Struvite stones causing recurrent pain in a child with cerebral palsy: a lesson for a pragmatic approach to pain in children with cerebral palsy and cognitive impairment.

Children with severe cognitive impairments (CI) from any cause, such as cerebral palsy (CP), dysmorphic or chromosomal syndromes, traumatic brain injury, neurodegenerative disorders, and epileptic syndromes, experience pain more frequently than healthy peers. Although it is a common problem, pain is many times unrecognized because these patients are often unable to self- verbalize it or exhibit uncommon behaviors when they experience it, leading to a delay in the recognition and management of pain by the physicians. Untreated chronic or recurrent pain profoundly affects the quality of life of these children and interferes with their performance and adaptive function. Recognition, measurement, and treatment of pain in this population is challenging, and a clinical diagnosis of urinary tract infection or lithiasis may not be immediate.

treatment of pain in this population is challenging, and a clinical diagnosis of urinary tract infection or lithiasis may not be immediate.

Case presentation:
We report the case of an eight-year-old child with cerebral palsy who was admitted for recurrent abdominal pain lasting for one month. While blood laboratory tests were all in the normal range, the diaper examination revealed multiple stones. Urine culture tested positive for Providencia stuartii, a Gramnegative bacteria, and an antibiotic treatment with ceftibuten was started for two weeks. The patient fully recovered in three days without any recurrence. Conclusions urine analysis, to detect an infection, and renal and bladder US, to rule out stones, should be systematically considered in patients with cognitive impairment with unexplained pain. In a pragmatic, concise approach, the basic principles of diagnosis and treatment of pain in children with cognitive impairment are reviewed.

Background
Children with severe cognitive impairments (CI) from anycause,such as cerebral palsy (CP), dysmorphic or chromosomalsyndromes,traumatic brain injury, neurodegenerative disorders, andepilepticsyndromes, experience pain more frequently thanhealthypeers 1 . Although it is a common problem,painis several times unrecognized because these patients areoftenunable to self-report it 2 or may exhibit uncommon behaviorswhenthey suffer, and physicians are sometimes less prone torecognizeit 3 .Physicians should be fully aware ofthis issue since untreatedchronic or recurrent pain profoundlyaffects the quality of life ofthese children and interferes withtheir performance and adaptivefunction 4 . We report struvite stones asthecause of recurrent pain in a child with cerebral palsy andwediscuss the approach to the possible causes of pain inthesepatients.

Case Report
An eight-year-old child was admitted for ve-weeks ofrecurrentabdominal pain. The pain was reported to be present almostdaily,disrupting sleep and causing episodes of agitationandrestlessness, with sudden and incessant crying and increasedheartrate, particularly when the child was moved from the strollertohis bed. The mother reported a partial improvement afteribuprofenadministration. His previous history was remarkablefordevelopmental delay, cerebral palsy, spastictetraparesis,drug-refractory epilepsy treated with vigabatrin,levetiracetam,topiramate, phenobarbital, and the placement of apercutaneousendoscopic gastrostomy six years earlier. The parentsdid notreport any recent history of vomiting, diarrhea,constipation, orfever. A dental evaluation ruled out tooth decay,and an orthopedicevaluation excluded an osteoarticular problem.Laboratory testswere performed to investigate possible causes ofpain, includingwhite blood cell count, glucose, alanineaminotransferase,aspartate aminotransferase, creatinine,electrolytes, bilirubin,amylase and lipase, and they were all inthe normal range.
Physical examination was unremarkable, but stones were notedwhenthe diaper was removed (Fig. 1).
The stones analysis showedstruviteaggregates. A urine culture was performed, testing positiveforProvidencia stuartii, a Gram-negative-bacteria.Therefore,antibiotic treatment with ceftibuten was started for twoweeks,with no pain episodes after three days. A renal ultrasounddid notreveal endoluminal other stones and ruled out a pelvic orureteraldilatation. No additional episodes were noted in thefollowingyear, and follow-up ultrasound scans did not revealvesicoureteralre ux or incomplete bladder emptying.

Discussion And Conclusion
Pain assessment in children with cognitive impairment andchronicillness such as cerebral palsy or syndromic diseases ischallenging,and a clinical diagnosis of urinary tract infection orlithiasis canbe di cult. Remarkably, these patients are prone tobe affected byurinary stones, due to several predisposing factorssuch ashypercalciuria, bone demineralization,dehydration 5 andtopiramate treatment forconcomitant epilepsy 6 .Struvite stones are a subset ofkidney stones, composed of magnesiumammonium phosphate (struvite)and calcium carbonate-apatite, whichform as a result of urinarytract infections with urease-producingpathogens. It is known thatthis type of stone is formed quickly,within a few weeks, in thepresence of urease producingbacteria 7 , from generasuch as Proteus,Providencia, Klebsiella, Staphylococcus. When theproduction ofammonia increases and the urine pH is high, thesolubility ofphosphate decreases, and struvite stones candevelop.
Prevalence of struvite stones in children has decreased overthepast decades: in France, they accounted for 11% of allurinarystones in the 1980s, then reduced to 6% inthe2000s 8 . Inaretrospective analysis, Gnessin et al. 9 showed how immobile patientswithmusculoskeletal anomalies were prone to form struvite stones(18.4%vs. 6.2% in the control group). This event is due to theseveralrisk factors of UTIs in this population, such as incompletebladderemptying, vesicoureteral re ux, catheterization,neurogenicbladder 10 .
Diagnostic workup should include urinalysis, renal andbladderculture, and ultrasonography, which can detect a denselycalci edmass, producing marked posterior acoustic shadowing;indeed, aplain radiograph can also be able to identify radiopaqueimages,appearing as branching calci c densities overlying therenaloutline. Stone culture is recommended to identifyurease-producingbacteria and direct antibiotic therapy, sincebacteria identi edby urine culture do not always match thosecultured from thestone 12 .
Treatment includes an initial antibiotic regimen, suchasamoxicillin-clavulanate or ce xime, before an eventualremoval.Timing and duration of therapy have not beende nitivelyestablished: 1-2 weeks of enteral antibiotics speci cfor urineculture are recommended, if available, with the additionofbroadspectrum parenteral preoperativeantibiotics 13 . Aftertreating the episode, imagingand urine cultures should be repeatedwithin 3 months to con rmstone-free status or identifyrecurrence 11 . Pain recognition.
Since the response to pain and its expression in thispopulationis heterogeneous, recognition may be delayed; however,theexperience of pain is often persistent and frequent, sometimesevenon a daily basis 14 .
Speci c pain assessment scales (r-FLACC 15 , INRS 16 , NCCPC-R 17 , PPP 18 ) have been introduced based ontheobservation of pain behaviors, none of which are recommendedonanother, however all being more precise than genericpainassessment tools 19 .Themain advantage of these scales is that they include physiologicandbehavioral items aiming at complete pain recognition. Thesescales'main disadvantage is that they require minimal speci ctrainingand are more time-consuming. The revised Face, Legs,Activity, Cry,Consolability (r-FLACC) scale (Table 1) is based on 5items, with a score rangingfrom 0 to 10; it has been rated bynurses and physicians as havinghigher clinical utility in terms ofcomplexity, compatibility, andrelative advantage when compared tothe Non-Communicating ChildrenPain Checklist-Postoperative Version(NCCPC-PV) 20,21 .The latter appears more suitable inthe absence of a pre-de nedpain assessment with parents, asrequired by the revised FLACC.Overall these scales should be usedaiming at individualization ofeach child speci c pain behaviors,such as the misleading"freezing," laughter or selfinjuriousbehaviours, establishing ashared knowledge, and common languagewith parents. Broader use ofthese tools can help go beyond falsebeliefs such as the allegedindifference to the pain of some ofthese children or the"neuro-irritability" sometimes used to explainincreased tone andmovement. Remarkably, pain assessment andmanagement in thesechildren should never disregard a positiveinteraction with theirparents, which remain the best proxy measureof their kids'pain 22 . Amilestonepaper 23 described howexperiential learning leads mothers to "develop asense ofknowledge"of their children, managing to be competentinterpretersand translators of their sons'pain and nding the bestbalancebetween pain treatment and adverse consequences ofpainmedications. Health professionals should support this processsothat recognition and action based on parent's concerns willhelpreach the best pain-related decisions about their children.Thisprocedure requires a speci c attitude of empathy and theabilityto listen. The role of parents is also crucial indistinguishingfear and anxiety from pain. In children with moderateto severecognitive impairment, anxiety, and fear have been shown toplay anessential role in procedural pain and worsen its perceptionandimpact.. Their relevance should not be underestimated and shouldbeapproached in a holistic perspective 24 . A recent study demonstratedasigni cantly different cortical activation patternduringvenipuncture in children with CPI compared to healthypeers,suggesting that a possible lack of frontal to limbicareasconnection may cause an impaired controlofemotions 25 .
Pain assessment and diagnosis.
A proposal for a possible diagnostic workup for pain inpatientswith cognitive impairment is shown inFig. 2.
When trying to address the different causes fromanepidemiological perspective, based on the frequency ofevents,various aspects should be considered.
The issue of painful contractures and dystonia should bemanaged,with a child neurologist and physiotherapist in order tooptimizethe use of splints, tutors, as well as, the need forbaclofen orbotulinum toxin treatment. Intractable pain due to adislocated hipmay be approached with an intra-articular steroidand a topicalanesthetic injection, which may allow months ofwellbeing 26 .
The gastrointestinal tract is one of the most common sourcesofpain among these patients. Impaired gastrointestinalmotility,insu cient hydration, and immobility lead toconstipation in upto 75% of patients, and an adequate amount o ber should beprovided to them in a delicate balance through whichhigh berformulas can slow down gastrointestinalemptying 27 .
Gastric emptying in children with a PEG and Nissenfundoplicationmay be delayed causing pain and nausea. On the otherhand, anaccelerated gastric emptying can be facilitated by anextensivelyhydrolyzed formula, but can cause either a persistentunpleasantsense of gastric emptying or even a dumping syndromewith anirritable, sweaty and restless child with hypoglycemia twohoursafter the meal. In this perspective, a trial with adifferentfeeding should always be thought 28 .
GERD should be considered an unlikely cause of pain inpatientsalready treated with adequate dosage proton-pumpinhibitors, whosetherapy can be continuedinde nitely 29 . Ifpresent, the PEG tube should beexamined to rule out gastrostomyinfections, granuloma,dislocation, occlusion, or buried bumpersyndrome.
Even when no speci c concerns are identi ed, adentalassessment should be deemed if not already performed in thepastyear 30 .
Osteopenia is found in up to 95% of non-ambulating childrenwithcognitive impairment, 20% will experience a femoral fractureduringtheir life 31 ,with ade nite risk of recurrence. Radiography or bone scan shouldbeperformed to rule out fractures or hip dislocationswhenpositioning, bathing, or dressing are di cult because ofthepain. If osteopenia-related back pain is suspected, especiallyincase of pain that worsens at night or while the child is moved,anex juvantibus trial with bisphosphonates maybeconsidered 32 . Lastbutnot least, the urinalysis to detect an infection and renalandbladder US to rule out stones should besystematicallyperformed 33 .
A consult with a child neurologist with speci c experienceinthe eld should always be considered when a clear cause isnotidenti ed, to rule out and treat possible dystonic disorders,ormore rare epileptic equivalents that need a speci ctherapeuticapproach such as tetrabenazine 34 .
Once ruled out the above causes, an empirical medicationtrialdirected to neuropathic pain should be evaluated whileconsideringfurther invasive diagnostic tests in children withlong-standingirritability and pain behaviors.
Remarkably some syndromes, as the Noonan syndrome,arespeci cally associated with an higher risk ofneuropathicpain 35 .
Given its safety and its effect on peripheral andcentralneuropathic pain, visceral hyperalgesia, autonomicdysfunction andspasticity in adults, gabapentin is an off-label butreasonable rst-line choice 30 .The bene t of this therapy wouldindirectly con rm theneuropathic source of pain and avoidrepeating testing andinterventions for months in search of a cause,which often delaysappropriate pain management.
Sleep quality should be addressed as this is a relevant issueinchildren with chronic or recurrent pain 36 . Remarkably, a sleep disorder canalsobe mistaken for chronic pain, due to the reciprocal in uenceofthese domains 37 .Finally, in cases of extreme pain anddystonia that do not respondto conventional treatment, thesymptomatic intranasal use ofdexmedetomidine at home could beconsidered in the setting ofpalliative care 38 Tables   Table 1. Revised Face, Legs, Activity, Cry, Consolability(R-FLACC) scale (from Malviya etal. 15 ).  CAREchecklistEnglish.docx