Postherpetic neuralgia Reactivation of varicella zoster virus infection, which has been dor mant within sensory neurons, results in painful eruptions along the distribution of the ner ve (also known as shingles), and approximately 14% of adults develop persistent neuropathic pain (i.e. postherpetic neuralgia, PHN; Delaney et al., 2009 ). Overall, zoster infection and PHN are less common in children (Hall et al., 2006 ), but children who are immunocompro mised, particularly in association with cancer treatment, are at higher risk. In a series o f 226 children with acute lymphoblastic leukemia, zoster eruptions occurred 90 times, with recurrent episodes in 14 children. All expe- rienced pain with the acute eruption and were treated with acyclo- vir, and fi ve developed postherpetic neuralgia, which persisted for g reater than 2 months in two patients (Sorensen et al., 2011 ). Diagnosis and management Th e diagnosis is based on measurement of plasma alpha-galactosi- dase A activity (although levels may be normal in carrier females), and of plasma or urinar y Gb3 or lyso-Gb3; and is confi rmed by genetic analysis of GLA gene (Mehta et al., 2010 ). Enzyme replacement therapy with alpha-galactosidase A reduces glycolipid storage in tissues , but eff ects on pain take time. Improvement in all dimensions of pain perception aft er 2 4 months has been reported (Hoff mann et al., 2007 ), with reductions in neu- ropathic \200\230pain at its worst \200\231 scores in both boys and girls (2.8 to 1.5) and \200\230 average pain \200\231 from 2.2 to 0.9, and a reduced requirement for neuropathic treatment with anti-convulsants (Pintos-Morell and Beck, 2009 ). In others, the overall prevalence of pain was not altered by enzyme replacement therapy, but those with pain at the onset of th erapy did show a decrease in severity (Ramaswami et al., 2011 ). Trigeminal neuralgia Clinical features Clinical features of trigeminal neuralgia include (B ender et al., 2011 ; Solth et al., 2008 ; Yue, 2004 ): \231 Unilateral pain in the distribution of the trigeminal nerve. Th e trigeminal innerva tion is divided into three zones: V1 ophthal- mic (scalp, forehead, upper eyelid, eye), V2 maxillary (lower eyelid, cheek, nose, upper teeth and gums), and V3 mandibular (lower teeth and gums, jaw, parts of external ear). Pain may be experienced in one or more zones \200 \224most commonly V2 followed by V2/3 combined. Neurological disorders Neuropathic pain is a feature of several neurological conditions. Pa in associated with neurofi bromatosis, Guillain \200\223Barr syndrome, neuromuscular dis orders and pain associated with HIV are covered by Mherekumombe and Collins (Chapter 32, th is volume). CHAPTER 21 neuropathic pain in children 211 \231 Pain is described as sharp, lancinating or shooting, electric-shock (1) Loss of function and congenital insensitivity to pain (Cox et al., like, and occasionally burning. 2006 ; Staud et al., 2011 ), or \231 Pain is intermittent and paroxysmal. (2) Gain of function and increased pain (Cummins et al., 2007 ; Dib-Hajj et al., 2005 ; Wax man and Dib-Hajj, 2005 ). Point mutations at different sites result in two distinct phenoty pes: paroxysmal extreme pain disorder (PEPD) or primary EM (Cheng et al., 2010 ; Fertleman et al., 2006 ; Estacion et al., 2008 ). Mutations associated with EM alter channel activati on, reduce threshold and increase \201 ring frequency, and increase excitability. \231 Intermittent paroxysms of pain can be triggered by light touch in the trigeminal reg ion (cutaneous trigger zones), chewing, brush- ing the teeth, cold wind, or exercise. Pain may also be associated with spasm of the facial muscles, or tic doloureux . Incidence Th e incidence of trigeminal neuralgia is much lower in children (Hall et al., 20 06 ), and less than 1.5% of patients with trigemi- nal neuralgia report an onset of symptom s before 18 years of age (Bender et al., 2011 ). Case series report trigeminal neuralgia in children aged from 3 to 18 years, with median ages of 11 to 13 years (Bender et al., 2011 ; Resnick et al., 1998 ; Yue, 2004 ). Age-dependent e \200 ects Th e degree of change in channel kinetics varies with the site o f the mutation, and larger depolarizing shift s have been associated with onset of symptoms at younger ages (Ahn et al., 2010 ; Han et al., 2009 ). However, variable expression of ne onatal and adult isoforms of the channel may also infl uence the age at which symptoms fi r st appear (Choi et al., 2010 ). Management Diverse views of the pathophysiology of EM have resulted in a range of treatments directed at vascular (vasoactive drugs such as topical GT N, sodium nitroprusside infusion, clonidine; Cohen, 2000 ), anti-infl ammatory, and neuropa thic aetiologies (amitriptyl- ine, gabapentin; Natkunarajah et al., 2009 ). With awareness of the potential involvement of Na v 1.7 in EM, there has been increased use of drugs with sodium channel blocking activity. Diff erent EM-related mutations may be more responsive to either mexile- tine (Choi et al., 2009 ; Iqbal et al., 2009 ; Nathan et al., 2005 ) or car bamazepine (Fischer et al., 2009 ). Pathophysiology Trigeminal neuralgia may be classifi ed as idiopathic or result from compre ssion within the intracranial course of the nerve either by vasculature (Bender et al., 201 1 ; Resnick et al., 1998 ; Solth et al., 2008 ) or by tumor (da Silva et al., 2006 ). As id iopathic trigeminal neuralgia and glossopharyngeal neuralgia (pain in the posterior tongue, pharynx, beneath angle of lower jaw and/or in ear) are rare in children, appropriate imagi ng and investigations are required to exclude underlying causes (Arruda et al., 2011 ). A 1 -year-old child who presented with episodic crying and raising the hand towards the left ea r, had marked allodynia over the ear, and was found to have a schwannoma in the trigeminal nerve (da Silva et al., 2006 ). Neuropathic pain and genetic disorders Erythromelalgia Clinical features Erythromelalgia (E M) is characterized by severe episodic pain and redness aff ecting the hands and feet (Waxm an and Dib-Hajj, 2005 ). Bilateral pain and redness of the ears may also represent a varian t of EM (Brill et al., 2009 ; Vivas et al., 2011 ). Pain is aggravated by warmth, prolonged standing and exercise, and relieved by cooling and submer- sion in iced water, but is oft en poorly responsive to analgesia. Paroxysmal extreme pain disorder PEPD can present soon aft er birth with episodic pain in a ssocia- tion with redness over the buttocks, legs and feet. Th rough infancy and childhood, the condition progresses to include episodes of (Fertleman et al., 2006 ): \231 Rectal pain, oft en induced by a bowel movement, and burning pain and redness in the lower limbs. \231 Brief episodes of intense burning ocular pain associated with redness around the eyes and runny nose and eyes. Pathophysiology Th e pathophysiology of EM has been attributed to vascular, infl am- matory and neuropathic causes (Waxman and Dib-Hajj, 2005 ). Both microvascular ischaemic (vasocon strictive) and reactive-hy- peraemic (vasodilatory) subtypes have been postulated, resultin g in treatment with a wide range of vasoactive drugs (Cohen, 2000 ). EM has also been repor ted in association with myeloproliferative or auto-immune disorders, and in such cases may be termed second- ary EM (Novella et al., 2007 ). \231 Bilateral mandibular pain and redness, which may be triggered by cold, eating or emotional state. Mutations at diff erent points in the SCN9A gene result in altered channel kinetics (impair ed inactivation, prolonged action poten- tial, and repetitive fi ring) and a phenotype that diff ers from EM (Estacion et al., 2008 ). PEPD has been reported to be diff erentially se nsitive to carbamazepine (Fertleman et al., 2006 ). Conclusion Neuropathic pain is a frequent reason for referral to a pediatric chronic pain c linic, and diagnosis is predominantly based on the pain history and descriptors. NP followi ng trauma is more common when the initial injury occurs later in childhood (e.g. following amputation at greater than 6 years). However, NP can occur at younger ages, particularly in higher-risk populations (e.g. cancer, chemotherapy and immunosuppression) or in associatio n with specifi c conditions (e.g. Fabry \200\231s disease). Pharmacological Primary EM has recently been associated with a genetic mutation, which may occur spontaneou sly, or in association with a positive family history. Nine subtypes of voltage gated sodiu m channels have been identifi ed (Na v 1.1 to Na v 1.9). Na v 1.7 is of particular importan ce for pain as it is selectively expressed within nociceptive dorsal root ganglion and symp athetic ganglion neurons (Dib-Hajj et al., 2009 ; Drenth and Waxman, 2007 ; Fischer and Wax man, 2010 ). Mutations in the SCN9A gene, which encodes the Na v 1.7 channel, can result in either: SECTION 4 pain in specific populations and diseases 212 management of NP is largely extrapolated from adult studies (see Rastogi and Campbell, Chap ter 48, this volume). However, pain is oft en severe and only partially responsive to pharm acological interventions, and multidisciplinary care is required. As discussed in other cha pters throughout this text, assessment and manage- ment of chronic pain (including NP) must also encompass non- pharmacological and psychological interventions, include family or car egivers, and address issues related to poor sleep and school attendance. Arruda , M. A. , Albuquerque , R. C. , and Bigal , M. E. ( 2011 ). Uncommon headache syndro mes in the pediatric population . Curr Pain Headache Rep , 15 , 280 \200\223288. Atherton , D. D. , Taherzadeh , O. , Elliot , D. , and Anand , P. ( 2008 ). Age- dependent development of chronic neuropathic pain, allodynia and sensory recovery aft er upper limb n erve injury in children . J Hand Surg Eur Vol , 33 , 186 \200\223191. Attal , N. , Lanteri-Minet , M. , Laurent , B. , Fermanian , J. , and Bouhassira , D. ( 201 1 ). Th e specifi c disease burden of neuropathic pain: results of a French nationwide surv ey . Pain , 152 , 2836 \200\2232843. Attal , N. , Cruccu , G. , Baron , R. , Haanpaa , M. , Hansson , P. , Jensen , T. S. , et a l . ( 2010 ). EFNS guidelines on the pharmacological treatment of neuropathic pain: 2009 re vision . Eur J Neurol , 17 (9), 1113 \200\223e88. Case example Bender , M. T. , Pradilla , G. , James , C. , Raza , S. , Lim , M. , and Carson , B. S. ( 2 011 ). Surgical treatment of pediatric trigeminal neuralgia: case series and review of the literature . Childs Nerv Syst , 27 , 2123 \200\2232129. A 10-year-old boy with severe vascular malformations of the lower leg has had multiple epis odes of infection and of bleeding requiring transfusion and now presents for a below- knee amputation. Preoperative preparation has included discussions with rehabilitation specialis ts and psychologists, and his perioperative pain management has been planned in coordinatio n with the anesthetist, pain service, and surgical team. As there are no contraindications, consent is gained for epidural catheter insertion and an infusion of local anesthetic and opioid is commenced immediately prior to surgery and continued for the fi rst 3 postoperati ve days, with good control of pain. Following cessation of the epidural he develops a sensa - tion of a larger than normal lower leg which is pointing down through the bed at an unusu al angle. In addition, he has par- oxysms of shooting pain extending below the stump, which are not relieved by oral opioids, and which are signifi cantly disrupt- ing his sleep. He is commenced on oral amitriptyline at night and oral gabapentin. Th e episodes of pain beco me less frequent, but remain severe, and gradually improve with escalation of the gabapenti n dose over the next 7 days. He is subsequently dis- charged for rehabilitation at a diff e rent center, where he receives ongoing multidisciplinary care (that includes psychological and family support and input from the pain service) regarding management of his amputation, phantom limb pain, fi tting of a prosthesis, and a gradual return to school is planned. Th ree months later he returns to the chronic pain clinic for review. He has occasional episo des of pain during the day, ongoing non- painful phantom sensations (although the size of t he phantom has signifi cantly reduced), and is sleeping well at night but feels a little dr owsy in the morning. Th e amitriptyline is weaned with- out any increase in pain, and he co ntinues to be reviewed with a plan to gradually wean the gabapentin as tolerated. Bennett , M. ( 2001 ). 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Schanberg Summary Musculoskeletal pain is a common symptom in infl ammatory arthritides such as juven ile idiopathic arthritis; however, identifying the underlying pathological process is oft e n challenging for health care providers due to the extensive diff erential diagnoses. In ch ildren with infl ammatory arthritides, physical examination abnormalities including swellin g and/or pain on movement and joint limitation accompany the pain at initial presentation. Control of disease activity through anti-infl ammatories and other disease- modifying agent s can limit disease progression and joint damage; however, pain may persist in spite of the se measures. Optimal treat- ment of pain in juvenile idiopathic arthritis and related condi tions is based on a biopsychosocial model, which addresses biological, environmental, and c ognitive-behavioral factors. Analgesics such as opioids and neuropathic pain medications, i n conjunction with other modalities such as pain coping skills training, aerobic exer- cise , and improved sleep hygiene may be appropriate in certain circumstances. Further research is needed to prospectively iden- tify patients and families early in the course of disease who would benefi t from additional support to optimize pain management and limit distress. In addition, future clinical trials should assess the impact of study interventions on pain as a primary endpoint, assessed independently from other response variables. pain processing. However, aggressive medical therapy alone is not suffi cient to optimally treat pain in children with rheumatic condi- tions. Other important concomitant factors bes ides disease activity impact pain perception and management. A biopsychosocial model of pai n more completely addresses all factors contributing to the pain symptoms of a child with a n underlying rheumatic disease, serving as an eff ective framework for treatment ( Figure 2 2.1 ). Mechanisms of arthritis pain Much of what is understood about the biology of joint pain com es from the study of neural pathways in mice models of experimental infl ammatory arthritis (McDougall, 2006 ; McDougall and Larson, 2006 ). Schaible \200\231s extensive work on the basis of pain resulting from infl ammatory arthritides such as rheumatoid arthritis (RA) an d JIA (Schaible et al., 2002 , 2005 , 2009 ) have described two primary mechanisms: periphe ral sensitization (increased sensitivity of noci- ceptive primary aff erent neurons) and ce ntral sensitization (hyper- excitability of nociceptive neurons in the central nervous syst em). Degenerative processes within joints, along with infl ammation, can trigger and exacer bate sensitization of pain pathways, resulting in the development and perpetuation of chron ic pain. Current mech- anistic theories behind the development of pain associated with infl ammation and arthritis in children with rheumatic disease have been reviewed (Kimura and W alco, 2007 ). Primary aff erent neurons have three main functions in nocic- eption: detection of noxious or damaging stimuli (transduction), conveyance of sensory input from the periphery to the s pinal cord (conduction), and synaptic transfer of input to neurons within spe- cifi c lamin ae of the dorsal horn of the spinal cord (transmission) (Kidd and Urban, 2001 ). C-fi bre n ociceptors are activated by ther- mal, mechanical, and chemical stimuli, and can also be se nsitized by mediators of the infl ammatory response (e.g. prostaglandin E2 and bradykinin; see Walker and Baccei, Chapter 6, this volume). Once sensitization occurs, low-level previo usly non-noxious stimu- lation elicits neural activity (Giordano, 2006 ), and pain can be p re- cipitated by routine movement in the presence of infl ammation or joint damage from tra uma or tissue injury. In infl ammatory arthri- tis, a complex interplay of mechanical facto rs and chemical media- tors such as release of bradykinins, prostaglandins, neuropeptides, cytokines, and ion channels is triggered, resulting in a decrease in