk et al., 1999). Revised criteria for diagnosis now require both optic neuritis (ON) and TM as well as two of the following: (1) LETM; (2) initial brain MRI nondiagnostic for MS; and (3) seropositivity for NMO IgG (Wingerchuk et al., 2006). Optic nerve involvement can be unilateral

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or bilateral. LETM is defined by spinal cord lesions that span at least three spinal vertebral bodies in length. The identification of a biomarker for NMO, termed NMO IgG (Lennon et al., 2004), has led to a marked increase in recognition of NMO and NMO-spectrum disorders (Wingerchuk et al., 2007), and is highly specific (85– 99%) but less sensitive (58–76%) for the diagnosis (Fazio et al., 2009). NMO IgG has been further defined as an antibody directed against aquaporin-4, an astrocytic water channel (Lennon et al., 2005). The pathophysiology of aquaporin-4-mediated disease in NMO remains to be defined, but possible mechanisms have been proposed (Graber et al., 2008). In a recent study using fetal astrocyte cultures and serum from NMO-positive adult patients, binding of NMO IgG to the fetal astrocytes was found to alter aquaporin-4 polarized expression and to increase permeability of the model endothelium/astrocyte barrier. The authors also demonstrated that NMO IgG binding to human fetal astrocytes altered transgression of immune cells through the endothelial barrier, providing a potential functional role for NMO IgG in disruption of the blood–brain barrier and a mechanism for the inflammation that characterizes clinical NMO (Vincent et al., 2008). Although NMO in both the pediatric and adult age groups has appeared to be more common in nonCaucasian individuals (McKeon et al., 2008), a Danish population-based study reported that 26% of patients initially classified as having MS, TM, or ON had NMO; the estimated yearly incidence rate was 0.4 per 100 000 person-years, and the prevalence was estimated at 4.4 per 100 000 (Asgari et al., 2011). In North America, NMO appears to be more common in Black children (Lotze et al., 2008), for whom prognosis may be especially guarded. Clinical features of NMO in children include a monophasic syndrome characterized by a single attack of ON and TM (Jeffery and Buncic, 1996), or by recurrent attacks of ON and TM (Banwell et al., 2008; Lotze et al., 2008). Optic neuritis in children with NMO may initially resemble idiopathic isolated ON or ON that occurs in children with MS. Visual deficits, relative afferent pupillary defect, red color desaturation, and pain with ocular movement are typical features. Unlike idiopathic ON or ON in the context of MS, however, the ON in children with relapsing NMO tends to be more severe, with profound visual loss or blindness (Lotze et al., 2008). Visual outcome in children with self-limited NMO appears to be better (Jeffery and Buncic, 1996). Spinal cord features of NMO resemble idiopathic LETM, with involvement of multiple contiguous spinal cord segments. Clinical deficits are as described above for acute TM, with the exception that patients with relapsing NMO are at higher risk for severe spinal lesions and profound deficits. In a study of nine children with

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NMO, all female, brain involvement was detected clinically or on brain MRI in all nine (Lotze et al., 2008). Some children with NMO may manifest with polyfocal deficits and encephalopathy, clinically indistinguishable from acute disseminated encephalomyelitis (ADEM) (Eichel et al., 2008). MRI of the spine typically demonstrates lesions with increased T2-weighted signal extending more than three spinal segments in length. Orbital MRI may demonstrate increased T2-weighted signal of the optic nerves or chiasm. Brain MRI may show clinically silent or symptomatic lesions in the hypothalamus, thalamus, peritrigonal white matter, and brainstem (which may or may not be contiguous with longitudinally extensive lesions of the spinal cord) (Pittock et al., 2006). The lesions in the diencephalic, peritrigonal, and brainstem regions represent aquaporin-4 water channel enriched areas (Roemer et al., 2007). Treatment of NMO includes management of acute attacks and long-term immunosuppression. Acute attacks carry a high risk of permanent disability, and thus most clinicians advocate prompt initiation of anti-inflammatory therapy with high-dose intravenous corticosteroids. Plasma exchange appears to provide additional improvement (Watanabe et al., 2007; Bonnan et al., 2009). Given that the risk for disability or even mortality increases with frequent relapses, chronic management is focused on relapse prevention. There are no published treatment trials in children, and thus pediatric NMO management has been extrapolated from studies of treatment in adults (reviewed in Cree, 2008). Oral azathioprine (2 mg/kg daily) and oral prednisone (1 mg/kg daily) have been used with some benefit, although the long-term efficacy has not been established. More recently, rituximab (Rituxan), a monoclonal antibody directed against the CD-20 antigen on human B cells, has been shown to reduce the relapse rate and to stabilize clinical disability in adults and in a small number of children with NMO (Jacob et al., 2008). Rituximab therapy is provided as an infusion (375 mg/m2 once per week for 4 weeks or 1000 mg infused twice with a 2-week interval between infusions). As rituximab treatment leads to B-cell depletion, long-term use is nonsustainable, and patients are transitioned from rituximab protocols to maintenance therapy with azathioprine. Future risks relating to immune suppression (malignancy, infection) add to the morbidity associated with NMO.

Multiple sclerosis Multiple sclerosis, a chronic relapsing inflammatory disorder of the CNS, is reviewed in detail in Chapter 133. The onset of MS during childhood is being increasingly recognized worldwide, likely in part due to the

increasing availability of MRI for diagnostic confirmation. The first attack of MS may manifest with deficits at any level of the neuroaxis, although involvement of the optic nerves (optic neuritis), brainstem (internuclear ophthalmoplegia, diplopia), cerebellum (ataxia, tremor), or polyfocal deficits involving several brain regions concurrently are the most common presenting features (Banwell et al., 2007). Isolated TM as a first manifestation of MS is relatively uncommon, occurring in approximately 14% of pediatric patients with MS (Banwell et al., 2007). Children presenting with polyfocal deficits as their first MS manifestation may have spinal cord involvement, and MS relapses involving the spinal cord occur in most children and adolescents with active MS. TM in the context of MS tends to be partial myelitis, with lesions preferentially involving the posterior region in the transverse plane of the spinal cord (Verhey et al., 2010). Focal lesions extending fewer than three vertebral body segments in rostral–caudal length are more typical of MS than monophasic idiopathic TM (Fig. 104.1C); however, 10% of children with MS will experience MS relapses characterized by large spinal cord lesions extending longitudinally more than three vertebral body segments (Fig. 104.1D) (Verhey et al., 2010). The clinical manifestations of TM in the context of MS may be severe at maximal deficit, but most children will recover from the acute episode (Verhey et al., 2010). Repeated relapses involving the brainstem and spinal cord are associated with an increased risk of long-term disability. Treatment recommendations for MS-related spinal cord relapses are provided in Chapter 133.

VASCULAR MYELOPATHIES The spinal cord is supplied by three longitudinal arteries. The anterior spinal artery, a caudal continuation of the two vertebral arteries, begins at the foramen magnum and courses in the ventral median fissure. The paired posterior spinal arteries branch from either the vertebral or posterior inferior cerebellar arteries. Segmental spinal arteries as well as small-caliber anterior and posterior radicular arteries reinforce the blood supply to the dorsal and ventral nerve roots. The anterior two-thirds of the spinal cord are more susceptible to infarction compared with the posterior third, which contains more anastomoses (Sliwa and Maclean, 1992). Furthermore, the thoracolumbar region has a significantly higher propensity for ischemic changes since it is supplied predominantly by a single vessel, the artery of Adamkiewicz (Singh et al., 1994). This somewhat tenuous vascular supply, particularly in the midthoracic watershed region between the anterior and posterior spinal vascular territories, may become compromised either due to inherent vascular

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and Geibprasert, 2009). Nonetheless, the available literature highlights several cardinal features of acute spinal cord vascular compromise, as detailed under each subtype below.

Spinal cord infarction Spinal cord ischemia in children is rare (Burnei et al., 2006). Putative etiologies and risk factors for spinal infarction in children are described in Table 104.3. Infarction can be divided into two main categories: diffuse Table 104.2 Primary spinal cord vascular disorders in children Vascular malformations ● Arteriovenous fistula ● Arteriovenous malformation ● Cavernous angioma Embolic myelopathy ● Fibrocartilaginous Thrombotic myelopathy Anterior spinal artery infarction Vasculitic myelopathy ● Small-vessel vasculitis ● Large-vessel vasculitis

Table 104.3 Etiologies and risk factors for spinal cord infarction

Fig. 104.1. MRI of inflammatory demyelinating spinal cord lesions in children. (A) Sagittal T2-weighted fast-spin-echo (FSE) image of the spine demonstrating LETM in a 14-yearold girl. Extensive spinal cord swelling is evident. (B) Sagittal T2-weighted FSE image of the same patient shown in A, illustrating significant spinal cord atrophy 1 year after acute illness. (C) Sagittal T2-weighted FSE image of a 17-year-old girl with relapsing–remitting MS. Two distinct lesions are noted (arrows), both of which are smaller than three vertebral body segments. (D) Sagittal T2-weighted FSE image of an 8-year-old girl with relapsing–remitting MS illustrating multiple lesions, at least one of which extends more than three vertebral body segments in length.

malformations, or by vascular occlusion by clot or inflammatory endothelial swelling (Table 104.2). Vascular myelopathies are rare in children, and information on pathophysiology, treatment, and outcome is limited (reviewed in Pelser and van Gijn, 1993; Krings

Systemic hypoperfusion ● Aortic dissection ● Cardiac arrest ● Cardiac tamponade Embolic ● Fibrocartilaginous ● Tumoral Thrombotic ● Prothrombin variant ● Primary antiphospholipid syndrome ● Protein S deficiency ● Anterior spinal artery thrombosis ● Sickle cell anemia Vascular malformations ● Arteriovenous malformation ● Arteriovenous fistula Iatrogenic ● Aortic surgery ● Vertebral angiography ● Cardiac catheterization ● Scoliosis repair/spinal surgery ● Umbilical arterial catheter in the neonate

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hypoxemia–ischemia of the cord and focal spinal cord infarction (reviewed in Novy et al., 2006). Diffuse spinal cord hypoxemia occurs in the setting of global ischemia such as near drowning, aborted sudden infant death syndrome, postprolonged cardiac arrest (spontaneous or in the context of cardiac surgery), or any situation associated with profound anoxia. One study noted that 2.3% of infants who died before 4 weeks of age demonstrated signs of hypoxic–ischemic spinal cord damage at autopsy (Sladky and Rorke, 1986). This suggests there may be a subset of children congenitally predisposed to spinal cord hypoperfusion or poor blood flow autoregulation secondary to prematurity (Sladky and Rorke, 1986; Singer et al., 1991). In non-neonates, diffuse spinal infarction occurs secondary to arterial insufficiency in the context of global hypoperfusion of the spinal cord (Robertazzi and Cunningham, 1998; Novy et al., 2006). Children undergoing spinal surgery (Mirovsky et al., 2007), aortic surgery, or prolonged aortic cross-clamping for cardiac repair are at particular risk (Brewer et al., 1972; Dasmahapatra et al., 1987; Serfontein and Kron, 2002). Patients with spinal cord infarction secondary to aortic surgery have a worse prognosis compared to those with infarct due to other causes (Salvador de la Barrera et al., 2001). Clinical symptoms relate to the severity of spinal cord damage. Given the marked clinical acuity of patients with diffuse hypoxic CNS injury, the manifestations of spinal cord involvement may initially be difficult to distinguish from those of global brainstem and cerebral ischemia. Focal spinal cord infarct appears to be less frequent in children than in adults, possibly due to differential age-related perfusion of the cord (Nance and Golomb, 2007). Differentiation of spinal infarction from idiopathic inflammatory TM can be challenging (Nance and Golomb, 2007). Diffusion-weighted imaging (DWI), especially echo-planar multishot sequences, of the spinal cord may provide additional information for the assessment of ischemic changes and help in differentiating the diagnosis (Zhang et al., 2005). Focal spinal cord infarction related to fibrocartilaginous emboli precipitated by minor trauma or prolonged spinal extension is an increasingly recognized etiology for spinal cord ischemia in children, adolescents, and adults (Davis and Klug, 2000; Avile´s-Herna´ndez et al., 2007; Tan et al., 2009). Activities associated with this entity include use of trampolines, sudden falls directly onto the buttocks, wrestling, surfing, and gymnastic activities. Presenting symptoms include sudden-onset back pain and a relatively rapid progression of neurological deficit. Axial loading of the vertebral column in conjunction with the Valsalva maneuver leading to increased intradiskal pressure is thought to be the inciting event. The increased intradiskal pressure leads to acute disk

herniation of the nucleus pulposus material and retrograde flow of the embolus from the vertebral sinusoids to the spinal circulation, passing into the arterial side via an arteriovenous anastomosis (Han et al., 2004). Although considered to be a rare and potentially fatal event (Naiman et al., 1961), based largely on autopsy series (Tosi et al., 1996), MRI studies suggest that fibrocartilaginous embolism may be a more common etiology for acute spinal cord infarction than previously recognized (Toro et al., 1994). Fibrocartilaginous embolism may account for some cases otherwise categorized as anterior spinal artery syndrome (Wilmhurst et al., 1999). Imaging features of fibrocartilaginous embolism may be absent acutely. Over the ensuing 24–48 hours, increased signal of the spinal cord becomes evident on T2-weighted fast-/turbo-spin echo images, consistent with spinal cord infarction. In addition to increased signal and swelling of the cord, increased T2-weighted signal of Schmorl’s nodes and loss of normal interdiskal height in the spinal cord region anterior to the area of infarction become visible. Neurological recovery is variable. Acute therapy is often guided by the degree of inflammation, with corticosteroids prescribed for children with significant spinal cord edema. As the etiology is generally thought to represent an acute insult relating to sudden axial loading of the spinal cord, recurrence is not anticipated. The fibrocartilaginous embolus itself is presumably very small, and likely has passed through the circulation well before the clinical diagnosis is confirmed.

CLINICALVIGNETTE A previously healthy 12-year-old girl experienced a fall while playing soccer. She was running, tripped, and landed directly onto her coccyx. She felt a “jarring” pain that traveled from her coccyx up her spine, lasting only a few seconds. She was able to resume play for about 1–2 minutes, then noted weakness in both lower limbs. Weakness worsened over approximately 5 minutes until she was no longer able to bear weight. On arrival in the emergency room, she had limited hip flexion, and marked weakness of all lower limb muscles. She was unable to void and required catheterization. MRI scans obtained within 2 hours of arrival to hospital were essentially normal, while a scan performed on day 2 clearly demonstrated swelling and increased T2-weighted signal of the spinal cord, as well as abnormal signal of the adjacent vertebral body. A fibrocartilaginous embolism was the presumed mechanism of insult. She experienced gradual improvement and was eventually left with only minimal lower limb weakness that did not interfere with function.

Spinal cord infarct also occurs in patients with acquired or genetically defined disorders of hematocoagulation.

INFLAMMATORY, VASCULAR, AND INFECTIOUS MYELOPATHIES IN CHILDREN Acquired hypercoagulable states, such as systemic infection, renal disease, severe dehydration, and oral contraceptive use, are more typically associated with thrombi of peripheral venous tributaries or cerebral venous sinuses. Genetically defined disorders associated with increased risk of arterial or venous thrombosis are also only rarely associated with spinal cord infarction. While cerebral infarction is a major cause of morbidity in children with sickle cell anemia (Al-Kandari et al., 2007), infarction of the spinal cord is exceedingly rare (Rothman and Nelson, 1980). Strategies for prevention of cerebral stroke in patients with sickle cell anemia include monthly transfusion, which has been shown to reduce stroke risk by over 90% (Pegelow et al., 1995; Adams et al., 1998). Spinal infarction can also occur in children with hypercoagulable states due to deficiency of protein C or protein S, factor V Leiden, or in acquired antiphospholipid or anticardiolipin syndromes (reviewed in Nance and Golomb, 2007). Identification of such patients is extremely important, as they have ongoing prothrombotic risks that can be therapeutically reduced. High-field strength MRI with shorter scan times and the use of multishot echo-planar DWI (b factors: 300 and 600 s/mm2, 6 directions) of the spinal cord can provide an early indication of the extent of ischemia (Sibon et al., 2003; Beslow et al., 2008). Spinal cord infarction may be difficult to visualize in young children owing to the relatively small cord volume and cross-sectional area. Treatment of focal spinal cord infarction in children is empirical. Corticosteroids are often used to reduce spinal cord swelling, but the efficacy of such treatment has not been documented. Antiplatelet therapies have been provided to adult patients, and might be particularly important if also required for a proven prothrombotic disorder. Recovery from spinal cord infarction is generally poor. In a review of 199 patients with spinal cord infarction, which included some children, 22% died, 24% did not show any improvement from acute deficit, 35% showed some improvement, and only 19% demonstrated marked improvement (Cheshire et al., 1996).

Vascular malformations of the spinal cord Vascular malformations of the spinal cord can be grouped into three main categories: (1) genetic hereditary lesions (e.g., hereditary hemorrhagic telangiectasia), (2) genetic nonhereditary lesions associated with coexistent cutaneous vascular lesions at the same dermatomal level (e.g., Cobb syndrome, Parkes–Weber syndrome), and (3) single vascular lesions that include spinal cord, nerve root, or filum terminale (e.g., arteriovenous malformation (AVM), arteriovenous fistula (AVF)) (Rodesch et al., 2002). Figure 104.2A and B delineates the MRI features of a metameric vascular malformation in a 10-year-old

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Fig. 104.2. MRI of vascular myelopathies in children. (A and B) Sagittal T2-weighted fast-spin-echo (FSE) spine MRI in a 10-year-old boy who presented with acute back pain and paraparesis. Large radicular arteries and draining veins are evident from T6 to T9. There is abnormal signal void within the vertebrae from T9 to T11, within the spinal canal from T7 to T12, and also in the erector spinae muscles and soft tissue dorsal to the spinal cord at T7–L2. Intramedullary hyperintensity extending from T5 to T9 is also evident. (C and D) Sagittal T2-weighted FSE spine MRI of a 10-year-old boy. Multiple small flow void lesions are visualized around the cervical cord from the foramen magnum extending caudally to the C6 level. An AVM lesion is evident on the dorsal aspect of the spinal cord at the C3–C4 level. There is no abnormal intramedullary signal. Images courtesy of Dr. M.M. Shroff, Division of Neuroradiology, The Hospital for Sick Children, Toronto, Ontario, Canada.

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boy, consistent with Cobb syndrome. Most vascular lesions of the spinal cord occur as solitary lesions, and are further categorized into dural and pial arteriovenous (AV) shunts, depending on the vessels feeding the lesion (Rodesch et al., 2002). According to a recently proposed embryological classification, vascular malformations can also be categorized as AVFs and AVMs. Extradural and intradural AVFs located on the ventral aspect of the spinal cord are delineated as those associated with: (1) insignificant blood shunting, (2) moderate shunting, and (3) considerable shunting. Dorsally located AVFs are divided into those with one vascular tributary and those with multiple tributaries (Spetzler et al., 2002). In children, AVMs as opposed to AVFs are more frequently observed and are likely to be found on the dorsal aspect of the spinal cord (Tacconi and Findlay, 2000; Du et al., 2009). This supports the notion that spinal dural AVFs may be acquired rather than congenital (Du et al., 2009). In a report of 1168 cases of spinal vascular lesions, 6.1% were children. Some 44% of the children had spinal cord AVMs and 24% had perimedullary AVFs, while the remaining 28% had Cobb syndrome, spinal cord cavernous angioma, vertebral angioma, epidural AVM, and spinal cord aneurysm (Du et al., 2009). Similar to adults, males may be affected more than females at a ratio of 2:1 (Du et al., 2009; Krings and Geibprasert, 2009). One study reported that the thoracolumbar region has an increased propensity for vascular malformations (Du et al., 2009), specifically the segments between T6 and L2, although AVMs can be present at any spinal cord level (Krings and Geibprasert, 2009), as our case demonstrates (Fig. 104.2C and D). Except for spinal dural AVFs, most vascular malformations are congenital in origin, being formed in the third embryonic week (Du et al., 2009). The age at clinical manifestation with spinal cord deficits occurs with a bimodal pattern. Peak ages are in early childhood before 2 years (Du et al., 2009), or after age 10 years (Kitagawa et al., 2009). The increased blood supply requirements during the rapid growth phases in infant and adolescent years together with the increased physical activity level seen in adolescence may explain the bimodal age of onset. The clinical manifestations of spinal cord malformations occur either in the context of subarachnoid hemorrhagic episodes or, less commonly, due to vascular occlusion (with manifestations similar to spinal cord infarction described above). Hemorrhage as the mechanism for symptom onset is seen in approximately 20% of patients with spinal vascular malformations (Berenstein and Lasjaunias, 1992; Swaiman et al., 2006) and may be suggestive of a more perimedullary (pial) AV shunt as opposed to a dural AVF (Krings and Geibprasert, 2009). In patients with vascular malformation-associated hemorrhage, sudden onset of

neurological symptoms is associated with severe back pain secondary to hematomyelia, bilateral lower limb weakness, and sensory deficits (paresthesias, diffuse or patchy sensory loss, and radicular pain that may affect one or both limbs). In patients with slowly expanding vascular malformations, neurological deficits are insidiously progressive. Bladder and bowel incontinence, urinary retention, and erectile dysfunction are more often seen in patients with long-standing spinal vascular malformations (Krings and Geibprasert, 2009). In patients with a more insidious clinical course, progressive vascular compromise to the spinal cord can lead to scoliosis due to mass effect on the growing spine and congestive heart failure secondary to increased spinal venous pressure and a vascular steal phenomenon. A cutaneous angioma, accentuated with the Valsalva maneuver, is seen in 20% of children with spinal vascular malformations. Auscultation of spinal bruit can enhance diagnostic suspicion, and it is imperative that lumbar puncture not be performed in the region of the malformation. Spinal vascular malformations must be considered a treatable cause for progressive spinal cord symptoms (Aghakhani, 2008; Krings and Geibprasert, 2009). Diagnosis is often based on MR angiography with confirmation by digital subtraction angiography (DSA) (Krings and Geibprasert, 2009). Hallmark findings on MRI include centromedullary edema (T2-weighted hyperintensity over multiple vertebral spinal segments) and perimedullary dilated vessels (rim of T2-weighted hypointensity) (Krings and Geibprasert, 2009). In the absence of these findings, coiled vessels suggestive of a vascular malformation may be apparent on postcontrast T1-weighted imaging, but will be better appreciated with 3D turbo-spin-echo imaging (Krings et al., 2007). Figure 104.2C and D delineates the MRI features of a spinal cord AVM in a 10-year-old boy. T2-weighted evidence of flow voids are often more pronounced on the dorsal, compared with the ventral surface. However, if the lesion is a slow-flowing shunt, the flow voids may be appreciated only on postcontrast T1-weighted imaging (Krings and Geibprasert, 2009). Diffuse enhancement is seen on postcontrast T1-weighted sequences signifying chronic venous congestion and blood–spinal cord barrier permeability (Chen et al., 1998). Contrastenhanced MR angiography has greatly aided in localizing AV lesions and guiding interventional radiological management (Krings and Geibprasert, 2009). Therapeutic management is focused on acute care and on preventative management to avoid further spinal cord injury secondary to recurrent hemorrhage or spinal cord compression. Acute management centers around achieving complete occlusion of the shunting site (Jellema et al., 2005). The optimal therapy is to occlude completely the most distal part of the artery and

INFLAMMATORY, VASCULAR, AND INFECTIOUS MYELOPATHIES IN CHILDREN proximal aspect of the draining vein at the shunting site (Jellema et al., 2005; Ferna´ndez et al., 2008). With only proximal occlusion of the distal artery, the malformation has a high likelihood of recurrence within a few months, resulting in collateral filling of the vascular lesion (Krings and Geibprasert, 2009). The two main treatment methods are surgical occlusion of the vein that was receiving the blood from the nadir of the shunt zone (Huffmann et al., 1995), or endovascular occlusion with a liquid embolic agent after superselective catheterization of the artery feeding the shunt zone (Krings et al., 2005). One recent study of children treated for spinal cord AV shunts reported 40% improved, 52% demonstrated no clinical change, and 8% experienced further neurological deficits after embolization treatment (Du et al., 2009). The risk of bleeding or re-bleeding is low due to improved venous drainage postembolization (Rodesch et al., 2005). However, patients requiring secondary surgical intervention due to incomplete endovascular embolization experienced a poor clinical outcome (Andres et al., 2008). Successful embolization may reduce risk of further hemorrhage, but may not reverse the ischemic damage already incurred during the acute event. The degree of clinical deficit is dependent upon the level of pre-embolization disability and duration of symptoms (Krings and Geibprasert, 2009). In severe cases, patients may experience worsening of symptoms despite complete occlusion, and erectile and sphincter dysfunction may not be reversible (Cenzato et al., 2004).

Vasculitis of the spinal cord Inflammation of the blood vessels supplying the spinal cord can lead to deficits due to either vascular compromise (angiitis or small vessel vasculitis), thrombosis (focal or involving the dural sinuses), or cytokine damage. Vasculitides involving the spinal cord may occur as isolated syndromes, or more commonly accompany systemic or multifocal manifestations of vasculitis in other organs ormultiple regions of the CNS. The clinical features are those of TM, and prognosis relates more to the underlying disease contributing to the spinal cord involvement. Acute management is guided by pathobiology – patients with thrombosis are managed as described for spinal infarction, while management of CNS vasculitis requires acute and chronic immunosuppression (Elbers and Benseler, 2008).

INFECTIOUS MYELOPATHY Viral or bacterial infection of the spinal cord is rare in the immunocompetent host, although specific infectious etiologies such as Borrelia burgdorferi, West Nile virus, human T-cell lymphotropic virus (HTLV1) and

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enteroviruses have emerged as more common etiologies in recent years. Table 104.4 delineates infectious agents associated with infection of the spinal cord. Specific etiologies will be discussed in more detail. Bacterial infections involving the spinal cord will not be reviewed, as the majority of such patients have concurrent bacterial meningitis (for example, Moffett et al., 1997), which is discussed in other chapters.

Lyme disease Lyme disease is a multisystemic infectious disorder transmitted to humans by the spirochete Borrelia burgdorferi, via the deer or black-legged tick in North America and the sheep tick in Europe. Molecular typing has demonstrated that B. burgdorferi represents a heterogeneous group of 11 similar species, of which at least three are identified as pathogenic in humans (Noseworthy, 2006). The differential geographical distribution of these three pathogenic species likely explains the regional variation in clinical phenotypes. Borrelia afzelii is primarily isolated from patients with acrodermatitis chronic atrophicans in Europe. Borrelia garinii Table 104.4 Infectious causes of myelopathy Viral ● Herpes simplex viruses ● Herpes zoster viruses ● Cytomegalovirus ● Epstein–Barr virus ● Enteroviruses ● Enterovirus-71 ● Poliovirus ● Coxsackieviruses A and B ● Echoviruses ● Varicella–zoster virus ● Adenovirus ● Flavovirus ● Human T-lymphotropic virus-1 ● Leukemia virus ● Human immunodeficiency virus ● Influenza virus ● Rabies ● West Nile virus Bacterial ● Mycoplasma pneumoniae ● Lyme borreliosis ● Syphilis ● Tuberculosis Postvaccinal ● Rabies ● Cowpox Other ● Amebic meningoencephalitis

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is predominantly seen in European patients with acute neuroborreliosis, and B. burgdorferi sensu stricto is associated with arthritis in patients in Europe and the USA (Lunemann et al., 2001). Lyme disease has a bimodal incidence with a childhood presentation (median age at presentation of 7 years) (Shapiro, 1995) and an adult-onset form (median age range 50–59 years). Lyme borreliosis is the most common vector-transmitted infectious disease in children in the USA (Huisman et al., 1999). Infection with B. burgdorferi involves the CNS (neuroborreliosis) in only 4–15% of infected children (Shapiro, 1995; Hattingen et al., 2004). Upon invasion of B. burgdorferi through the cerebral or spinal meninges, cranial neuritis, radiculitis, encephalitis, myelitis, and demyelinating lesions may become manifest. Facial nerve palsy and polyradiculitis are the most common neurological signs. Myelitis has been reported rarely as a presenting feature of Lyme borreliosis (Rousseau et al., 1986; Linssen et al., 1991), but should be considered in the differential diagnosis of TM. Spinal cord symptoms on neurological examination are typically those of a partial myelitis with concomitant polyradiculitis (Hattingen et al., 2004). The neurological spectrum of neuroborreliosis has been recently reviewed (Halperin, 2009). The neuroimaging features of neuroborreliosis in the spinal cord include diffuse or multifocal T2-weighted hyperintense signal abnormality. Enhancement of the spinal nerve roots, cauda equina, and leptomeninges on T1-weighted postcontrast images is typical and should prompt consideration of the diagnosis. In severe myelitis, intralesional enhancement may be observed (Hattingen et al., 2004; Agarwal and Sze, 2009). The diagnosis of neuroborreliosis should be based on the clinical symptoms and by the presence in serum of IgG and IgM antibodies against B. burgdorferi identified by enzyme-linked immunosorbent assay (ELISA) or western blot. CSF analysis is helpful when positive, but is negative in many patients with neuroborreliosis (Noseworthy, 2006). It is important to consider the regional differences in B. burgdorferi species, as ELISA and western blot assays may be falsely negative if not selected for the etiological species (Stanek and Strle, 2009). Treatment for neuroborreliosis requires parenteral antibiotics in all patients (Noseworthy, 2006). Doxycycline or amoxicillin is recommended as first-line treatment in the early stages of the disease, amoxicillin being the therapy of choice for children younger than 8 years of age (Swaiman et al., 2006). One study of 77 children with acute neuroborreliosis demonstrated that penicillin G sodium (400 000–500 000 IU/kg daily for 14 days) was not superior to intravenous ceftriaxone (75–93 mg/kg daily for 14 days), and that children in both groups improved dramatically with no clinical relapses

observed during the 6-month observation period (Mullegger et al., 1991). Although steroid therapy may challenge the eradication of the infection, corticosteroids may be indicated in patients with significant radiculo-neuritic pain (Noseworthy, 2006). When treated in a timely fashion with the appropriately indicated antimicrobial therapy, a complete recovery from neurological symptoms can be expected (Gerber et al., 1996; Skogman et al., 2008).

Human T-cell lymphotropic virus type 1 HTLV-1 is a retrovirus endemic in southwestern Japan, the Caribbean islands, central and western Africa, southern USA, and South America. The overall prevalence in these areas ranges from 0.3% to 1.6% (Bittencourt et al., 2006). The prevalence of HTLV-1 infection in children living in endemic regions remains much lower than in adults, suggesting primary infection acquisition in late adolescence or early adulthood in the majority (Bittencourt et al., 2006). Approximately 7–42% of breastfed children in HTLV-1 endemic areas acquire the infection vertically from their mothers (Oki et al., 1992; Hino et al., 1996). In non-breastfed children, HTLV-1 is likely transmitted transplacentally or during vaginal delivery. The frequency of transmission from mother to child in these instances varies from 3.3% to 13.8% (Oki et al., 1992; Hino et al., 1996). Therefore, in endemic regions, cesarean delivery is often encouraged to reduce the vertical transmission of HTLV-1 from mother to child. Host infection follows a slow insidious course characterized by spontaneous lymphoproliferation and cytokine production by T-helper (Th) 1 and Th2 cells. Infection-related immune compromise renders the individual more susceptible to other infections and parasitoses (Brites et al., 2002). Manifestations of HTLV-1 in children are typically related to infectious dermatitis (Bittencourt et al., 2006). Approximately 30% of children with infectious dermatitis related to HTLV-1 will develop HTLV-1-associated myelopathy/ tropical spastic paraparesis (HAM/TSP) (reviewed in Primo et al., 2009); HAM/TSP and T-cell leukemia/lymphoma are otherwise much more common in adults. Approximately 15 pediatric cases of HAM/TSP have been reported in the literature (LaGrenade et al., 1995; Arau´jo et al., 2002; Muniz et al., 2002; de Oliveira et al., 2004; Quintas et al., 2004; Primo et al., 2005; Bittencourt et al., 2006). Similar to adults, there appears to be a female predisposition. Clinical manifestations of HAM/TSP include chronic, progressive, pyramidal spastic paraparesis, with proximal lower limb weakness and bladder retention (Primo et al., 2005), which occurs at a more rapid pace

INFLAMMATORY, VASCULAR, AND INFECTIOUS MYELOPATHIES IN CHILDREN in childhood-onset disease than in adults. Lumbar pain, muscle cramps, and lower limb paresthesias may occur over time. Children are more likely than adult patients to experience bladder involvement (Arau´jo et al., 2002). The diagnosis of HAM/TSP follows World Health Organization guidelines, which require the presence of both clinical manifestations of progressive spastic paraparesis and the presence of serum and CSF anti-HTLV-1 antibodies (Primo et al., 2005). Since HTLV-1-associated dermatitis is the main manifestation of HTLV-1 infection in children, serology for HTLV-1 should also be examined in children presenting with significant eczema (Bittencourt et al., 2006). The factors mediating clinical expression of HTLV-1 infection remain incompletely understood. Infected siblings are more likely to be symptomatic if they have a symptomatic sibling (Primo et al., 2005). The potential contribution of genetic factors is further supported by studies in Japan which demonstrated that HTLV-1 positive individuals who carry the human leukocyte antigen (HLA)-A*02 gene had a lower HAM/TSP risk and tended to have a lower serum viral load (Jeffery et al., 1999), while individuals with HLA-DRB1*0101 had an increased risk in developing clinical HAM/TSP (Usuku et al., 1988). Treatment of HAM/TSP revolves around reduction of antibody titers and CSF cell counts. A 3–5-day course of intravenous methylprednisolone followed by a 3-month oral taper (starting at oral prednisone 1 mg/kg daily) is recommended for children presenting with rapid functional deterioration and an inflammatory CSF pattern (Primo et al., 2005). Interferon-a and interferonb1a have been evaluated in small randomized and open trials where interferon-a was only transiently beneficial (Izumo et al., 1996), and interferon-b1a reduces HTLV-1 mRNA load but not HTLV-1 provirus load. In a randomized double-blind placebo-controlled study of combined nucleoside analogs (zidovudine, lamivudine), no change in provirus load was detected and clinical symptoms did not improve (Taylor et al., 2006). Clinical improvement in motor function is modest following treatment (Oh et al., 2005). As HAM/TSP may be progressive for several years prior to diagnosis, spasticity, muscle cramps, and neuropathic pain are significant clinical aspects of the illness. Management is discussed below in the section discussing general care of patients with spinal cord dysfunction.

Enterovirus-71 After the first outbreak of enterovirus-71 (EV71) that occurred in 1969 (Schmidt et al., 1974), there has been a striking increase in both magnitude and severity of EV71 epidemics worldwide, especially in the Asian-Pacific

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region. Children younger than age 4 years are at highest risk for EV71-associated neurological disease. EV71 most often manifests as herpangina or “hand, foot, and mouth disease” (HFMD) – clinically indistinguishable from that caused by Coxsackie virus A16. Molecular genetic studies have shown that EV71 and Coxsackie virus A16 are closely related and both belong to the group Picornaviridae Enterovirus (Oberste et al., 1999); however, Coxsackie virus is less frequently associated with neurological disease. The most common EV71-associated neurological disorders are aseptic meningitis, rhombencephalitis, and acute flaccid paralysis (AFP) – a paralysis indistinguishable from that caused by poliomyelitis (McMinn et al., 2001). Infection by EV71 is now one of the leading causes of AFP in children, given the worldwide eradication of poliovirus. Spinal cord involvement in EV71 infection follows a biphasic clinical course with an initial viral prodrome, followed by neurological deficits. The mean age of onset is 2.5 years (range: 3 months to 8.2 years) with the highest incidence in 1–2-year-old children. Approximately 1–7 days prior to the onset of AFP, children experience a prodromal illness, lasting a mean of 3.2 days, characterized by fever, vomiting, coryza, malaise, headache, diarrhea, rash, vesicular lesions of the hands and feet (usually on the dorsal surface), and ulcerative lesions of the buccal mucosa, tongue, palate and gums (Huang et al., 1999; Chen et al., 2001). In those children who develop neurological involvement, neurological symptoms manifest approximately 2–5 days after the prodromal phase. The onset of AFP is rapid and progressive. Children present with unilateral or bilateral weakness in upper and/or lower extremities. Transient neurogenic bladder has also been reported (Huang et al., 1999). Prior to the onset of paralysis, some children with AFP may also show signs of rhombencephalitis, including myoclonus, tremor, and ataxia (Huang et al., 1999; Liu et al., 2000). MRI features of EV71 infection of the spinal cord are predominantly restricted to unilateral or bilateral increased T2-weighted signal of the anterior horn cells at the region of involvement (Chen et al., 2001). In some children, this may be accompanied by ventral root enhancement on T1-weighted postcontrast imaging. Enhancement of the dorsal roots is not typically seen, consistent with the absence of sensory deficits. Unilateral anterior horn cell T2-weighted hyperintensity may be suggestive of better outcome than bilateral involvement. Severe cases of EV71-associated AFP show persistent T2-weighted signal abnormality and myelomalacia of the anterior horn cell region. A normal MRI may be predictive of a reversible disease and better recovery. Treatment with intravenous immunoglobulin has been minimally efficacious and antiviral therapy for

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EV71 is not currently available. Neurological outcomes reported in the literature for children with EV71associated AFP are variable and range from complete recovery to residual motor weakness in children after 14 months of observation (Chen et al., 2001). Considering the increased frequency of EV71 outbreaks worldwide and the increased magnitude and severity of neurological sequelae in children with EV71, the development of a vaccination against EV71 infection is of significant importance.

West Nile virus AFP associated with West Nile virus (WNV) infection is well documented in adults; however, few cases have been reported in children and little is known of the outcome of children with neurological manifestations of the disease (Hainline et al., 2008). The clinical manifestations of WNV infection in children remain limited to review articles, case reports, and case series (Swaiman et al., 2006; Lindsey et al., 2009). West Nile virus, indigenous to Africa, Asia, Europe, and Australia, was first isolated from serum of a febrile patient in the West Nile region of Uganda in 1937 (Smithburn et al., 1940). As a flavivirus, WNV shares close antigenic interrelationships with the Japanese encephalitis, Murray Valley encephalitis, St. Louis encephalitis, and Kunjin viruses. The appearance of WNV in New York City in 1999 (Centers for Disease Control and Prevention, 1999) and the subsequent spread of the virus through eastern USA and southern Ontario, Canada in 1999–2001 (Centers for Disease Control and Prevention, 2002) demonstrated the ability of these viruses to become established in new regions (Campbell et al., 2002). Mosquitoes are the primary transmission vector. Transmission to mosquitoes is from virally infected birds, with the bird population acting as a host capable of amplifying the virus. Human infection can occur through percutaneous inoculation (mosquito bite) or airborne transmission (aerolization of bird droppings). Horizontal transmission between humans has not been observed (Campbell et al., 2002). West Nile viral infection in children is typically asymptomatic, and thus the seroprevalence for infection exceeds reported clinical cases. In a US epidemiological study, 1478 children (59% males) with WNV were reported to the Centers for Disease Control and Prevention from 41 states – 68% with West Nile fever, 30% with West Nile neuroinvasive disease (WNND), and 2% with varied clinical presentations (Lindsey et al., 2009). Of the children with WNND, 47% had meningitis, 37% reported encephalitis or meningoencephalitis, and 1% had isolated AFP. The WNND semiology was not specified in 15% of the reported cases. The

median US national annual incidence of WNND was 0.07 cases per 100 000 children. Median age of WNND was 14 years (range 1 day to 17 years), with 42% of the children aged 15–17 years. Symptomatic infection in children typically includes flu-like symptoms such as fever, headache, maculopapular rash, muscle pain, or gastrointestinal symptoms. The majority of children manifest between July and September. Symptoms usually remit within 1 week, although generalized fatigue may be prolonged (Campbell et al., 2002; Civen et al., 2006; Hayes, 2006; Lindsey et al., 2009). Only 4% of all WNND cases occur in children (Lindsey et al., 2009). Of the children with WNND, only a very small proportion will manifest with spinal cord involvement. Children present with AFP similar to that seen with poliomyelitis or EV71. Onset of AFP is rapid, with asymmetrical flaccid paralysis of the upper and/or lower extremities progressing over 48 hours. Sensory modalities in all extremities are typically spared (Sejvar et al., 2003; Heresi et al., 2004). CSF analyses may show mild pleocytosis or elevated protein levels. Similar to EV71, MRI of the spinal cord shows evidence of anterior horn cell hyperintensity on T2-weighted sequences in any region along the rostral–caudal length of the spinal cord with or without spinal nerve root enhancement of the cauda equina (Heresi et al., 2004; Hainline et al., 2008). West Nile virus-associated AFP has a poor long-term prognosis. Although the number of reported children is scarce, persistent motor weakness is well described (Sejvar et al., 2003; Lindsey et al., 2009). Although no viral-specific therapy currently exists and no controlled studies of corticosteroid prophylaxis have been conducted, short-course high-dose corticosteroids have been proposed as a means to reduce infectionassociated inflammation and edema of the spinal cord (Campbell et al., 2002). Several antiviral therapies have been tested in WNV-infected cell lines in vitro such as purine and pyrimidine analogs (e.g., ribavirin, which is thought to inhibit replication and cytopathogenicity of WNV in neural cells) (Jordan et al., 2000) and interferon a-2b (which protects spinal cord neural cells and increases their survival when inoculated with WNV) (Anderson and Rahal, 2002). Such therapies are not yet applied to children with WNV infection.

Poliovirus Over the last two decades, many countries worldwide have been certified polio-free. However, re-emergence of the poliovirus or continued transmission of the infection has been reported in Indonesia, Somalia, Yemen, Angola, Ethiopia, Chad, Sudan, Mali, Eritrea, Cameroon,

INFLAMMATORY, VASCULAR, AND INFECTIOUS MYELOPATHIES IN CHILDREN and India (Ong and Fisher, 2005; Paul, 2009), and rare vaccine-related cases of poliomyelitis have been reported (Minor, 2009). As such, clinicians should be aware of the clinical and laboratory features of poliomyelitis. Poliovirus is a neurotropic RNA virus of the group Picornaviridae Enterovirus (Marx et al., 2000). Three poliovirus serotypes are recognized: type 1 is the most frequent in epidemics of paralytic disease, and types 2 and 3 are less neurovirulent. Transmission is horizontal through fecal–oral and oral–oral routes, or less frequently may be transmitted through water reservoirs (Marx et al., 2000). Children less than 5 years of age are most frequently affected. Only about 0.1–1% of infected individuals manifest symptoms of paralysis (Marx et al., 2000). Children less than 15 years of age manifest a diphasic presentation, initially with nonspecific symptoms such as fever, fatigue, headache, vomiting, constipation, neck stiffness, and limb pain. In the second phase, children demonstrate features of acute-onset flaccid paralysis (Horstmann, 1949), similar to that seen in the context of WNV infection. Paralytic poliomyelitis is typically asymmetrical, preferentially affecting proximal over distal muscles with sensory modalities preserved (Sutter et al., 1999). On spinal MRI, increased T2-weighted signal in the region of the anterior horn cells of the affected spinal cord region is characteristic and similar to that seen in WNV and EV71 infection (Choudhary et al., 2010). Midbrain substantia nigra T2-weighted hyperintensity has also been reported (Choudhary et al., 2010). The pathophysiological mechanism is thought to be destruction of motor neurons consequent to virus adherence and replication on motor neuron cells that express poliovirus receptors (Mendelsohn et al., 1989). Evidence of inflammatory cell invasion into anterior horn cells and motor neuron loss is seen within the first 2 weeks, leading to loss of muscle function. Axonal sprouting is thought to account for limited functional recovery (Daube, 1985). Asymmetrical muscle atrophy and skeletal deformity often occurs. Paralytic poliomyelitis is associated with a significant mortality rate, ranging from about 5–10% among patients to as high as 30% during poliovirus outbreaks (Greenberg et al., 1950). Mortality is closely related to availability of intensive care facilities. Two effective polio vaccines have been pivotal in progressing toward global polio eradication: the live oral polio vaccine (OPV) consisting of live attenuated poliovirus of three serotypes (Saban, 1957), and the inactivated polio vaccine (IPV) (Salk et al., 1954). Despite the advantages of OPV over IPV (cost-effectiveness, ease of administration, mucosal and humoral immunity, and spread to contacts to achieve group immunity – all important factors for achieving eradication in

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underdeveloped nations) (Robbins, 1988), cases of vaccine-associated paralytic poliomyelitis (VAPP) in vaccine recipients and their contacts occur at a rate of 1 case per 1–2 million administered doses (Strebel et al., 1992; Kew et al., 2005). VAPP is thought to be the result of reversion of attenuated vaccine polio strains to neurovirulent strains that can lead to paralytic disease as well as possible transmission to nonvaccinated individuals (Minor, 2009). VAPP does not occur with the inactivated vaccine, and although IPV does not produce the intestinal immune responses seen with OPV, the achieved mucosal immunity is acceptable and results in reduced fecal shedding (Finn and Bell, 1998). IPV is used almost exclusively in most counties of the Western hemisphere. The significant cost is a major impediment for use of IPV in the developing world.

GENERAL MANAGEMENT OF CHILDREN WITH ACQUIRED NONTRAUMATIC MYELOPATHY Many children with acquired nontraumatic spinal cord insults will have incomplete recovery. Residual symptoms of spasticity, muscle weakness, muscle cramps, neuropathic pain, and bladder and bowel dysfunction vary from mild to severe, with variable impact on independent ambulation, self-care, and quality of life.

Spasticity Comprehensive reviews of the management of spasticity in children have been well described (Tilton, 2009). Treatment requires multimodal strategies including physical rehabilitation and medication. Rehabilitation centers around muscle relaxation, stretching, and maximizing activity. Some children will regain range of motion as well as some symptomatic relief of spasticity through activities such as swimming, yoga, or passive range of motion exercises. Medications may be oral (baclofen, benzodiazepines, tizanidine), local injections (BOTOX), or intrathecal (baclofen pump). Orthopedic procedures may provide benefit for children with severe spasticity in specific muscle groups (i.e., hamstring muscles or gastrocnemius soleus muscles), or for children with severe spasticity-related subluxation of the hip. Any sudden increase in spasticity should prompt exclusion of bladder infection, skin irritation, or fracture.

Neuropathic pain Neuropathic pain may accompany any spinal cord insult. Pain is particularly more common in patients with neuroborreliosis-related involvement of the peripheral nerves or proximal nerve roots, or any patient with radiculopathy. Neurontin, carbamazepine, and other

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anticonvulsants can provide symptomatic relief (reviewed in Walker, 2008). Little has been described specifically regarding the management of chronic pain in children with inflammatory, thrombotic, or infectious insults to the spinal cord.

Bladder and bowel impairment Impaired control of bladder or bowel function has major physical and psychological consequences (Pannek and Kullik, 2009). The risk of bladder stasis, with subsequent recurrent urinary tract infection is a major cause of both morbidity and mortality in children and adults with chronic spinal cord dysfunction. Management of bladder dysfunction requires urodynamic evaluation and consultation with urology to determine whether the primary issues relate to a neurogenic bladder (failure to empty the bladder) or bladder dysenergia (disorganized bladder contraction leading to frequent voiding and ineffective bladder control). Management of chronic bladder dysfunction in children and adolescents, including discussion of the benefits and challenges of clean intermittent catheterization, indwelling catheters, and medications to improve bladder contraction or to limit bladder neck spasticity are best decided with a multidisciplinary approach (reviewed in detail in Verpoorten and Buyse, 2008; MacLellan, 2009).

Adaptation and coping Acute myelitis is a devastating illness. Children who gain full or nearly complete neurological recovery have nonetheless experienced an extremely frightening experience of often profound neurological impairment. Many children do not recover, resulting in previously healthy children who are now wheelchair-dependent, often with the need for self-catheterization and bowel care issues. Coping with such a dramatic change in independence and facing the long-term prospect of permanent paraplegia is aided by the support of a multidisciplinary healthcare team. Many acute care hospitals partner with rehabilitation facilities to ease the transition from inhospital care to home. Modifications to the family home are often required to permit maximal independence and safety, and parents may require purchase of a vehicle capable of transporting a wheelchair. Costs associated with these changes can pose severe challenges for the family, and add to an already enormously stressful experience. Care for the psychological needs should commence during the acute hospitalization. Both child and parents require the opportunity to express their fears, anger, frustrations, and to learn to see the mechanisms available to optimize their future. Young children may express themselves through drawing, and art therapy may be particularly beneficial.

FUTURE DIRECTIONS The neurological sequelae and outcome of children with spinal cord damage remains poor with long-term motor, sensory, and bowel and bladder functional impairment. Most therapies to date target the acute event and are aimed at prevention of further spinal cord tissue damage. Regenerative techniques such as stem cell and nerve graft implantation may hold promise for spinal cord repair, although many aspects of neural repair require further elucidation, and the long-term safety of stem cell or neural engraftment remains unknown. The widespread availability of the World Wide Web has led many families to inquire about potential stem cell transplantation for their children. Healthcare providers often require accurate and up-to-date information on the research advances in this field (Belegu et al., 2007; Eftekharpour et al., 2008). Stem cell transplantation may provide the environmental growth factors to facilitate nerve growth and myelin repair in the damaged spinal cord. It is likely that the optimal time for transplantation into the injured spinal cord is after the inflammatory response and excitotoxicity has subsided, but prior to glial scar formation (Coutts and Keirstead, 2008). While the precise function of injected stem cells in an injured neural tissue is not yet known, animal studies suggest that stem cells secrete growth factors that mediate the successful regeneration of residual spinal cord neurons and astrocytes. Stem cells may also secrete factors that inhibit the normally expressed endogenous inhibitors, thus improving capacity for neural outgrowth (Coutts and Keirstead, 2008). After transplantation of adult brain-derived neural precursor cells (NPCs) into mice with spinal cord damage, NPCs survive substantially longer in mice with acute lesions compared to those with chronic lesions, and the grafted cells migrate more than 5 mm in the rostral– caudal axis from the implantation site. Neural precursor cells integrate along white matter tracts, and approximately 50% of the grafted cells form oligodendrocytes or oligodendroglial precursor cells (Eftekharpour et al., 2007). These findings associate with functional improvement on motor tasks in the treated animals (Karimi-Abdolrezaee et al., 2006). Maximizing the potential benefit of injected stem cells requires that these cells migrate to the areas of spinal injury. Neural stem/progenitor cells (NSPCs), cultured ex vivo on the inner lumen of an artificial implantable biodegradable scaffold (such as a chitosan matrix tube) and implanted into a completely transected spinal cord, demonstrate robust NSPC survival and differentiation into astrocytes and oligodendrocytes (Zahir et al., 2008). This artificial matrix not only provides a guidance mechanism for implanted cells, but also provides an

INFLAMMATORY, VASCULAR, AND INFECTIOUS MYELOPATHIES IN CHILDREN environment conducive to cell–cell interactions. In such models, neurons can be identified forming preliminary axonal connections between the transected aspects of the spinal cord. Further work has shown that intramedullary implantation of a chitosan matrix tube containing peripheral nerve grafted axons led to “bridging” of these engrafted axons across the injured spinal cord segment (Nomura et al., 2008a, b). Apart from stem cell therapy, neuroprotective agents and stimulation of endogenous repair mechanisms are avenues being investigated for treatment of CNS injury. The role of the Rho pathway in controlling neuronal responses to inhibitory growth proteins after spinal cord injury is well established. Cethrin or BA-210 is a drug that blocks activation of Rho and holds promise as a neuroprotective agent for spinal cord injury. A phase I/IIa openlabel clinical trial demonstrated safety and tolerability of the drug when applied during surgery following acute cervico-thoracic spinal cord injury in adult patients. Patients with cervical spinal cord injuries treated with 3 mg Cethrin showed the greatest improvements in motor function at 12 months postinjury (Fehlings et al., 2011). While stem cell transplantation and regenerative strategies hold promise, there remains a great deal to be learned regarding their clinical application. Current management remains focused on acute care, prevention of further spinal injury, and maximizing function.

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