Upload
vonga
View
214
Download
1
Embed Size (px)
Citation preview
1500
experienced in the management of children in singlespecialty units--eg, neurosurgery, plastic surgery,and bums-which are understandable when most oftheir work may be adult oriented. This lack of
familiarity with the handling of children by allmembers of staff may predispose to mistakes in
management and resembles the situation in adultintensive care units that have to undertake the care ofchildren and in some centres even infants.An encouraging feature of this report is the finding
of local audit meetings to review the management ofinfants and children in 83% of cases. This policy is adirect result of the stimulus to the assessment of the
quality of care provided by the 1987 report and by theincorporation by the Royal College of Surgeons ofclinical audit into approved training programmes forsurgeons. A discouraging feature is the inadequacy ofdata systems within the National Health Service.
Contemporary information on admissions,operations, and deaths is not available. Thus theresults of comparisons between hospitals, districts, orregions are impossible to attain. Whether informationwill be more readily available after 1991 remains to beseen, but it is clear that the data systems will not be
uniform, thereby adding to the difficulties of futureassessments.
As a result of this report it seems that there must be
changes in surgical practice. The child under 3 yearsneeds special skills and facilities and should betransferred to a regional surgical unit. A corollary isthat paediatric services need to be improved in singlespecialty units. These changes can be partly achievedby ensuring that surgeons and anaesthetists do notundertake occasional paediatric practice. This policyhas already been adopted for cardiac surgery.As the health service reorganisation starts to bite,
there may be a reluctance to transfer patients forfinancial reasons. That is to be deplored and couldonly result in a deterioration in the care of youngpatients.The steering group who conducted the NCEPOD
enterprise have produced a thought-provoking reportthat aims to improve the quality of care of surgery andanaesthesia for young patients. It should be read andstudied in detail by every surgeon and anaesthetist,whether established or in training.
1. Campling EA, Devlin HB, Lunn JN. The report of the NationalConfidential Enquiry into Perioperative Deaths 1989. NCEPOD,35-43 Lincoln’s Inn Fields, London WC2A 3PN.
2. Editorial. Accounting for perioperative deaths. Lancet 1987; ii: 1369-71.
HEREDITARY TYROSINAEMIA
Hereditary tyrosinaemia type 1 (McKusick 27670) is ametabolic disorder characterised by progressive liver
damage, hypophosphataemic rickets, and excretion of
tyrosine and its metabolites.1 Clinical severity is variable.The acute form causes death from liver failure in the first
year of life, in the more chronic form, if no treatment isgiven, death occurs at the end of the first decade or later,again from liver failure or from hepatoma. Inheritance is
autosomal recessive but the clinical phenotype can vary evenwithin affected family members. The renal tubular defect,and hence growth and wellbeing, improve on a diet low intyrosine and phenylalanine but liver damage and thedevelopment of hepatoma are not prevented. Liver
transplantation has been successful,2 although renal failuremay be a late complication post transplant because toxicmetabolites continue to be produced by the kidney.3The primary defect in hereditary tyrosinaemia is
deficiency of fumarylacetoacetate hydrolase (EC3.7.1.2), anenzyme that catalyses the last step of tyrosine degradation.1Maleyl and fumaryl acetoacetate accumulate and are
metabolised to succinylacetone, which is found in increasedconcentrations in blood and urine of affected individuals.
They also excrete excessive quantities of 8-aminolaevulinicacid (8-ALA) in their urine, a feature recognised beforesuccinylacetone was isolated. Lindblad and colleagues4showed that succinylacetone, a competitive inhibitor of8-ALA dehydratase (porphobilinogen synthetase), is
responsible for the high 8-ALA excretion. They suggestedthat deficiency of fumarylacetoacetate hydrolase would leadto raised succinylacetone concentrations and so must be theenzyme defect in hereditary tyrosinaemia.
Excretion of 8-ALA is also increased in patients withacute intermittent poryphyria (AIP), symptomatic leadpoisoning, and familial 8-ALA dehydratase deficiency, all ofwhich are associated with peripheral neuropathy.Neurological crises, resembling those seen in AIP, havebeen reported in isolated cases of hereditarytyrosinaemia. 1,5,6 Mitchell and colleagues’ have now
suggested that these episodes of severe, acute peripheralneuropathy are both common and an important cause ofmorbidity and mortality. These researchers reviewed thehospital records of 48 patients with hereditary tyrosinaemiadiagnosed in Quebec province since 1970. 20 patients (42%)had been admitted to hospital on at least one occasion with aneurological crisis. Mean age of onset was 11-7 months(range 1-21) and half the episodes were preceded by aninfection, usually of the upper respiratory tract. Features ofthe crises included hypertonia, pains poorly localised in thelegs and abdomen, weakness (ventilation was necessary oneight occasions), vomiting, seizures, self-mutilation,hypertension, and hyponatraemia. 14 of the 20 patients havedied, in 11 cases directly as a result of respiratoryinsufficiency or problems associated with mechanicalventilation. Peripheral nerve conduction studies were
carried out during eleven episodes and showed reduced orundetectable motor action potentials with normal or slightlyreduced nerve conduction velocity. Axonal degeneration orsecondary demyelination was found on examination ofperipheral nerves from 3 patients; these changes resemblethose in AIP.8 There was no reliable correlation betweenclinical status and 8-ALA excretion in individual cases, butin the patients as a group mean 8-ALA excretion during thecrises was higher than during neurologically symptomlessperiods. In AIP there is also only a loose correlation between8-ALA excretion and clinical status.
There was no evidence that the patients with neurologicalcrises were less well controlled on their diet than thosewithout such episodes. Dietary treatment reduces but doesnot correct succinylacetone and 8-ALA excretion.9 Livertransplantation appears to reduce succinylacetone andcorrect 8-ALA excretion and, although experience is
limited, prevent neurological crises.’A combination of mechanisms may be responsible for the
1501
neuropathological features. Lack of haem synthesis or thetoxic effects of pathway intermediates are two possibilities.5-ALA itself may be directly neurotoxic. In-vitro studieshave shown that -ALA inhibits y-aminbutyric acidrelease10 but at higher concentrations than those found invivo.8 Hepatic haem deficiency may also have an indirecteffect because the plasma concentration of haem determinesbrain levels of tryptophan and therefore the synthesisof 5-hydroxytryptamine.* Increased synthesis of
5-hydroxytryptamine may account for some of the
symptoms and signs.Mitchell and colleagues suggest that, in the nervous
system hereditary tyrosinaemia causes effects that are at leastas severe as those of primary or secondary porphyrias; theonset is also earlier.7 Nevertheless, their patients may beespecially predisposed to neurological crises, or the neonatalscreening programme in Quebec, and therefore earlytreatment, may allow these extrahepatic manifestations tobecome apparent, because these features are not as commonin patients seen elsewhere. However, neurological crises areclearly important and may be an additional reason toconsider early liver transplantation in this condition.
1. Goldsmith LA, Laberge C. Tyrosinemia and related disorders. In:Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic basis ofinherited disease. 6th ed. New York: McGraw-Hill, 1989: 547-62.
2. Tuchman M, Freese DK, Sharp HL, et al. Persistent succinylacetoneexcretion after liver transplantation in a patient with hereditarytyrosinemia type 1. J Inherited Metab Dis 1985; 8: 21-24.
3. Kvittingen EA, Jellum E, Stoteke O, et al. Liver transplantation in a 23year old tyrosinemia patient: effects on the renal tubular dysfunction.J Inherited Metab Dis 1986; 9: 216-24.
4. Lindblad B, Lindstedt S, Steen G. On the enzymic defects in hereditarytyrosinemia. Proc Natl Acad Sci USA 1977; 74: 4641-45.
5. Gentz J, Lindblad B, Lindstedt S, Levy L, Shasteen W, Zetterstrom R.Dietary treatment in tyrosinemia (tyrosinosis): with a note on thepossible recognition of a carrier state. Am J Dis child 1967; 113: 31-37.
6. Strife CGF, Zuroseste EL, Emett EA, Finelli VN, Petering HG, BerryHK. Tyrosinemia with acute intermittent porphyria: &dgr;-aminolevulinicacid dehydratase deficiency related to elevated urinary aminolevulinicacid levels. J Pediatr 1977; 90: 400-04.
7. Mitchell G, Larochelle J, Lambert M, et al. Neurologic crises in
hereditary tyrosinemia. N Engl J Med 1990; 322: 432-37.8. Kappas A, Sassa S, Galbraith RA, Nordmann Y. The porphrias. In:
Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic basis ofinherited disease. 6th ed. New York: McGraw-Hill, 1989: 1305-65.
9. Sassa S, Kappas A. Hereditary tyrosinemia and the heme biosyntheticpathway. Profound inhibition of &dgr;-aminolevulinic acid dehydrataseactivity by succinylacetone. J Clin Invest 1983; 71: 625-34.
10. Brennan MJW, Cantrill RC. &dgr;-aminolevulinic acid is a potent agonist forGABA autoreceptors. Nature 1979; 280: 514-15.
TREATMENT OF HERPES SIMPLEX LABIALIS
After primary infection, herpes simplex virus (HSV)establishes latency, predominantly in the dorsal root ganglia.More than 90% of the UK population show serologicalevidence of previous infection. Periodic reactivation maylead to mucocutaneous lesions; such lesions usually resolvein immunocompetent individuals but occasionally causesevere disease with pain and general malaise. In
immunocompromised subjects there may be a widespreadprolonged active infection. Certain triggers or stimuli maystimulate reactivation, and because of the prodrome manypeople can predict the onset of such an episode.
Little is known about the detailed events, especially theirtiming, after HSV reactivation in human beings. However,it can be assumed that virus reactivates within one or moreneural cell bodies and travels down the axon to the peripherywhere viral particles spread locally to infect cells in the skinadjacent to nerve terminals. Subsequently successiverounds of replication involve more cells, provoking an
immune response and in most cases leading to a
characteristic herpes simplex labialis. In immunocompetentindividuals disease severity ranges from symptomlessshedding to a fullblown herpetic cold sore with crusting andeventual resolution. The role of the immune response in the
pathogenesis of herpes simplex labialis is unclear and thesize of the viral antigenic load at the periphery whenprodromal symptoms first appear is unknown. There maybe considerable interindividual variation in this respect.However, for a given individual there is often a remarkablyconsistent clinical pattern from one reactivation episode tothe next.
A detailed knowledge of this background is important ifantiviral agents such as acyclovir are to be used to best effect.Acyclovir is available in various formats for topical, oral, orintravenous use; the first two are realistic options for herpessimplex labialis. Acyclovir becomes active after
phosphorylation by the HSV-specific thymidine kinase andfurther phosphorylation by cellular kinases to the
triphosphate derivative, which produces premature chaintermination of DNA replication by the HSV-induced DNApolymerase. Although initial evidence indicated thattreatment of herpes simplex labialis with topical acyclovirwas successful,l more recent studies have not shown it to beof much value in immunocompetent individuals.2.3 Thedifficulty would appear to be how to achieve adequate drugdelivery to the deeper cells of the epidermis.The next question is whether oral acyclovir is effective
and if so when therapy should start to contain an individualepisode. Spruance and colleagues showed that the oralpreparation was effective if given prophylactically over abrief high-risk period.4 The same workers have nowconfirmed and extended their earlier studies, and haveshown that some patients may benefit if oral acyclovir isstarted early in the development of herpes simplex labialis.5In a double-blind randomised trial in adults, oral acyclovirreduced the mean duration of pain by 36 % and hastened thehealing time to loss of crusts by 27%. Other features of theprocess were not affected significantly. However, therapymust begin early in the evolution of the lesion; in 97% ofpatients treatment started within an hour of the first sign orsymptom of a recurrence and was initiated by the patient.Presumably the effect achieved by acyclovir is to reduce theviral antigenic load presented to the immune system, andsince viral replication occurs exponentially the window ofopportunity for achieving this goal is very small.
Interestingly, acyclovir delayed the process of evolution tocomplete resolution, so prolonging the duration of residualswelling.
Other antiviral agents that are potentially effective
topically have not been as extensively evaluated. In a similarstudy Spruance et al6 investigated the efficacy of topical15% idoxuridine in 80% dimethylsulphoxide and 5%watery Duration of pain in the lesions and healing time toloss of hard crust were reduced by 49% and 38%,respectively, with little or no other effects on the evolution ofthe process. Essentially similar results had previously beenreported for foscarnet sodium.7 Therapy with these agentsshould also begin as early as possible in the evolution of thedisease. Another possibility is topical interferon beta.Glezerman et al8 recorded a reduction in symptoms and
severity of herpes simplex labialis, although the number ofpatients in the trial was small; this approach needs furtherinvestigation.
Is the cost of producing what is usually a minor and