 \231 Many conditions associated with NP in adults are rare or not associated with signifi cant pain in children (e.g. Parkinson \200\231s dis- ease, Alzheimer \200\231s disease, po st-stroke pain). \231 Pain history including: evaluation of intensity (assessed by numerical rating scale or visual analog scale), quality (sensory descriptors), temporal aspects of pain (frequency , spontaneous/ paroxysmal or continuous, aggravating/relieving factors), and response to tr eatment. History remains the mainstay of diagnosis, and many children use descriptors that are considered \200\230typical \200\231 of NP, such as burning, shooting, radiating, burni ng, electricity-like, pain on contact, stabbing, pricking, tingling, pins and needles, and pinching (Krane and Heller, 1995 ; Wilkins et al., 1998 , 2004). However, young children ma y be unable to clearly describe their pain in these terms. \231 Th e incidence of post-herpetic neuralgia and trigeminal neural- gia is much lower in children (Hall et al., 2006 ). \231 Painful diabetic neuropathy is a feature of more prolonged dis- ease and is rarely r eported before 14 years of age (Hall et al., 2006 ), but sensory changes have been detected in children prior to onset of pain (Blankenburg et al., 2012 ). \231 Some NP conditions are increasingly recognized in children (e.g. CRPS, phantom limb pain, or NP following trauma or surgery; Walco et al., 2010 ). \231 NP may be the presenting symptom during childhood of spe- cifi c genetic conditions (e.g. Fabry \200\231s disease or erythromelalgia; Fischer and Waxman, 2010 ; Ramaswami, 200 8 ). \231 Sensory examination to verify the lesion of the somatosensory system (sensory, motor , and autonomic signs; allodynia and SECTION 4 pain in specific populations and diseases 206 Post-surgical neuropathic pain Neuropathic pain can occur acutely or as a feature of persis tent post- surgical pain in adults (Kehlet et al., 2006 ; Macintyre et al., 2010 ). Th ere has been limited prospective evaluation of postoperative NP in children, and most data come s from retrospective questionnaires. Table 21.1 Neuropathic pain conditions in children Classi \201 cation Examples Trauma \227\206 Post surgery \227\206 Phantom limb pain \227\206 Brachial plexus injury \227 \206 Peripheral nerve injury \227\206 Spinal cord injury Th e largest study (response rate 63%, n = 651) surveyed 18- to 19-year-olds who had underg one inguinal hernia repair before 5 years of age (Aasvang and Kehlet, 2007 ). Pain from the operated groin was reported by 13.5% of respondents; 5.2% had pain at rest with an average intensity of 2.5 (range 1 \200\2239 on 0 \200\22310 visual analog scale, VAS); and in 2% p ain was frequent and moderate or severe (VAS 6.3, range 4 \200\2239). Neuropathic descripto rs were reported by 53% and sensory descriptors by 72%, including tender, annoying, and sho ot- ing. Th ere was no diff erence in incidence if surgery was performed before 3 months of age. Pain was frequently precipitated by exercise and activity, and this led the authors t o conclude that a signifi cant component of the pain may arise from muscle and/or ligamento us sources rather than being predominantly neuropathic pain. Complex regional pain syndrome \227\206 Following trauma/fracture \227\206 No precipitating cause \227\206 Guillain \200\223Barr disease \227\206 Trigeminal neuralgia \227\206 Multipl e sclerosis Neurological and neuromuscular disease Metabolic disease \227\206 Fabry \200\231s disease \227\206 HIV/AIDS \227\206 Post-herpetic neuralgia Neuropathy following infection Eighty-eight of 91 patients who underwent thoracotomy for repair of coarctation of the aort a between 1965 and 1985 at ages between 0 and 25 years were assessed at an average time of 39.3 7.7 years following surgery (Kristensen et al., 2010 ). An increased propor- tion r eported pain for greater than 3 months following their sur- gery if it was performed at a l ater age: 1/31 at 0 to 6 years; 7/36 at 7 to 12 years, and 6/21 at 13 to 25 years. Th ree p atients, who had initial surgery between 7 and 25 years, still reported pain with neu- ropa thic descriptors at the surgery site. As the authors noted, this retrospective study is sub ject to signifi cant recall bias, particularly for those who had surgery before 6 years of age. Tumor \227\206 Nervous system tumor (neuro \201 bromatosis) \227\206 Invasion/compression by tumor \227\206 E \200 ect of treatment (e.g. post surgery, chemotherapy) \227\206 Erythromelalgia \227\206 Paroxysmal extreme pain disorder Genetic hyperalgesia; hypoaesthesia and hypoalgesia). Sensory abnor- malities on clinical examinati on are more diffi cult to elicit in infants and young children. Quantitative sensory testin g evalu- ates patterns of change in association with NP in adults (Maier et al., 2010 ), bu t pediatric use of this technique is oft en limited to research studies (Lebel et al., 2008 ;Sethna et al., 2007 ; see also Hermann, Chapter 40, this volume). Neuropathic pain was reported in six children (within a group of approximately 40) with cer ebral palsy undergoing multilevel surgery to reduce contractures (tendon release/lengthenin g/transfer) and/or improve sitting position or gait. Pain with neuropathic descriptors comm enced 4 to 9 days aft er surgery, was associated with allodynia in fi ve of six patients, a nd required referral and ongoing manage- ment in a chronic pain clinic (Lauder and White, 2 005 ). \231 Assessment of disability, quality of life, sleep, and mood. In adults, NP is associa ted with a greater disease burden than other forms of chronic pain, with eff ects on qualit y of life, impaired sleep, higher anxiety/depression scores, and increased use of health ca re and specialist services (Attal et al., 2011 ; Smith and Torrance, 2012 ). Th e impact of chronic pain on quality of life, mood, and disability is covered in many chapters througho ut this text, but relatively few pediatric series have evaluated the impact of NP per se on quality of life (Jan and Wilson, 2004 ). Early-onset localized pain in surgical scars was reported in three cases following surgery at 14 to 17 years. Symptom onset was delayed for 6 to 12 months in a further two cases foll owing surgery at 8 and 10 years respectively (Nayak and Cunliff e, 2008 ). Ulna nerve injury with sensory and/or motor signs occurred in 6% of children (average age 6 .5 years) having pins inserted for supracondylar fractures of the humerus. Recovery occurre d aft er a mean of 9.3 (range 6 \200\22336) weeks, but the presence or absence of associate d NP was not specifi cally reported (Eberl et al., 2011 ). \231 Additional tests may be indicated, although many are limited to research settings or specifi c cases (e.g. electroneuromyogra- phy, microneurography, functional brain imaging, skin biopsy). Investigations may be required to confi rm a specifi c underlying diagnosis (e.g. Fabry \200\231s disease) or to exclude other causes. In summary, neuropathic pain can occur following surgery in children, but additional larger studies are required to evaluate the prevalence and duration of symptoms, and also determi ne if sus- ceptibility is related to age at time of surgery. Neuropathic pain following trauma and surgery Laboratory models of traumatic peripheral ner ve injury have dem- onstrated a reduced susceptibility to neuropathic pain if the injury is performed at a younger age (fi rst 3 postnatal weeks in the rodent; see Vega-Avelaria and Beggs, Chapter 7; Walker, Chapter 3, this vol- ume). Clinical studies are also suggestive o f an increased likelihood of neuropathic pain following trauma or surgery at older ages. Phantom limb pain Altered sensory function following limb amputation is generally classifi ed as non-painful phantom sensations or phantom limb pain. Th e majority of current literat ure is based on retrospective case series with diff ering methodology and variable response rates ( Table 21.2 ). Characteristics of phantom pain Pain that is experienced in the region of the missing limb follow- ing amputation (i.e. phantom limb pain) has been described by CHAPTER 21 neuropathic pain in children 207 Table 21.2 Studies on phantom pain in children Study Pain incidence overall + subgroups Sensation incidence Identi \201 ed patients Number Age Krane and Heller, 1995 Overall: 83%; 1/2 congenital deformity; 9/10 cancer; 10/12 trauma/infection 100% Medical records 2 hospitals; amputations between 1980 and 1990; children <19 years age n = 24; (54 mailed; 12 undelivered) 24/42 = 57% RR Current age: 5 \200\22319 yrs; Age at operation 2 \200\22316 yrs Time since op. 1 mth \200 \2237 yrs Wilkins et al., 1998 Overall: 29%; 1/27 congenital de \201 ciency 16/33 surgery ( \211 6 yrs 9/19; >6 yrs 14/ 14) 42% 2/27 congenital de \201 ciency 23/33 surgery Recruit from Canadian Child Amputee Program (CHAMP) n = 60 (247 letters sent; 74 responded; 60 agreed) 60/247 = 24% RR Current age: congenital 12.4 2.6 yrs; surgery 12.7 2.4 yrs (time since op. 6.6 4.3 yrs Th omas et al., 2003 Overall: 38%; major burn injury 20% (3/15) \202 ame 53% (10/19) electrical Retrospective medical record review; single hospital 1972 \200\2232002 n = 34 (39 cases, 4 died, one major neurological injury) Age at amputation: median 11 yrs (3 \200\22322 yrs) Melzack et al., 1997 4% (3/75) congenital de \201 cient; 22% (11/49) amputation <6 yrs 20% (15/76) congenital de \201 cient; 50% (26/49) amputation <6 yrs Recruit from Canadian Child Amputee Program (CHAMP) and single hospital n = 125 (184/329 questionnaires returned; 46 interviewed at hospital; 125 met inclusion cri teria) Age at assessment: 14.7 yrs Burgoyne et al., 2012 Overall: 76%; 26 cancer (20/26 primary bone tumors) Retrospective medical record review; single hospital 2000 \200\2232007 n = 26 (2 excluded based on age 5/12 and 2 yrs old) Age at assessment: 6 to 27 yrs; (median 15 yrs; 9/26 >18 yrs) Smith and Th ompson, 1995 Overall: 44%; 48% (32/67) cancer; 12% (1/8) trauma Retrospective medical record review; single hospital 1983 \200\2231993 n = 75 (293 records reviewed, 75 met inclusion criteria) 5 \200\22317 years children as sharp, tingling, stabbing, pins and needles, throbbing, piercing, squeezing, ti ght and uncomfortable (Krane and Heller, 1995 ; Wilkins et al., 1998 , 2004). numb, itching, and prickling (Krane and Heller, 1995 ; McGrath and Hillier, 1992 ; Wilkins et al., 1998 , 2004). Despite reported mean intensities of 4 to 5 (0 = no sensation, 10 = s trongest imaginable sensation), phantom sensations had minimal impact on daily activ- ities (Wilkins et al., 1998 , 2004). Phantom pain is frequently of moderate or severe intensity, with reported mean ratings of 5 .29 2.4 (Wilkins et al., 1998 ) and 6.4 1.8 out of 10 (Wilkins et al., 2004 ). Typica lly, pain is episodic, lasts for seconds or minutes, with a frequency varying from daily to monthly, and only a small proportion of children have reported constant pain (Wilkins et a l., 2004 ). Stump pain oft en coexists with phantom limb pain but may also occur in isolation. A higher incidence has been reported following surgery than in children with a congenitally absent limb (Wilkins et al., 1998 , 2004). Exercise, objects approaching the stump, cold weather, and \200\230feeling nervous \200 \231 have been reported to trigger episodes of phan- tom pain (Wilkins et al., 1998 ). Psyc hosocial triggers were more common in girls, whereas pain was triggered by physical stimuli in a higher proportion of boys (Wilkins et al., 2004 ). Incidence of phantom limb pain It is now well established that NP can follow amputation in chil- dren, but it is diffi cult to accurately estimate the incidence. Much of the data com es from retrospective questionnaires with response rates below 50% or from medical case not es that may not accurately record all symptoms. Samples are oft en small, may be derived fr om the community or clinics, and the duration between surgery and assessment is oft en vari able. Phantom pain has been reported to produce minimal interference with daily activity (Wilkins et al., 1998 ). In a series of 88 children, fi ve of 24 following lower limb amputation an d one of 64 with congenital lower limb defi ciency reported phantom pain, but 89% were able to use their prosthesis for the whole day; 95% were able to walk; and 93% of those over 4 years were able to cycle (Boonstra et al., 2000 ). It is not clear from this series if phan tom pain infl u- enced the ability to tolerate the prosthesis, but it has been reported tha t phantom limb sensations were less apparent while wearing a prosthesis (Melzack et al., 19 97 ). Reported incidences of phantom limb pain are summarized in Table 21.2. Factors that have be en associated with an increased inci- dence in children include: \231 Surgical amputation (49 \200\22376%) versus congenitally defi cient limbs (3 \200\2234%). \231 Older age at time of amputation. A negative correlation has been reported between ag e at disruption and onset of a phantom limb (i.e. amputation at older age, shorter time to phantom onset) but it is not clear if this relationship holds for phantom pain as well as p hantom sensations (Melzack et al., 1997 ) Associated phenomena Non-painful sensations experienced in the region of the missing limb ( i.e. phantom sensations) are reported by 50% to 100% of children following surgical amputat ion and in 7% to 20% of chil- dren with congenitally defi cient limbs (Table 22.2). Th ese have been described as tingling, pins and needles, tickling, \200\230feels asleep \200\231 , \231 Cancer and chemotherapy. Phantom pain following amputations for cancer has been repo rted in 48 \200\22390% of children (Burgoyne SECTION 4 pain in specific populations and diseases 208 et al., 2012 ; Krane and Heller, 1995 ), and in one small series the rate was higher than f ollowing amputations for trauma (32/67 versus 1/8; Smith and Th ompson, 1995 ). Chemotherap y may also increase the risk of phantom pain as the incidence ranged from 74% in children e xposed to chemotherapy before or at the time of amputation, to 44% if chemotherapy was only administered aft er the amputation, and was lowest (12%) in those who did not require chem otherapy (Smith and Th ompson, 1995 ). Other causes of can- cer-related neuropathic pain ar e discussed later in the chapter. In addition, it is diffi cult to diff erentiate neuropathic pain associated with the initia l injury from pain related to: re-innervation following early microsurgical repair and nerv e graft s; subsequent surgical pro- cedures (e.g. tendon transfers or rotational osteotomie s) that may be required throughout childhood to improve function; trophic inju- ries associ ated with reduced sensory function; and musculoskeletal pain. Th ese issues are highlighted by the following case series. \231 Twenty-four patients with OBPI (20 operated and four non-oper- ated) were assessed a t intervals ranging from 3 to 23 years. Neither patients nor parents reported symptoms sugg estive of neuropathic pain in the aff ected limb. Pain in a scar associated with surgery at 4 years was reported in one case. Restoration of sensory function and accurate stimulus lo calization was documented in 16/20 fol- lowing microsurgical repair (Anand and Birch, 2002 ). \231 Major burns due to electrical (10/19) versus fl ame (3/15) injury (Th omas et al., 2003 ). \231 Preoperative pain. Th e presence of pain prior to amputation was reported in 35% to 75% of patients who developed phantom pain (Krane and Heller, 1995 ; Wilkins et al., 1998 ) . Th e impact of preoperative pain on the incidence or degree of phantom pain has not been assessed in children, although in one series both patients with the most persistent pain ha d also experienced pain prior to amputation (Burgoyne et al., 2012 ) \231 A retrospective chart review of OBPI cases between 1990 and 2002 noted self-mutilati ng behavior in 3.9% (11/280) of infants (McCann et al., 2004 ), which may be a response to sensory loss, and/or painful dysaesthesias in a hypoaesthetic or reinnervated area. Th e in cidence was infl uenced both by the occurrence and the type of prior surgery; increasing fr om 1.4% (2/147) in the non- surgical group, to 6.8% (9/133) in those who had surgery prior to developing self-mutilating behavior. Within the surgical group, the rate was much higher in association with microsurgery involv- ing the plexus (29.1%; 7/24) than following bone or tendon surgery (1.8%, 2/109). Th e median onset 8 months aft er surgery and reso- lution of behavior 4 to 7 months later also suggest a time course related to re-innervation dysae sthesia in at least some patients. Time course Onset of pain in the early postoperative period was reported in 85% (Krane and Heller, 1995 ) and 53% (Wilkins et al., 1998 ) of children with phantom pain, within weeks or months in 20% or 30%, and in one patient from both series the onset of pain was delayed for more than a year. An earlier onset of phantom pain (mean 6 days versus 12.3 days) was n oted in children receiving perioperative chemo- therapy (Smith and Th ompson, 1995 ). Th e mean time to onset of phantom limb sensations was 2.3 years in children with surgical amput ation before 6 years, and 9 years in those with a congenitally absent limb (Melzack et al., 1997 ). \231 A survey of 53 7- to 8-year-old children with OBPI (61% response rate) reported pain in the shoulder, upper arm and neck, particu- larly during writing, in 45% of children. Th e authors attributed pain to musculoskeletal causes (Spaargaren et al., 2011 ). Th ere is a perception that phantom limb pain resolves more rap- idly in children than in a dults, but there is limited supporting evi- dence. Phantom pain is oft en poorly documented in medical case notes (Krane and Heller, 1995 ), and there has been little prospective fol low-up, although in a single case a progressive reduction in the duration, frequency and in tensity of phantom pain episodes was noted over the fi rst 28 postoperative days (McGrath a nd Hillier, 1992 ). In 20 children requiring amputation for cancer, trauma or infection, pa in reduced in intensity and frequency in 13 (with reso- lution aft er months in two and yea rs in four), but was unchanged in seven (Krane and Heller, 1995 ). Phantom limb pain was do cu- mented in the charts of 19 of 25 patients (age 6 to 27 years) aft er cancer-related amp utation, and only two patients (both of whom were older than 18 years and had pain prior to the amputation) still had pain at 1 year (Burgoyne et al., 2012 ). \231 Pain in the aff ected upper limb was reported by 31% of 112 patients, on average 13. 5 (range 5.6 \200\22331.5) years aft er OBPI. In nine patients, local pain was associated w ith non-union of the clavicle (divided to improve access during initial surgery). It is not clear if patients had features suggestive of neuropathic pain, related either to the ini- tial or to subsequent injuries which were relatively common (11% burns, 15% other injuries; Kirjavainen et al., 2008 ). Persistent neu- ropathic pain was reported in one of 70 patien ts with OBPI, now aged 7 to 20 years. \200\230Most participants \200\231 reported discomfo rt in the arm, usually in the shoulder or elbow aft er exercise. Quantitative sensory testi ng demonstrated reduced thermal sensitivity in 16% of patients, but as seen in other studie s, there was better recovery of sensory than motor function (Strombeck et al., 2007 ). Trauma during childhood Brachial plexus injury during childhood Trauma during childhood can result in brachial plexus injury (BPI), but the number of reports and details of associate d pain are limited. Ten children aged 3 to 16 years had BPI and fractures following motor v ehicle accidents. Reconstructive surgery was performed 1 to 8 months later, and there were no reports of deaf- ferentation pain (El-Gammal et al., 2003 ). In a further 25 cases of tr aumatic BPI (2/12 to 14 years) related to motor vehicle accidents, 16 required plexus explo ration and several subsequent orthopae- dic procedures. Two teenagers with root avulsions c omplained of moderate pain, but there are no further details of the nature or time Obstetric brachial plexus injury (OBPI) Th e brachial plexus innervates the upper limb and is formed from the lower cervical (C5,6,7,8) and the fi rst thoracic (T1) nerve roots. Obst etric complications, such as shoulder dystocia or breech delivery can be associated with tr action injuries of the brachial plexus injury in the newborn. Th e associated nerve lesions range in degree from neuropraxia to complete root avulsion, and can aff ect part or all of the plexus. Surgical exploration and repair, where possible, is oft en performed if there is no spontaneous recovery or elbow fl exion by 3 to 6 months (Malessy and Pondaag, 2011 ). Associations between OBPI and pain in later life have been assessed in a number of series, which vary in the outcomes measured and the time since injury. CHAPTER 21 neuropathic pain in children 209 course of symptoms (Dumontier and Gilbert, 1990 ). By contrast, BPI in association with pro ximal humerus fracture in four patients (10 \200\22314 years), was associated with neurolog ical recovery by 5 to 9 months, but all had NP (oft en described as burning) for at least 6 months (Hwang et al., 2008 ). Friedman, 2010 ). Pain is experienced by up to 46% of children with plexiform neurofi broma s (Serletis et al., 2007 ), and increas- ing pain and rapid growth of the tumor may indicat e develop- ment of a malignant nerve sheath tumor (Ardern-Holmes and North, 2011 ). Pain ca n also have signifi cant impact on health- related quality of life in children with NF (Kra b et al., 2009 ) and this condition is also discussed by Mherekumombe and Collins (Chapter 32, this volume). Peripheral nerve injury A series of 49 children with distal upper limb nerve injury were fo l- lowed for an average 2 years and 3 months (Atherton et al., 2008 ). As seen following am putation, an increased proportion of older children developed neuropathic symptoms. No chil dren under 5 years (0/15) had pain or allodynia, whereas the fi ve children with spontaneou s pain were all aged over 12 years at the time of injury. A further eight children aged old er than 5 years had increased sen- sitivity to thermal or pinprick stimuli (Atherton et al. , 2008 ). \231 Tumor invasion or compression of neural structures (spinal cord, spinal nerve roots, nerve plexus, peripheral nerves). As the inci- dence of solid tumors is lower in children, tumor invasion/ compression is less common in children than in adults, but can result in s evere pain with high analgesic requirements. Pain may be diffi cult to control with opioids alone, and in some cases requires regional blockade with local anesthetic (Butkovic et al. , 2006 ; Collins et al., 1995 ; Cooper et al., 1994 ). Spinal cord injury (SCI) Pain aft er SCI in adults is classifi ed as nociceptive (musculosk eletal, visceral, other) or neuropathic (Bryce et al., 2012 ), with the latter categorized as: Cancer treatment-related neuropathic pain Treatment-related NP may occur following surgery (e.g. post- amputation pain; see \200\230Phantom limb pain \200\231 section) or chemo- the rapy. Perioperative chemotherapy has also been associated with an increased incidence and e arlier onset of post-amputation pain (Smith and Th ompson, 1995 ). \231 \200\230At level SCI pain \200\231 occurring in a segmental pattern within three de rmatomes of the neurological level of the injury, and likely due to injury to the nerve roo ts and/or cord. \231 \200\230Below level SCI pain \200\231 occurring more than three dermatomes below th e neurological level of injury, which is a result of damage to the spinal cord, and can occ ur following either complete (no motor function preserved below the level) or incomplete in juries. Peripheral neuropathy occurs in 50% to 90% of those treated with platinum compounds (cispla tin) and almost half with vinca alka- loids (vincristine; Vondracek et al., 2009 ). In 21 c hildren with solid tumors and nine with leukemia aged between 10 and 17 years, neuropathic pain symptoms (paraesthesia, numbness and burning pain in the fi ngers and toes, hyperalges ia and tactile allodynia) com- menced within days of beginning chemotherapy. In addition, p ain was severe (mean baseline VAS >75/100) (Vondracek et al., 2009 ). In a retrospective re view, 174/498 patients developed peripheral neu- rotoxicity with vincristine treatment for acute lymphoblastic leukae- mia (Anghelescu et al., 2011 ). Associated NP occurred in 35%, with recurrent episodes in 16% to 30.6%. Age at diagnosis ranged from 1 to 19 years, but ha d minimal infl uence on the rate of NP, which var- ied from 31% in the 1- to 5-year-group, to 40% in those aged 16 to 20 years. Pain was described as aching, burning, cramping, tingl ing, numbness, sharp, or stinging; and was most common in the lower limbs, back and jaw (An ghelescu et al., 2011 ). \231 Other coexistent causes of NP not related to the spinal lesion (e.g. trigeminal neuralgia). Only 3% to 5% of new cases of SCI are in children, but SCI can occur in neonates as a compl ication of delivery, and tends to have a better recovery than seen at older ages (Pape, 201 2 ). Complete cord lesions are more common in younger age groups, and there is a male predo minance at all ages. Follow-up an average of 15 years following SCI (mean age at injury 14 years, n = 216) reported an overall incidence of pain at any site of 69%, with younger age at injury associated with orthopedic complications such as scoliosis and hip subluxation, a nd older age at injury associated with ankle pain and spasticity (Vogel et al., 2002 ). NP has been reported to be less common if injury occurs at a younger age: 26% (24/91) before 2 0 years of age versus 45% (139/311) at older ages (Werhagen et al., 2004 ). In a series of 31 participants, aged between 5 months and 18 years at the time of SCI, 65% reported chroni c pain, and this had neuropathic features in 19%, but was associated with less interfer- en ce in daily activities than in adults (Jan and Wilson, 2004 ). Treatment of high-risk neuroblastoma with a monoclonal anti- body directed against the tumo r-associated disialoganglioside GD2 can result in severe acute pain in children (Wallace et al., 1997 ; Yu et al., 2010 ). Laboratory studies have confi rmed mechani- cal allodynia a s a result of C-fi bre activation (Xiao et al., 1997 ) and complement activation (Sorkin et al., 2010 ), which is reduced by gabapentin (Gillin and Sorkin, 1998 ). Current clinical t reatment protocols incorporate NP management strategies, such as oral gabapentin, and addit ion of intravenous ketamine or lidocaine if pain is inadequately controlled by intravenous opioid (Wallace et al., 1997 ; see also Rastogi and Campbell, Chapter 48, this volume). Cancer-related neuropathic pain Neuropathic pain occurs in 20% to 40% of adult patients wit h cancer (Bennett et al., 2012 ). Th e overall rate of cancer-related neuropathic pain is l ikely to be lower in children, but as noted earlier phantom limb pain is more common in chi ldren who require amputations for cancer and perioperative chemotherapy. Signifi cant pain may occur in specifi c populations: Metabolic disorders Fabry \200\231s disease Clinical features Pain is a common presenting s ymptom in Fabry \200\231s disease, and oft en has an onset during childhood (Hoff mann et a l., 2007 ; \231 Primary tumors within the nervous system. Neurofi bromatosis type 1 (NF1) and type 2 (NF2) are neurocutaneous disorders associated with tumors aff ecting the central and perip heral nervous systems (Ardern-Holmes and North, 2011 ; Jett and SECTION 4 pain in specific populations and diseases 210 Multiple sclerosis Multiple sclerosis (MS) is a chronic infl ammatory disease produc- ing d emyelination and axonal damage in the brain and spinal cord (Mariotti et al., 2010 ). Pain is common in adults with a prevalence from 57% to 65%, and 43% to 54% have pain at the time of diag- nosis. Patients with MS may experience multiple types of pain (including tonic sp asms, back pain, and headache) but additionally may experience central neuropathic pains. Pintos-Morell and Beck, 2009 ; Ries et al., 2005 ). As pain may be the only feature for som e years, Fabry \200\231s disease should be considered in the diff erential diagnosis of pai n clinic referrals (Pagnini et al., 2011 ). Episodic burning pain and \200\230pins and nee dles \200\231 may initially be restricted to the hands and feet, but pain becomes more pers ist- ent and generalized with time (Hoff mann et al., 2007 ) and can be triggered by change s in environmental or body temperature, exer- cise, or emotional stress (Ries et al., 2005 ). Pain is not only present in over 70%, with a higher incidence in males (80% versus 65%; Hoff mann et al., 2007 ), but it has a signifi cant impact on quality of life (Ramaswami et al., 2006 ; Ries et al., 2005 ). Other features of Fabry \200\231s disease include hypo- o r hyperhidrosis, gastrointestinal disturbances and abdominal pain, angiokeratomas, and opht hal- mological abnormalities (cornea verticillata) (Mehta et al., 2010 ; Ramaswami, 2008 ). \231 Dysaesthetic extremity pain occurs in up to 23% of patients. Pain is burning, typica lly bilateral, oft en in the legs and feet, worse at night, and is exacerbated by exercise. \231 Trigeminal neuralgia is more common than in the general population with a higher rate of bilateral symptoms. \231 Brief electric shock sensations in the back of the neck, lower back, or other parts of body, are brought on by neck fl exion (Lhermitte \200\231s sign). Pathophysiology Fabry \200\231s disease is an X-linked recessive disorder, and females typi cally have less severe symptoms that develop at a later age. Mutations in the GLA gene that encodes the lysosomal enzyme alpha-galactosidase A result in failure to catabolize lipids con- taining alpha-D-galactosyl moieties. Accumulation of glycolipids, including globotriao sylceramide (Gb3) in cells and tissues results in dysfunction of multiple organ systems inc luding heart, kidney, gastrointestinal tract, and nervous system (Hoff mann et al., 2007 ). Small fi bre loss in peripheral tissues and glycolipid accumulation in the dorsal root gan glia or nerves may underlie the neuropathic pain symptoms (Borsook, 2012 ). An estimated 2% to 5% of patients experience their fi rst symp- toms of MS before 16 years of age, with onset usually between 8 and 14 years, and a higher incidence in females (rangi ng from 1.3 to 3 times). Cohorts of pediatric MS patients report sensory symptoms in 13% to 69%, but there is little information about the proportion with neuropathic pain (Ness et a l., 2007 ). Headache is more fre- quent in pediatric than in adult patients with MS (Mariot ti et al., 2010 ). Th e course of the disease may be slower in children, but can have a sig nifi cant impact on schooling and psychosocial function (Ness et al., 2007 ); further reduc tions in quality of life have been associated with increasing age and duration of illness. Th e impact of disease-modifying therapies, such as interferon, on pain symp- toms are not clear (O \200\231Connor et al., 2008 ). Age Reported ages at diagnosis range from 5 to 77 years (Pagnini et al., 2011 ). However, p ain has been reported from 3 years of age in boys and 6 years in girls, with neuropathic fe atures at a mean age of 7.8 3.2 years (Ries et al., 2005 ). Similarly, neuropathic pain was reported in 59% of boys (median 7 years) and 41% of girls (median 9 years) (Hopkin et a l., 2008 ). 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 ).