July 17, 1989 Vol. 151 THE MEDICAL JOURNAL OF AUSTRALIA 100 CASE REPORTS Mitochondrial encephalomyopathy with corticosteroid dependence Sasson S. Gubbay, Graeme J. Hankey, Noel T. S. Tan and Julia M. Fry ABSTRACT A 12-year-old boy with corticosteroid-responsive mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) is described. His mother proved to have an asymptomatic mitochondrial myopathyon examination of a musclebiopsyspecimen.Three weeksafter the onset of vomiting, headache, ataxia and visualand speech impairment, he presented with a background of somatic growth retardation, deafness and school failure. Examination revealed disorientation, dysphasia, dyspraxia, optic atrophy, hemianopia,hemiparesisand sensory inattention. A cranial computed tomographicscan disclosed a large, low-density area, which was consistent with infarction, in the left posterior hemisphere and marked calcification of the basal ganglia bilaterally. Within two weeks of the commencement of corticosteroid treatment, the neurologicaldysfunction resolved. Attempts to decrease the dosage of dexamethasone caused an exacerbation of symptoms repeatedly. Twoweeks after ceasing corticosteroid therapy, the patient developed a serious neurological relapse and a new, large,low-density area, whichresembled an infarction, in the right posterior hemisphere on a computed tomographic scan. The reintroduction of corticosteroid therapy again resultedin the rapid resolution of all symptoms. It becameevidentthat the patient had an exquisitely sensitive corticosteroid dependency, whereby a reduction in the dexamethasone dosage of even 0.25 mga day causedconfusion, headaches and increasing lacticacidaemia. Although it is difficult to assess the impact of various therapies in MElAS because of the episodic natural course of the disease, this remarkable corticosteroid responsiveness alsohas been noted in four previously reported patients with MELAS syndrome; therefore, it would seem reasonable to suggestthat corticosteroid therapy now should be considered as standard treatment for this condition. However, corticosteroid therapy in other forms of mitochondrial disorders still awaits careful evaluation. (Med ) Aust 1989; 151: 100-108) itochondrial diseases are a heterogeneous group of disorders in which mitochondrial dysfunction produces clinical disease. Mitochondrial myopathies are mitochondrial diseases in which the clinical presentation and course are determined by the pathological involvement of extraocular and/or other skeletal muscles. Frequently, they are hereditary disorders that are characterized by ptosis, external ophthalmoplegia, proximal weakness and lactic acidaemia. With evolution of the disease process, multisystem (for example, retinal, peripheral-nerve, cardiac) involvement may become manifest but, in other cases, the disease appears to remain restricted to one tissue. 1 Mitochondrial encephalomyopathy (or cytopathy) is a multisystem mitochondrial disease in which both muscles and the central nervous system are involved but, in contrast to the mitochondrial myopathies, central-nervous-system dysfunction dominates the clinical picture." Morphologically, skeletal-muscle mitochondria are non-specifically abnormal. Histochemical examination of muscle biopsy specimens usually shows subsarcolemmal accumulations of abnormal mitochondria as a characteristic abnormality that is termed "ragged, red fibres". Biochemically, defects of substrate utilization, oxidationphosphorylation coupling or the respiratory chain are present within the affected tissues.' The respiratory chain is responsible for the transfer of reducing equivalents from oxidized nicotinamide adenine dinucleotide (NADH) and succinate, which are generated by the oxidation of metabolites by way of the tricarboxylic-acid cycle, to molecular oxygen. It consists of four multienzyme complexes that are termed M Royal Perth Hospital, Wellington Street, Perth, WA 6000. Sasson S. Gubbay, MB BS, MD, FRACP, Neurologist. Graeme J. Hankey, MB BS, FRACP, formerly Neurology Registrar. Noel T. S. Tan, MB BS, FRCPA, Neuropathologist. Department of Clinical Chemistry, Princess Margaret Hospital for Children, Roberts Road, Subiaco, WA 6008. Julia M. Fry, BSc(Hons), PhD, Senior Technologist. No reprints will beavailable. Correspondence: Dr G.). Hankey, Department ofClinical Neurosciences, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, Scotland. complex I (NADH-coenzyme Q oxidoreductase), complex II (succinate-coenzyme Q oxidoreductase), complex III (coenzyme Qcytochrome c oxidoreductase), and complex IV (cytochrome c oxidase), which are embedded in the inner mitochondrial membrane, d an two molecular-weight redox carriers, coenzyme Q and cytochrome c.' The energy that is generated by the oxidation-reduction reactions of the respiratory chain is stored in an electrochemical proton gradient (energy pool), which can be coupled to the synthesis of adenosine triphosphate from adenosine diphosphate and inorganic phosphorus by adenosine triphosphate synthetase (complex V).' This process is called respiratory chain-linked oxidative phosphorylation or, merely, oxidative phosphorylation. Respiratory-chain dysfunction d pro uces symptoms and signs of disease that primarily are a result of energy insufficiency. The specific clinical picture most likely depends on the degree of enzyme deficiency and the specific tissue(s) that is affected. Mitochondria contain their own DNA and a complete system for its replication, transcription and translation. However, the majority of the mitochondrial proteins are coded by nuclear DNA; only 10010 are coded by mitochondrial DNA (mtDNA).' To date, 13 polypeptides (seven subunits of complex I, one subunit of complex III, three subunits of complex IV and two subunits of complex V) have been identified as being coded by mtDNA.6 Mitochondrial DNA is inherited primarily from the mother because sperms have few mitochondria and almost all the mitochondria of the zygote are derived from the ovum.' Therefore, genetic information from the mitochondrial genome is transmitted only from women to either male or female offspring, hence the term "maternal inheritance". A disorder that is transmitted through the mitochondrial genome should show a maternal inheritance pattern and cannot be transmitted by affected men. Most human mitochondrial disorders have occurred sporadically but several large sibships have been reported where cytoplasmic (maternal) inheritance appeared likely,' and there have been other reports in which inheritance patterns were more consistent with an autosomal pattern, which would implicate the nuclear genome as at fault. 8 Twenty per cent of patients with mitochondrial myopathies have similarly affected relatives, and the rate of maternal-to-paternal transmission is approximately nine to one." The increased incidence of maternal, as opposed to paternal, transmission in familial mitochondrial myopathies suggests that these disorders may be caused by mutations of mtDNA. 7 Human mtDNA has been estimated to have a mutation rate of approximately IO-times that of nuclear DNA.' Holt et al. recently have demonstrated that mtDNA heteroplasmy can occur in humans and that human disease may be associated with defects of the mitochondrial genome." Symptoms that are referrable to the central nervous system in mitochondrial encephalomyopathy vary widely. This apparent heterogeneity may not only possibly reflect mitochondrial inheritance but also variations in the degree of deficiency of each of the five enzyme complexes, or the varying metabolic consequences that may be seen with the same degree of deficiency of each of the enzyme complexes. Nevertheless, three distinct syndromes of mitochondrial encephalomyopathy are distinguishable on clinical grounds: the Kearns-Sayre syndrome; 11.12 myoclonus epilepsy with ragged, red fibres (MERRF);I3·14 and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS).'s Hybrid forms hi h ti b h f f W IC some Imes ear t e eatures 0 two-or-more subtypes such as MERRF and MELAS do occur. 16 D m-Itt N.H.s. Smg to blets 100 plus 5 Repeats aQ. .. . ~,., 00 lus 1 Repeo'l LaSlX ~:H:s: ---. - - - ~- - Hs4 Omg tablets " ' 1 P2 Lompou es S x m 20mg ,nleel,on d AUGUSl 1989. 5 DAON IL AND LASIX· F •m..r... _ fonnot N. H. S. 1ion "wa .lla bl. 0tI t~ ..... _ ORIGIN Al .PRODUCT • 0.. re-g;I '.'1'd ........ , "'- --'1" aftd La,,,. I.. ,.,;.~ . 110dem~ ~ ."..~ .... 01byHoech.1 AG. u "- . ' ;",le. ' """'""9 .... odo..... 10 hstrB Hoec Um~ed. ;nt£} ~t ~_,_ Inc. hst Australlo elbccme VIC J Kilda Road, M M 1031 S221212 .... . . July 17, 1989 Vol. 151 THE MEDICAL JOURNAL OF AUSTRALIA 102 Daonif active ingredient: glibenclamide Abridged Product Information Indications: Initial and change over therapy for maturity onset diabetes. Actions: The pharmacological effects ofglibenclamide oncarbohydrate. protein andfat metabolism are those of insulin. whose secretion itstimulates. Precautions: Because ofits high efficacy dosage. adjustment is particularly important to avoidhypoglycaemia. Excessive alcohol intake. Also. see interactions. Contralndlca· tlons: Type 1diabetes. serious impairment ofrenal function , diabetic coma and pre-coma. Use In Preg· nancy & Lactation: (Category C) Oral hypo· glycaemics are not recommended during pregnancy and lactation. Adverse Reactions: Mild gastrointestinal disturbances are rarely encountered . Hypoglycaemia due to dietary habits and dose . Allergy, very rarely haemoipoietic reactions. Inter· actions: Combination with the following may cause hypoglycaemia: long acting sulphonamides, tuberculostatics (ethionamide). phenylbutazone, salicylates, chloramphenicol, tetracycline, compounds. cyclophosphamide, MAO inhibitors, B-receptor blockers orcoumarin derivatives. Long term treatment with corticosteroids and thiazides may cause some deterioration in control. Adult Dosage: Commencing at 2.Smg per day, the dosage range is: 2.Smg-20mg per day. Up to10mg taken asa single daily dosage. Pr8lenlaUon: Smg white oblong tablets. PBS 1001S repeats. Further information available onrequest. LasiX active ingredient: frusemlde Abridged Product Information Composition: Frusemide. Indications: Cardiac, renal and pulmonary oedema. hypertension of mild or moderate degree. Precautions: Before diuretic therapy is started. hypovolaemia. hypotension or greatly reduced serum electrolytes should be corrected. Although Lasix seldom causes hypokalaerna, a high-potassium diet is an advantage. During long-term treatment. serum electrolytes. creatinine. non-protein nitrogen, serum urea, etc should be checked regularly. Appropriate surveillance and replacement therapy are essential. Administer with caution during pregnancy and lactation. Contraindlcatlons: Renal failure due topoisoning with nephrotoxic or hepatotoxic substances or when accompanied by hepatic coma. Severe hypokalaemia. hyponatraemla. hypovolaemia and subseguent hypotension. Use In Pregnancy: (Category C); USI In lactation: Frusemide passes into the breast milk. Adverse reactions: Disturbances of water and electroly1e balance may arise particularly with high doses. Possible complications include thrombosisand embolism. Allergic reactions, such as rashes or thrombocytopenia. areencountered only occasionally. Extremely rare, afew instances of leukopenia. acute pancreatitis. anaphylactic reactions orimpainment ofhearing have occurred. Great caution should beexercised in administering curare or its derivatives to patientsundergoing Lasix therapy. Dosagl, Adults: Lasix hasa wide therapeutic range. Oedema: 2D-400mg, with 2D-40mg once daily sufficing inmost cases. Hypertension: 4D-BOmg is recommended. Children: 1-3mg/kg day upto40mg max. Presentation: Tablets 40mg: SO's: tablets 20mg: 50·s. 10mg/mL oral solution; 30mL: Ampoules. 20mg/2mL: S·s.Polson schedule: 84. Further Inlonmatlon available on request. Hoechstl'B Hoechst Australia Limited Incorporated in A.C.T. 60651 Kilda Road, Melbourne. VIC 3004 Daoni~ and Lasi~ are registered trademarks of Hoechst AG. HAL86PI/Slaner The MELAS syndrome was not recognized as a discrete entity until 1984, when Pavlakis et al. gathered nine cases from the medical literature and added two of their own. IS All cases shared the features of ragged, red fibres on examination of a muscle biopsy specimen, normal early development, short stature, seizures and hemiparesis, hemianopia or cortical blindness. Lactic acidaemia was a common finding. Four familial cases of MELAS have been reported - two sibling pa irs,":" one mother-and-son pair " and a family with four normal sons and an affected mother, son and daughter." MELAS appears to be familial but the mode of inheritance is uncertain. Transmission may be either by mendelian or maternal inheritance with defects of either a nuclear or mitochondrial genome." The coordinated actions of both the nuclear and mitochondrial genomes are required for the biosynthesis of a normal respiratory-enzyme complex . If either is dysfunctional, the system fails. Many cases of MELAS now have been reported and in-vitro stud ies of muscle mitochondrial metabolism in these patients have identified a variety of functional biochemical defects in the mitochondrial respiratory chain. I , J . 22 The defects that have been reported most commonly have involved respiratory-chain complex pHS or complex IV/ 9 both of which contain polypeptide subunits that are encoded by mitochondrial genes." As specific biochemical defects in mitochondrial function are being identified, future efforts also will be directed at molecular studies in mitochondriopathies to define the underlying mutations and the products of mutated genes (defective respiratory-enzyme polypeptides) and to uncover the biochemical mechanisms which determine and/or modulate the clinical manifestations of the genetic disorders. Therapeutic experience in MELAS is limited but corticosteroid-responsiveness has been reported in four cases of presumed MELAS.2.30-32 We report here a boy with MELAS syndrome who repeatedly has shown a substantial clinical response to treatment with corticosteroid agents. Several attempts at corticosteroid withdrawal have resulted in a relapse of the disorder. FIGURE 1: Plain cran ial computed tomographic scan showing a low-density area in the left temporooccipital region and calcification of the basal ganglia bilaterally. bilateral optic atrophy, an incongruous right homonymous hemianopia and right sensory inattention were present. A cranial computed tomographic scan showed heavy calcification of the basal ganglia bilaterally, and a large area of low density in the periphery of the left temporal, parietal and occipital lobes (Figure I). Electroencephalography revealed lowto-moderate amplitude Band d activity on the left side, which was more-prominent posteriorl y. Cerebrospinal-fluid examination was normal , apart from a mildly elevated protein level of 0.60 giL (normal, 0.15-0.45 giL). On Day 5, he developeda right hemiparesis and right hemianaesthesia. A cerebral glioma was suspected and, therefore, dexamethasone therapy (5 mg twice a day) was instituted. The patient's vomiting subsided the following day and over the next two weeks his hemiparesis, aphasia and apraxia resolved. On Day II, he suffered two right-sided partial motor seizures that prompted treatment with phen ytoin (200 mg a day). Left temporal epileptiform activity and bilateral slow-wave activity were present on a repeat electroencephalogram (subsequent electroencephalograms five and II months later gave normal results). The daily dose of dexamethasone was reduced gradually to 2 mg by Day 19, when the patient was discharged home. Clinical record Subsequent investigations A 12-year-old boy presented on July 1,1983 after the onset of intermittent morning vomiting that was associated with headache. gait ataxia, wordfinding difficulty and blurred vision in the right visual field. After a normal birth and early infancy, he had walked at 14 months of age and his speech had developed normally. Since the age of three years he suffered from gradually progressive left-sided deafness and his academic record was poor. Examination revealed a physically underdeveloped right-handed boy who weighed 20 kg. He was disorientated, mildly dysphasic and dyspraxic bimanually with slow mentation. Mild An electrocardiogramshowed non-specificT-wave inversion in the anterior chest leads and STsegment depression in the lateral chest leads. Echocardiography gave normal results. Audiometry revealed severe bilateral hearing loss of 70-80 db. Visual evoked potentials were of low amplitude but of normal latencies bilaterally. The resting plasma lactate level was elevated significantly (2.2-5.3 mmol/L; normal, 0.3-1.3 mmol/L) throughout his illness. Blood leukocyteand plasma lysosymeenzymelevelswere normal, as were plasma long-chain fatty-acid and carnitine levels. Nerve conduction studies were normal but THE MEDICAL JOURNAL OF AUSTRALIA Vol. 151 July 17, 1989 • 103 FIGURE 2: Cryostat section. Succinate dehydrogenase preparation showing positively stained crescents at the periphery tbsr» 100 I'm). FIGURE4: Plain cranial computed tomographic scan showing a new low-density area in the right temporooccipital region, and the older area of low density in the left temporo-occipitallobes with dilatation of the posterior horn of the left lateral ventricle. Calcification of the basal ganglia is present bilaterally. FIGURE 3: Elecrronmicrograph showing mitochondrial inclusion and circular arrangement of cristae. (Magnification x 54 900, reduced to 55%.) needle electromyography showed patchy myopathic changes in the right biceps brachii muscle. A biopsy of the left vastus lateralis muscle revealed increased variation in muscle-fibre diameter (20-80 Iilll) and ragged, red fibres on examination of a Gomori's trichrome-stained preparation. Dark fibres in the NADH and succinate dehydrogenase preparations were suggestiveof a mitochondrial abnormality (Figure 2). Electronmicroscopy disclosed large accumulations of mitochondria in the subsarcolemmal region. Abnormal variations were present in the structure of the cristae with electron-dense inclusions within some mitochondria (Figure 3). Biochemical analysis was performed on the muscle. The muscle carnitine concentration was 0.92 nmol/mg wet weight (normal, 0.6-4.0 nmol/ mg wet weight) and 38.0 nmol/mg non-collagen protein (normal, 10-50 nmol/mg non-collagen protein). The muscle cytochrome oxidase duplicate concentrations were 1.28 and 1.34 nmol/min-mg' wet weight (normal, 1.33-2.17 nmol/rnin-rng' wet weight) and the concentration of muscle carnitine palmitoyl transferase, by means of the exchange method, was 17.9 nmol/min-mg' wet weight (normal, 12-28.5 nIDol/min'mg-' wet weight). The fibroblast cytochrome oxidase concentration was 24.6 nmol/min·mg-' protein (normal, 21.5-25.7 nmol/min'mg-' protein) and the rolenone-insensitive NADH cytochrome c reductase concentration was 25 nmcl/min-mg' protein (control, 20 nmol/min·mg-' protein). Studies of pyruvate and malate oxidation did not reveal any decreases in C"-pyruvate and uniforrn-C' malate under all the conditions that were tested. No obvious defect was apparent in the fibroblast respiratory chain. A biopsy specimen of the left vastus lateralis muscle from the patient's mother showed an increasein the variability of muscle-fibrediameters (30-90 um) but no ragged, red fibres were identified. Electron-dense inclusions, which were similar to those that had been seen in the patient's muscle, were seen infrequently in mitochondria on electronmicroscopy. His mother's serum lactate level was normal. Progress On September 15, 1983, the patient developed a headache which responded immediately to an increase in dexamethasone therapy from 2.0 to 2.5 mg a day. The dose then was reduced very gradually and the drug finally was ceased by mid July 1984. However, two weeks later, the patient experienced the acute onset of headache, ataxia, vomiting and confusion. He was drowsy and manifested left sensory inattention and a dense, incongruous left homonymous hemianopia. A cranial computed tomographic scan showed a new area of diminished attenuation in the right temporo-occipital region in addition to the old left temporoparietal-occipital lesion (Figure 4). Dexamethasone therapy was reintroduced and a rapid improvement in the patient's mental state was apparent within hours. Two weeks later (mid August 1984), his neurological examination was normal apart from bilateral optic-disc pallor. By January, 1985, it had become obvious that the patient had an exq uisitely sensitive corticosteroid dependency. A dosage of dexamethasone of 1.0 mg a day proved to be a satisfactory maintenance dosage, whereas 0.75 mg a day of dexamethasone resulted in confusional episodes, sometimes with headache and nausea. On October II, 1987, the patient presented with diabetic ketoacidosis. His arterial pH was 6.97 and his plasma level of glucose was 72 mmol/L (normal, 3.3-5.5 mmol/L), of bicarbonate was 6 mmollL (normal, 22-30 rnmol/L), of lactate was 5.3 mmol/L (normal, 0.3-1.3 mmol/L) and of ketones was 1.5 mmol/L. The hyperglycaemia responded promptly to an insulin-and-dextrose infusion but the ketoacidosis persisted for four days. Upon his regaining awareness, a new left homonymous hemianopia was detected. Therefore, the dose of dexamethasone was increased temporarily to 3 mg a day and then gradually was reduced to his maintenance dosage of I mg a day after two weeks, by which time the hemianopia had resolved. Discussion This patient manifested somatic growth retardation, deafness, encephalopathy with borderline mental deficiency, stroke-likeincidents and seizures together with lactic acidosis, "ragged, red fibres" in skeletal muscle and multiple low-density areas and bilateral calcification of the basal ganglia on cranial computed tomographic scan. The clinicopathological findings meet the criteria for the MELAS syndrome." Non-specific calcification in the basal ganglia, especially the globus pallidus, often is described in cases of mitochondrial encephalomyopathy;':":" its significance is not clear. The treatment of mitochondrial encephalomyopathy aims to minimize the energy demands on dysfunctional mitochondria and to manipulate the mitochondrial milieu Prescribing Information COMPOSITION Cefotaximc sodium Description. Claforan is a semisynthetic cephalosporin for usebyinjection only. It is a whiteto paleyellow crysta1line powder, solublein water(greaterthan 20%)and producesa paleyellow solution. The pKa valueis 3.35. The pH of the formulated material is4.5 to 6.5. Raising the pH (as byadditionofstrong base)will resultin an intenseyellow colourand possible degradation. The sodium content of the formulated material is approximately 2.09mmol (48mlllper g of Claforan. Pharrnaco1otlY pharmacokinetics. Claforan isverypoorlyabsorbedafteroral ingestion and thereforeis administered byintramuscular and intravenous injection. Following intramuscular administration of a Ig dose of Claforan to normalvolunteers. the mean peak plasmaconcentration at 30 minutespost administration wasapproximately 20mcgImL. Afterintravenous dosage.administered overa 2-5minuteperiod,a peak plasmalevel of approximately 102mcglmL was obtained.For intravenous infusion administered overa 30 minuteperiod,a mean concentration of approximately 40mcg/mL was obtained.The respective concentration declined as follows: (111I IV IVinfusion 1M I hour 2Omcg/mL 14 15 2 hours 8 4 10 3 hours 1.8 1.5 4.0 Repetitive dosingshowed no significant evidence of accumulation. The meanelimination half-life after intramuscular administration was 1.45hour. 1.06huur after rapid intravenous injection. and1.13hour after30 minuteintravenous infusion. Claforan is desacetylated in the body, withconcentrations of the desacetyl metabolite appearingboth in the bloodand urine.The processis rapidwithmeasurable levels detectablein the plasmawithin 5 minutesafteradministration. The desacetyl metabolite is microbiologically activeagainsta similarspectrum of bacteria, but is lessactivebya factorof 2 103. The desacetyl metabolite has alsobeen shown to be degraded 10an open lactoneform.This metabolite is not microbiologicaDy activeand onlyverylowlevels can be detectedin the plasmaafteradministration of normaltherapeutic doses.Studiesin humanvolunteers measuring radioactive recovery in the urinehave indicated that 20 - 36% of administered drug isexcretedas unchanged drug, 15 - 25% as the desacetyl metabolite and 20 - 25% as the openedlactonederivative of the desacetyl metabolite. Claforan is 32 - 44% boundto plasmaprotein.while the desacetyl derivative is onlyboundbyhalfof this value. The affinity for plasmaproteinsis low, as evidenced bythe highurinaryclearance. 85 - 90% of the administered dose is recovered in the urine,while the faeces accounted for 7 - 9.5% of the recovery total. 70 - SO,. of the administered dose is recovered in the first4 hoursafteradministration. The elimination half-life of Claforan is 0.7 - 1.3 hours,while that of the metabolites is approximately 2 hours. Meanpeak urinaryconcentrations obtainedafter Ig administration of Claforan intravenously, intramuscularly and byintravenous infusion at 4 hours were1309mcgImL, 903mcg/mL. and 599meglmL, respectivel~ Following IVadministration of Ig Claforan mean peak concentrations of 35mcg/mL wererecordedin the bileafter30 minutesand declined103.30mcg/mL after4 hours.Concentrations of Claforan in the CSF are considerably lowerthan in the plasma. ~-onowing Ig intramuscular dosagethe meanplasmaclearance is 318mL/minll.73m!Studieshaveshown that concomitant use of 0.5% lignocaine solutiondoes not affectthe pharmacokinetics or bioavailability of Claforan formintramuscular administration. Interaction studiesbetween parenterally administered Cla/oran and orallyingested probenecid, showed that probenecid increased the retentionof Claforan by14 - 40%,and decreasedthe renalclearance by 11-32%. Mkrobio1otlY. Atplasmaconcentrations achieved withthe recommended therapeutic doses Claforan is usually activeagainstthe following micro-o'lf;lOisms in vitro: Gram-positive: staphylococci, including penicillinase producing strains.Streptococcuspyogeoes. Diplococcus pneumoniae, (Streptococcus faecalis are mostly resistant). Gram-negative: Escherichia coli, Klebsiella pneumoniae. Haemophilus influenzae. Neisseria sp.• gonococcus (including penicillin resistantgonococcus), Proteus mirabilis, Proteus mO'lf;lOii, Proteus vulgaris, Proteus rettgeri. Serratia marcescens. Approximately 25% of Pseudomonas aeruginosastrainsand 43% of bacteroides strains havean in vitro MIC olless than or equalto 16mcg/mL. There is in vitroevidence of synergy between Claforan and aminoglycoside antibiotics suchas gentamicin againstsomespeciesof Gram-negative bacteriaincluding somestrainsof pseudomonas. Claforan is resistant10manyB lactamases (penicillinases and cephalosporinases). Claforan's bactericidal effectis due 10inhibition 0: cellwall synthesis. Sosceptibility tests. Quantitative methodsthat requiremeasurement of wne diametersgivethe most preciseestimatesof antibiotic susceptibility. Interpretation involves correlation of the diametersobtained in the disc test withminimum inhibitory concentration (MIC) values for Claforan. Reportsfromthe Iaboralory giving results of the standardised singlediscsusceptibility test usinga 30meg Claforan discshouldbe interpretedaccordingto the following criteria: Susceptible o'lf;lOisms producewnes of inhibition 23mmor greaterindicating sensitivity and that the testedorganism is likely to respond10therapy. O'lf;IOisms of intermediate susceptibility producewoes of inhibition 1510 22mm,indicating that the tested organtsm would be susceptible if high dosage is used or ifthe infection is confined 10tissuesand fluids (eg.urine)in which highantibioticlevels are attained'. Resistant organisms producezones of 14mmor less.indicating that other therapyshouldbe selected. A bacterial isolatemaybe considered susceptible ifthe MIC valueforClaforan is lessthan 16mcglmL. Organisms are considered resistantifthe MIC value is greaterthan 32mcg/mL. INDICATIONS '\\'eatmentof infections causedbysusceptible mkroo'lf;lOisms. Efficacy has been demonstrated in the following: infections of the respiratory tract (upper and lower): infections of the urinarytract: septicaemia (cefotaxime has been administered withgentamicin for septicaemia. and such therapymaybe institutedpriorto isolation of causative o'lf;lOism): intra-abdominal infections: gonorrhoea (including gonorrhoeacausedby B lactamase producing strainsof N.gonorrhoeae): ENTinfections: soft tissueinfections: boneand jointinfections: meningitis (Claforan shouldbe combined with chloramphenicol in the initialtreatment of meningitis in adultsand childrenpendingthe availability of cultureand sensitivity results.appropriatetherapy shouldthen be instituted, it shouldnot be usedeither as a single drug in initial therapy or in infants andneonates). InseriouscasesClaforan maybe usedbeforethe resultsof sensitivity testsbecome available. Claforan maybe usedfor the prevention of postoperative infection in obstetrical surgery, vaginal hysterectomy and abdominal hysterectomy (see Dosage and Administration). CONTRAINDICATIONS Claforan shouldnot be used in patientswithknown hypersensitivity 10 cephalosporins. Cautionshouldbe exercised in penicillin allergic patients.as the possibility of cross sensitivity exists. Ugnocainehydrochloride shouldnot be usedas a diluentfor intramuscular injection in patientswhoare sensitive to lignocaine. WARNINGS Claforan is physically incompatible withaminoglycosides. Wherean aminoglycoside antibintic isadministered at the sametimeas Claforan theyshouldbe administered separately and not mixed together as a singlepreparation. Aswithother broad spectrumantibiotics. colitis including rare instancesof pseudomembranous colitis. hasbeen reported withClaforan. PRECAUTIONS Claforan shouldbe usedwithcautionin patientswithknown hypersensitivity to penicillin or other B Iactam anb'biolics. The possibility of severe or fatalanaphylactic reactionsshouldbe borne in mindand appropriatetreatment kept available. Usein pregnancy. The safetyof Claforan in pregnancy has not beenestablished. Claforan has not been shown to cause anyembryotoxic orteratogenic effects inanimals. However, Claforan crosses thepl3i:enta and it shouldbe administered duringknown or suspectedpregnancy onlyif in the iudllement of the treatingclinician suchuse is deemedessential 10the patient'swelfare and the expectedbenefitsoutweigh any potential risks. Usein lactation.Claforan is excretedin the milk. Peak concentrations, measured2 or 3 hoursafter IV administration of Ig doses,rangedfrom0.25100.52mcg1mL (mean0.32±0.09). Theseconcentrationsin breast milkcouldaffectthe oropharyngeal floraof the suckling infant. Therefore,Claforan is not recommended for nursingmothersunlessthe expectedbenefitsoutweigh anypotentialrisk or if alternative arrangements for feeding the infantcan be made. Liverand renal disease.ll'ansient rises in hepaticenzymes, urea and creatininehavebeen seen in some patientsgivenClaforan. so careful monitoring of hepaticand renalfunction is advised whereany dysfunction exists.For dosageadjustment in moderateand severerenal impaitment see Dosage and Administration. Repeated useof lignocaine hydrochloride shouldbe avoided in patientswithsevereliverdiseaseor decreased hepaticbloodflow due 10the possibility of lignocaine toxicity (resulting fromdecreased metabolism and accumulation). Superinfection withnonsusceptible organisms, including fungi, mayoccur and requiresappropriate therapy. Cephalosporin antibiotics in highdosesshouldbe givenwithcaution10patientsreceiving aminoglycoside antibiotics or potent diuretics suchas frusemide. ADVERSE REACTIONS Hypersensitivity. Skinrasheseg. maculopapular rash or urticaria. pruritus. eosinophilia, feverand rarelyother allergic reactionshavebeen reported. Blood.Leucopenia and granulocytopenia havebeen reportedrarely. Somepatientshavedeveloped positive directCoombstestsduringtreatmentwithClaforan. Liver. Increases in serumtransaminases and alkaline phosphatase levels havebeen noted. Localreactions.Pain,phlebitis and tendernesshavebeen reportedin approximately 4.8" of cues. Gastroinleslina1. Nausea. diarrhoea. Aswithother broad spectrumantibiotics colitisincluding rare instancesof pseudomembranous colitis,has been reported withClaforan. Kidney•. Elevations in serumcreatinine and bloodurea havebeen reported infrequently. DOSAGE AND ADMINISTRATION Claforan shouldbe administered onlybythe intramuscular or intravenous routes. The dosage, route of administration and dosageinterval will dependon the site and severity of the infection. sensitivity of the pathogensand condition of the patient. Dosage in adults. For urinarytract infections the recommended dose is 2g dailyin divided doses.For other infections the minimum recommended dosageis 2g dailyin divided doses.This dosage maybe increased103, 4 or 6g dailyaccording to the severity of the infection. sensitivity of causative o'lf;lnisms and condition of patient. For preventionof posloperative infection. In vaginal or abdominal hysterectomy: Ig shouldbe administered intramusCularly 30 to 60 minutesbeforeincision and repeatedthereafteron completion of surgeryand at 8 hourlyintervals for a total durationof 24 hours. In obstetrical surgery(Caesarian section): Ig shouldbe administered intravenously afterthe cord has been clamped and thereafterat 6 and 12 hours. For the treatment of gonorrhoea.Uncomplicated gonorrhoeadue 10non B Iactamase producing organisms: Onesingleintramuscular dose of Ig. Uncomplicated gonorrhoeadue 10B lactamase producingorganisms: one singleintramuscular dose of 0.5g of Claforan plusprobenecid, Ig orall~ givenI hour earlier. Paediatric.......e. Children: Theusualdosagerange is 10010ISO mg/kg/day in 3to 4 divided doses. However in verysevereinfections doses of up to 2oomg/kg/day maybe required. Neonates: There is insufficient data 10recommend the use of Claforan in neonates. Mode andduration of administration. Intravenous injection: Forintravenous injection thecontents of one vial of Claforan Ig aredissolved in atieast4mL Waterfor Injection and then injectedovera periodof 310 5 minuteseither intoa veinor into the distalpart of a clamped off infusion tube. Intravenous infusion: For short infusion, 2 vialsClaforan Ig are dissolved in 40mLWaterfor Injection or an infusion solution(eg.Dextrose Solution,Haemaccel, Macrodex, Rheomacrodex) and then infused over 20 to 30 minutes. For continuous intravenous infusion, 2 vialsClaforan Ig are dissolved in 1000L of an isotonic salineor dextrosesolutionand infused over4 hours.Sodiumbicarbonatesolutionsmustnot be mixed withClaforan. Intramuscular administration: For intramuscular injection the contents of one vialof Claforan Ig are dissolved in 4mLWaterfor Injection and then injectedlaterally deep intothe gluteusmuscle. It is not advisable to injectmorethan 4mLintoeither buttock.The pain of injection can be avoided bydissolving Claforan Ig in 4mL of 0.5% lignocaine solution. (seePrecautions and Contraindications). Intravascular injection of this solutionmustbe strictlyavoided. Ifthe dailydoseexceeds2g,or ifClaforan 2g is administered morethan twicedaily, intravenous injection is to be preferred. In administering the 500mg dose,halfthe amount of anyone of the solutionsmentioned abovemaybe used. The duration of treatmentdependson the patient'sresponse. It shouldbe continuedfor at least three daysafternormalisation of the bodytemperature. Usein patientswithimpairedrenalfunction.Fromthe limited data available in this patientpopulation the biological half·life of the desacetyl metabolite of cefotaxime increasessignificantly and progressively below creatinine clearanceof 2OmLlminute. Furthermore, whenthe creatinine clearance is lessthan 5mUminute the haIf·life of the parent compound is also increased. Because of these changesin the pharmacokinetics of the drug it is recommended that dosageadjustments shouldbe madein patientswithcreatinineclearancesof lessthan 20mUminutein order to achieve approximately equal peak serumlevels during repeated dosage. Asa guideit is SUlflIested that the dosebe reducedby halfin patientswithcreatinineclearanceslessthan 20mLIminute withfurtherreductions in patientswitha clearanceolles.' than 5mUminute. DRUG INTERACTIONS Claforan exhibitsan additive microbiological effectwithgentamicin. However. becauseof physical incompatibility Claforan shouldnot be mixed withan aminoglycoside antibioticinto a singlepreparation. Administration of oral probenecid decreasesrenalclearanceslightly and increasestotal body concentrations. (SeePharmacokinetics). Compatibility. Claforan is compatible withthe following commonly usedintravenous infusion fluids which do not containsodiumbicarbonate and in which it retainssatisfactory potencyfor up 1024 hours at 25 degrees C:SodiumChloride Injection BP,5,. Dextrose Injection BP.Dextrose and SodiumLactate Injection BP,Compound Sodium Lal1ate Injection BP (Ringer·Lactate Injection). Claforan is alsocompatible with0.5" lignocaine. Freshly preparedsolutionsshouldbe used.Caution: Thesesolutionsfor I.m.injections onl~ Provided the recommended storageconditions are observed, there is no changein potencyor safety. After the periodmentioned aboveany unusedsolutionshouldbe discarded. OVERDOSAGE Nocasesof Claforan overdosage havebeen reported.Animal evidence suggests that Claforan has a verylowtoxicpotential. The LDSO studiesin rats and miceadministered Claforan intravenously haveshownno mortality nor associated symptoms of inloxication up 10doses of 2000mgIkg and 716mg1kg respectively. Serumlevels of cefotaxime maybe reducedbyhaemodialysis. PRESENTATION Injection. vials500mg, Ig. 2g: Is. Storage.The vial containingthe powdershouldbe stored in a coolarea (below 25 degrees C)and away fromheat and light.The shelflifeof the powder. whenstored underthese conditions. is 2 years. Reconstituted solution: Ig of Claforan reconstituted with4mLof Waterfor Injection is stablefor up to 24 hoursunder refrigeration. .. Registered trademark ROUSSEL~RoUS8el Phermeceuticals Ply Ltd, 7 Gledstone Rued, Castle Hill, NSW2154 ceftazicime 100 100 80 80 60 60 40 40 20 20 o ' ; " ' ; ' - - _.1lisl pric:tp~ (DerNed from Aclrill989 PBS) """'" " do5et "".y ....-..num ..,"" .. 1 ~ 'IiOII ceftrialcne S8 9J $17.00 dOWt IIbximl,m ~ o Cl!'f1azicime* -- 12",17 $tU S $15.92 S3267 1~ 1~ cefotaxime THE COST EFFECTIVE CEPHALOSPORIN t AJu ir i.v. J. ~ l:t" f,,,m rrl."M: ri" lnJ: inf" I"Ill<1U' 'fl ",IlMS Ann ual19d9 • Preces are h.o>eJ "n r 1ldnn....:C'ur ical .. hol.......kr rn",n . fuI pr estrbng infor ma tion aqacem ~~~~~L~ Castle Hil. NSW 2154 Q. Il, 89 106 biochemically so as to permit optimal function. Conditions that increase the body's energy demands are known to exacerbate mitochondrial encephalomyopathy." Therefore, general measures in patient management should include the avoidance of extremes of temperature (that is, exercise, fever) and/or treatment with antipyretic agents; the avoidance of severe lactic acidosis and of glucose intolerance; the maintenance of adequate hydration; and the ingestion of small, frequent meals, rather than permitting prolonged periods between meals. Drugs that inhibit the function of the respiratory chain (phenytoin, barbiturate agents) and inhibit mitochondrial protein synthesis (chloramphenicol, tetracycline) should be avoided if possible. Specific therapeutic modalities which have been tried for the various mitochondrial disorders include compounds that can act as artificial electron acceptors, such as vitamins C and K3;33 riboflavin (vitamin 8 2);34 a longchain, fatty-acid-free diet;" L-5-hydroxytyptophan and carbidopa;" coenzyme Q;31 and corticosteroid agents. 38.3• Therapeutic successes have been sporadic but at times dramatic. As there is a tendency to report successful results only, therapies with detrimental effects need to be reviewed carefully. Indeed, major deterioration occurred in two cases with the Kearns-Sayre syndrome after corticosteroid therapy.40 The response to corticosteroid therapy in this case of MELAS was striking. Total neurological resolution occurred within two months of the commencement of dexamethasone at the first presentation and repeated attempts to decrease the dose of dexamethasone resulted in an exacerbation of the symptoms. Two weeks after corticosteroid therapy initially was ceased, the patient developed headache, drowsiness, ataxia, vomiting, a left homonymous hemianopia, left sensory inattention and a left hemiparesis. A new large area, which resembled an infarction, was present in the right cerebral hemisphere posteriorly on computed tomographic scan. The reintroduction of corticosteroid therapy again resulted in a rapid resolution of all symptoms. It subsequently became evident that the patient had an extremely sensitive corticosteroid dependency, whereby a reduction in the dosage of dexamethasone of even 0.25 mg a day resulted in the recurrence of symptoms. As the natural history of MELAS is quite erratic and episodic, there is a potential hazard in interpreting the efficacy of various therapies in isolated cases overzealously, particularly if their institution may have coincided with the natural resolution of symptoms and signs. Nevertheless, the consistently rapid and dramatic clinical improvement which followed the institution of dexamethasone in this case was most impressive and, it seemed, beyond coincidence. July 17, 1989 Vol. 151 THE MEDICAL JOURNAL OF AUSTRALIA There have been four instances where the treatment of MEL AS with dexamethasone," methylprednisolone" or prednisolone'':" has resulted in a clinical improvement; two of these cases were corticosteroid-dependent to the point where attempts at the withdrawal of medication resulted in an exacerbation of symptoms."-" Shapira et al. have postulated that instability of the mitochondrial membrane may have caused an uncoupling of oxidative phosphorylation and that the improvement that was associated with corticosteroid therapy might have been the result of a membrane-stabilizing effect, thus permitting more efficient oxidative phosphorylation and lowering the demands on glycolysis for energy. 2 It also is possible that corticosteroid agents exert their effects by the induction of antiphospholipase compounds. The efficacy of corticosteroid therapy in our case, both in the prevention of encephalopathic events and the enhancement of recovery from stroke-like episodes, together with the similar experience of others,2,30-32 would suggest that corticosteroid treatment is of value in patients with MELAS and should be considered at this time to be standard therapy for this disorder. As the number of similar cases is small and the natural history of MELAS is episodic, caution must be exercised in the interpretation of therapeutic interventions, and more-substantial evidence willbe derived from randomized, prospective multicentric therapeutic trials. The role of corticosteroid therapy in other mitochondrial disorders still is unclear and awaits careful evaluation. References I. Morgan-Hughes J, The mitochondrial myopathies, In: Engel AG. Banker BQ, eds. Myology. New York: McGraw-Hili, 1986: 1709-1743, 2, Shapira Y, Harel S, Russell A, Mitochondrial encephalomyopathies: a group of neuromuscular disorders with defects in oxidative metabolism. 1ST J Med Sci 1977; 13: 161-164, 3. DiMauro S, Bonilla E, Zeviani M, et al. Mitochondrial myopathies, Ann Neuro/I985; 17: 521-538, 4. Peterson PL, Martens ME, Lee CP, Mitochondrial encephalomyopathies. Neurol Clin 1988; 6: 529-544, 5. Lee CP, Martens M. Mitochondrial respiration and energy metabolism in muscle. In: Engel AG, Banker BQ, eds. Myology, New York: McGraw Hill, 1986: 643, 6. Kroon AM, Van den Bogert C. Biogenesis of mitochondria and genetics of mitochondrial defects. J Inherit Metab Dis 1987; 10 (suppl I): 54-61. 7. Egger J. Wilson J. Mitochondrial inheritance in a mitochondrially mediated disease, N Engl J Med 1983: 309: 142-146, 8. Schnitzler ER, Robertson we. Familial Kearns-Sayre syndrome, Neurology 1979; 29: 1172-1174, 9. Brown WM, George M Jr, Wilson AC. Rapid evolution of animal mitochondrial DNA, Proc Natl Acad Sci USA 1979; 76: 1967-1971. 10, Holt IJ, Harding AE, Morgan-Hughes JA. Deletions of muscle mitochondrial DN A in patients with mitochondrial myopathies, Nature 1988; 331: 717-719. II. Kearns TP, Sayre GP. Retinitis pigrnentosa, external ophthalmoplegia and complete heart block: an unusual syndrome with histologic study in one of two cases. Arch Ophthalmo/1958; 60: 280-289. 12. Berenberg RA, Pellock JM, DiMauro S, et at. Lumping or splitting? "Ophthalmoplegia~plus" or Kearns-Sayre syndrome? Ann Neuro/1977; I: 37-54, 13, Fukuhara N, Tokiguchi S, Shirakawa S, Tsubaki T, Myoclonus epilepsy associated with ragged red fibres (mitochondrial abnormalities): disease entity or syndrome? Light and electron microscopic studies of two cases and review of the literature. J Neurol Sci 1980; 4: 117-133. 14. Fitzsimons RB, Clif'tcn-Bilgh P, Wolfenden WH, Mitochondrial myopathy and lactic acidaemia myoclonic epilepsy, ataxia and hypothalamic infertility: a variant of Ramsay-Hunt syndrome? J Neural Neurosurg Psychiatry 1981; 44: 79-82, CORDI LOX® PATIENTS GET ON WITH LIFE. tverepemn hydrochloride) Abridged Prescribing Information Generic name: Verapamil hydrochloride. Chemicalname: x-;sopropyl-x-[(N-methyl-N-homoveratryl)-y-aminopropyJ}-3,4dimethoxyphenyl-acetonitrile hydrochloride. ChemicalCharacteristics: Verapamil hydrochlorideis a white,or almostwhite.odourlesspowder. M.P.about146°C.Solubility:Water1 in 20. Ethanol1 in 25. Chloroform1 in 1.5.Etherpracticallyinsoluble.A 5% aqueoussolutionhasa pH of 4.5 to6,5, INDICATIONS, o Hypertension o Anginaof effort o Anginaat rest o Vasospastic angina(including Prinzmetal'svariantangina) o Tachyarrhythmias including paroxysmal supra-ventricular tachycardia o Atrialfibrillation with rapidventricularresponse o Atrialflutter with rapid ventricularresponse Usein pregnaney: Onlylimited informationis availableon the useof Cordiloxin pregnancy. Thedrug shouldthereforenot be usedin pregnantwomen,or thoselikely to becomepregnant,unlessthe expectedbenefitsoutweighany potential risks. Usein lactation: Theuseof Cordiloxduring lactationshould be avoidedunlessexpected benefitsoutweighany potentialrisk. However, preliminary resultsindicate that verapamilmayreachconcentrationsof 10-65nglml in the milk of nursingmothers.Such concentrationsare unlikelyto produce clinical effectsin the infant. CONTRAINDICATIONS: o Cardiogenicshock. o Recentmyocardialinfarction. o Knownhypersensitivity to verscemn hydrochloride;or to aspirin or azo dyes.since the 120mg oralformulationcontains tartraztne. WARNING: Useverapemn hydrochloridewith caution in conjunction with beta adrenergicblockingdrugsas the myocardialdepressanteffectsof each drug may be additive. Precautions: In sick-sinussyndromeand secondand third degreeheart block, Cordilox mayfurther impair SAor AVnodaifunction respectively. In the presenceof cardiacfailurefull compensationwith cardiac glycosides should be ensuredprior to administrationof Cordilox. Cautionis necessaryin initiatingtreatment,or increasingdosageof Cordiloxin patientswith cerebrovascular accidents,sinus bradycardia, heartblockand hypotension. Interactions: BothCordiloxand betablockingdrugs mayslowAVconduction and depressmyocardialcontractilitybydifferent mechanisms.Cardiac function,heart rateand rhythm,and bloodpressureshould be closely monitoredduring simultaneousoraladministration. Otheranti-arrhythmic.anti-hypertensive and cardiodepressantdrug therapyshouldbe reviewed prior to introductionof Cordilox. Cordifox has beenreportedto increaseplasmalevelsof digoxin. Physicians should be alertfor symptomsof possibledigitalisintoxication. and maywish to measuredigoxinlevelsin plasma.Howeverextensive experienceindicatesthat this possibleinteractionis of onlyslight clinical relevance. DOSAGE AND ADMINISTRATION: In mild and moderatehypertension: Theusualstartingdoseis one80 mg tablettwo or three timesa day.The maintenancedosemay beadjustedto one 160 mg tablettwo or three timesa day, Usualmaintenancedose 160 mgtwicedaily: Theindividualdose.and frequencyof dosing,should be determinedin accordancewith the indicationand individualpatient response. Paediatric: Doserange40-360 mg perday in 2 or 3 divideddaily doses accordingto ageand response. Geriatric/renal failure:Therecommended dailydosageis usuallywell tolerated. Hepaticfailure:Cautionshould be exercised when initiating therapysince the pharmacological actionof Cordiloxmay be increasedor prolongedby hepaticinsufficiency. ADVERSE REACTIONS: Corditox is usuallywell tolerated. Morecommonreactionsincludeconstipation,flush,headacheand dizziness. Hypotension. bradycardia,developmentor worseningof symptomsof cardiacfailureand rhythm disturbanceshavebeenreported. Rarelynon-specificimmunologicalreactionssuchas skin rashesmay occur. Individualhypersensitivity to verapaml!in the absenceof accumulationor overdosage, has beendescribed. OVERDOSAGE: Symptoms: Bradycardia, cardiacarrest,secondand third degreeAV block, hypotension and myocardialinsufficiency. _Imenl: Seriousoraloverdosage should be treatedby induced emesis,or gastric lavage and aspiration.prior to admissionto intensivecare. Repeated intravenouscalcium gluconate(10 ml, 10%solution)and sodiumbicarbonateif metabolicacidosisdevelopsrepresentlogical therapy. Intravenous fluids and cardiorespiratorysupport may be necessary. Dialysiswouldnot seempotentiallyuseful. Othertreatment,selectedin accordancewith the presentingsymptoms, mayincludeatropine,isoprenaline(isoproterenol), dopamine.cardiac glycosidesand noradrenaline(norepinephrine).Recordedoverdoses survivedinclude a 14yearold girl who ingested2.4 g and a 28 yearold womanwhotook5.6 g. PRESENTATION: Cordi/ox 40 mg (100 tablets)NHSGeneralBenefit- 100tablets.5 repeats. Cordilox80 mg tablets)NHSGeneralBenefit- 100 tablets,5 repeats. Cordilox120mg uootebets) NHSGeneralBenefit- 100tablets.5 repeats. Cordilox 160 mg (60 tablets)NHSGeneralBenefit ~ 60 tablets,5 repeats. MANUFACTURER: KnollAG.WestGermany. DISTRIBUTOR: Schering Pty.Limited,27-31 DoodyStreet.Alexandria. NSW2015Australia. "Cordilox is a Registered Trademark. Full PrescribingInformationavailableon request. CWFSSCH 22] nco CORDILOX® PATIENTS GET ON WITH LIFE. Well tolerated calcium antagonist monotherapy for hypertension. Justone 160mgtablet twice a day. Before prescribing, please review Product Information by referring to the Advertisers' Index. ScheringPty. Limited,27-31 Doody Street. Alexandria. N.SW. 2015. CO,dIIO< iswrapamll Hel. ~ Reg,sle,e<;I Trademark UA 0903985 89 CWFSSCH227 July 17, 1989 Vol. 151 THE MEDICAL JOURNAL OF AUSTRALIA 108 15. Pavlakis SG, Phillips PC, DiMauro S, et al. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes: a distinctive clinical syndrome. Ann Neuro/1984; 16: 481-488. 16. Kuriyama M. Umezaki H, Fukuda Y. et al. Mitochondrial encephalomyopathy with lactatepyruvate elevations and brain infarctions. Neurology 1984; 34: 72-77. 17. Hart ZH, Chang CH, Perrin EV, et al. Familial polio dystrophy, mitochondrial myopathy, and lactic acidemia. Arch Neurol 1977; 34: 180-185. 18. Shapira Y, Cederbaum SD, Cancilla PA, er al. Familial poliodystrophy, rnitochondrial ptyopathy and lactic acidemia. Neurology 1975; 25: 614-621. 19. Yamamoto T, Beppu H, Tsubaki T. Mitochondrial encephalomyopathy: fluctuating symptoms and CT. Neurology 1984; 34: 1456-1460. 20. Driscoll P, Larsen PO, Gruber AB. MELAS syndrome involving a mother and two children. Arch Neurol 1987; 44: 971-973. 21. Rosing HS, Hopkins LC, Wallace DC, et al. Maternally inherited mitochondrial myopathy and myoclonic epilepsy. Ann Neurol 1985; 17: 228-237. 22. DiMauro S, Bonilla E, Zeviani M, et al. Mitochondrial myopathies. J Inherit Metob Dis 1987; 10 (suppl I): 113-128. 23. Kobayashi M. Morishita H, Sugiyama N. et al. Mitochondrial myopathy, encephalopathy,lactic acidosis and stroke-like episodes syndrome and NADH-CoQ reductase deficiency. J Inherit Metab Dis 1986; 9: 301-304. 24. Kobayashi M, Morishita H, Sugiyami N, et at. Two cases of NADH-coenzyme-Q reductase deficiency - relationship to MELAS syndrome. J Pediotr 1987; 110: 223-227. 25. Nishizawa M. Tanaka K. Shinozawa K, et at. A mitochondrial encephalomyopathy with cardiomyopathy. A case revealing a defect of complex I in the respiratory chain. J Neural Sci 1987; 78: 189-201. 26. Byrne E, Trounce I, Dennett X, et al. Progression from MERRF to MELAS phenotype in a patient with combined respiratory complex I and IV deficiencies. J Neural Sci 1988; 88: 327-337. 27. Schapira AHV, Cooper JM, Morgan-Hughes JA, et at. Molecular basis of mitochondrial myopathies: polypeptide analysis in complex-I deficiency. Lancet 1988; I: 500-503. 28. Ichiki T, Tanaka M, Nishikimi M, et al. Deficiency of subunits of complex I and mitochondrial encephalomyopathy. Ann Neurol 1988; 23: 287-294. 29. DiMauro S, Zeviani M, Bonilla E, et al. Cytochrome c oxidase deficiency. Biochem Soc Trans 1985; 13: 651-653. 30. Peterson P, Martens M, Lee CP, et al. MELAS: a disorder of mitochondrial metabolism. Neurology 1986; 36(suppl): 94. 31. Skoglund RR. Reversible alexia, mitochondrial myopathy and lactic acidemia. Neurology 1979; 29: 717-720. 32. Montagna P, Gallassi R, Medori R, et al. MELAS syndrome: characteristic migrainous and epileptic features and maternal transmission. Neurology 1988; 38: 751-754. 33. Eleff S, Kenneway NG, Buist NR, et al. 31P NMR study of improvement in oxidative phosphorylation by vitamins K3 and C in a patient with a defect in electron transport at complex III in skeletal muscle. Proc Nail Acad Sci USA 1984; 81: 3529·3533. 34. Arts WFM, Scholte HR, Bogaard JM, et al. NADH-CoQ reductase deficient myopathy: successful treatment with riboflavin. Lancet 1983; 2: 581-582. 35. Askanas V, Engel WK, Kwan HH, et al. Autosomal dominant syndrome of lipid neuromyopathy with normal carnitine: successful treatment with long-chain fatty-acid-free diet. Neurology 1985; 35: 66-72. 36. Feit H, Kirkpatrick J, Van Woert MH, Pandian G. Myoclonus, ataxia, and hypoventilation: response 10 L-5-hydroxytryplophan. Neurology 1983; 33: 109-112. 37. Bresolin N, Bet L, Binda A. Clinical and biochemical correlations in mitochondrial myopathies treated with coenzyme QIO. Neurology 1988; 38: 892-899. 38. Mastaglia FL, Thompson PL, Papadimitriou JM. Mitochondrial myopathy with cardiomyopathy, lactic acidosis and response to prednisone and thiamine. Aust NZ J Med 1980; JO: 660-664. 39. Przyembel H. Therapy of mitochondrial disorders. J Inherit Metab Dis 1987; 10: 129. 40. Curless RG, Flynn J. Bachynski B, et at. Fatal metabolic acidosis, hyperglycemia, and coma after steroid therapy for Kearns-Sayre syndrome. Neurology 1986; 36: 872-873. (Received January 31; accepted March 17, 1989) Familial Mediterranean fever in six Australian children Patrick J. Moore, Albert Mansour, John D. McDonald, Andrew Kemp, K. Ramanand Kamath and Stuart F.A. Dorney ABSTRACT Six Australian children fulfilled the diagnostic criteria for familial Mediterranean fever. None had a family history of the disease, but five children came from ethnic groups that typically were associated with the disease. The symptoms commenced before five years of age in all the children, and three children underwent unnecessary operations because of the symptoms of recurrent fever and abdominal pain. All six children benefited from colchicine prophylaxis by mouth. More cases can be expected to be recognized in Australia because of the large number of Australian children with a Mediterranean heritage. (Med J Aust 1989; 151: 108-110) F am ilial Mediterranean fever, or familial paroxysmal polyserositis, is a rare autosomal recessive disease of unknown aetiology which mainly affects persons from countries that border the eastern Mediterranean sea. 1 It is characterized by repeated, self-limited attacks of fever and serositis (peritonitis, pleuritis and/or synovitis). Less-common manifestations involve the skin, eyes and pericardium. Attacks occur unpredictably and may be associated with significant morbidity, but mortality is increased only in those patients who develop amyloidosis. Many series of patients with familial Mediterranean fever have been reported from the Mediterranean countries and the United States,':" and two cases of familial Mediterranean fever have been reported in Australian adults.'> However, we are unaware of any previous reports that have involved Australian children. We have diagnosed familial Mediterranean fever in six Australian children during the last 10 years. We have reported them to bring this disorder to the attention of Australian medical practitioners who care for children because, for many of the children, the diagnosis was delayed for years, during which time many unnecessary investigations and operations were performed. As it is a treatable disorder, early diagnosis can prevent much suffering. Clinical records The clinical features of our six patients are summarized in the Table. There were four boys and two girls; no two children were from the same family. None of the families had a history of familial Mediterranean fever, but five children came from ethnic groups that commonly are associated with the disorder: four children were of Mediterranean origin and one child was of Endocrinology Unit, Children's Hospital, Winnipeg, Manitoba, Canada. Patrick J. Moore, MB BS, FRACP, Fellow in Endocrinology. The Children's Hospital Camperdown, Pyrmont Bridge Road, Camperdown, NSW 2050. Albert Mansour, MB BS, PhD, FRACP, Visiting Physician. John D. McDonald, MB BS, FRACP, Visiting Physician. Andrew Kemp. MB, FRACP, PhD, Head, Department of Immunology. K. Ramanand Kamath, MD, FRACP, DCH, Head, Department of Gastroenterology. Stuart FA Dorney, MB BS, FRACP, Staff Gastroenterologist. Reprints: Dr S.F.A. Dorney. Armenian origin. The other child had one Dutch parent and one English parent. The age of onset of the symptoms ranged from 1.25 to five years (mean, three years of age) and the time between onset and diagnosis varied from one to eight years (mean, 4.75 years). All the children suffered typical recurrent attacks of fever and abdominal pain, with four children having pleuriticsymptoms and three children having joint involvementas well. The interval between the attacks ranged from one to two weeks, to two to three months. One child's joint symptoms were dominant and for some time he was thought to have juvenile rheumatoid arthritis. Four patients were labelled as having various other disorders that wereassociated with recurrent abdominal pain before familial Mediterranean fever was suspected. Three patients underwent a total of four unnecessary operations: one child underwent a tonsillectomy, one child underwent an appendicectomy and one girl underwent both a tonsillectomy and a laparotomy for suspected intestinalmalrotation. Extensive investigations were performed to exclude other disorders that were capable of explaining the episodes. All six children showed dramatic responses to prophylactic colchicine therapy by mouth, with the disappearance of the attacks of feverand serositis. Two children, who becamenon-eompliant, suffered subsequentrelapses, but their symptoms declined again after the reinstitution of the colchicine therapy. No serious side-effects have occurred so far. One of the patients, Case 4, suffered hypertension during his attacks. Estimations were made of his 24-hour urinary catecholamine levels which were found to be elevated. This patient, and one other, had a mildly raised urinary protein excretion rate. Discussion Familial Mediterranean fever first was recognized as an entity in 1958,' although reports that described similar disorders under various names had appeared from as early as 1908. 10 - 15 The diagnosis of familial Mediterranean fever is based on six clinical criteria: short attacks of fever which occur at varying intervals; painful manifestations in the abdomen, chest, joints or skin which accompany the fever; the absence of any other causative factor or pathological finding in vivo or at post-mortem examination that is capable of explaining the condition; amyloidosis, clinically of the nephropathic type, and pathologically of the perireticulin type; features of autosomal recessive inheritance; and a prevalence in persons of Mediterranean stock, especially Sephardic Jews and Armenians. I The first three criteria must be met for a diagnosis to be made. All our patients fulfilled these criteria, and five patients also were of Mediterranean stock. A syndrome that is similar to familial Mediterranean fever has been reported in the Dutch, and our other patient had one Dutch parent. The fact that all our patients showed dramatic responses to colchicine prophylaxis lends support I.