electroretinogram - bmjarchives ofdisease in childhood, 1989, 64, 1080-1087 personalpractice...

Archives of Disease in Childhood, 1989, 64, 1080-1087

Personal practice

The electroretinogramA HARDEN, G G W ADAMS, AND D S I TAYLOR*

Departments of Clinical Neurophysiology and *Ophthalmology, Hospital for Sick Children, London

SUMMARY The electroretinogram, findings, in response to a flash stimulus, was recorded from askin electrode placed on the bridge of the nose in 4465 infants and children seen over a 10 yearperiod. The electroretinogram was combined with a flash visual evoked potential. From thistotal, the electroretinographic findings in 240 patients, aged 1 day to 17 years, without suspectedretinal pathology and with a normal visual evoked potential, were used as controls and normalelectroretinographic parameters of different age groups defined.There were 332 patients who showed an absent or very reduced amplitude electroretinogram.

They were divided into primarily ocular disorders (n= 195), neurodegenerative disorders (n=94),and various syndromes (n=43). Fundus examination did not always show any obviousabnormalities. The use of this simple and reliable technique for recording the electroretinogrammade it possible to include this investigation as a routine procedure without the need for sedationin infants and uncooperative children. Electroretinographic studies, especially when combinedwith visual evoked potentials, and in some cases electroencephalography, may aid diagnosis in awide variety of paediatric conditions, many of which have genetic implications.

Electroretinography measures the field potential ofthe retina in response to a flash of light and can beused clinically to assess retinal function (mainly rodsand cones). The electroretinogram may show anabnormally small or absent response in retinaldisorders even when in some instances there areno detectable abnormalities on ophthalmoscopicexamination. In children there is a wide range ofdisorders in which the retina may be affected. Suchdisorders may be congenital or acquired and someevolve over a period of time. They include not onlyprimarily ophthalmological disorders but also somesystemic disorders or syndromes and certain neuro-degenerative diseases.

In the uncooperative infant or child it is importantto be able to record the electroretinogram reliablywithout the need for sedation or anaesthesia. Overthe last 20 years a simple method using averagingtechniques and recording from an electrode placedon the bridge of the nose has been developed inthe department of clinical neurophysiology at theHospital for Sick Children and some normal electro-retinographic parameters have been published. 'Recording of the electroretinogram has been

combined with the cortical visual evoked potentialand normal findings for the flash visual evokedpotential at different ages have been reported.2 Thematuration of the electroretinogram, in response toa flash of light, and particularly from birth to12 months, has not previously been described in anydetail particularly with this technique.

In this study the normal electroretinographicparameters at different ages from birth to 17 yearshave been measured and all patients seen over a10 year period showing a very reduced or absentresponse have been collected and grouped intodiagnostic categories, in an attempt to give acomprehensive range of paediatric disorders inwhich an appreciable reduction or loss of theelectroretinogram may occur.

Patients and methods

Over a 10 year period, 1977-86, 5572 electroretino-graphic recordings (combined with visual evokedpotentials) were made on 4465 patients referred tothe department of clinical neurophysiology. Beforethis period, criteria of normality of the flash electro-

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retinogram with the same technique was establishedin our laboratory in a series of 62 children aged1-14 years with congenital heart disease. Althoughthere have been only some changes in the averagingapparatus used since that time, it was consideredworthwhile to measure the electroretinographicparameters in a larger number of children includinginfants less than 1 year and compare findings atdifferent ages. For this purpose 240 infants andchildren from birth to 17 years of age were selectedfrom patients seen in the last 10 year period.Although many of these patients had some neuro-

logical problems, mainly seizure disorders or retarda-tion, or both, none had known ocular pathology andall had a normal flash visual evoked potential. Thesepatients were usually more difficult to test thannormal infants and children and therefore morecomparable with patient groups investigated forophthalmological problems.From the total patients seen over this 10 year

period, 332 were found to have an abnormalelectroretinographic response, which was defined asabsent or very reduced in amplitude (to less thanhalf the expected size for age and conditions oftesting). It should be noted that the number ofpatients with an abnormal electroretinogram wasvery much smaller than the number with an ab-normal visual evoked potential.Some details of techniques used in this department

for recording the averaged skin electroretinogram(together with visual evoked potential) have pre-viously been reported.34 In brief, a silver discelectroencephalographic electrode was placed onthe bridge of the nose and secured with sticky papertape. Contact was made with electrode jelly andimpedances of less than 2 Kohms obtained. Anelectrode placed over the vertex (using collodion)was used as a reference. A stroboscope (SLE)(emitting a flash set to produce 0-12 joules) washand held close to the eyes (5-10 cm) and any headmovements quickly followed. The room was notdarkened during the procedure. Stimulation was at a

The electroretinogram 1081

rate of approximately 2/second except in infantsunder 12 months of age when slower rates wereused. All children and infants were awake with theeyes open for as much of the time as possible. Greatcare was taken to exclude signals contaminated withmovement artefacts or muscle action potentials andit was often necessary to interrupt and restart thecollection of averaged data to achieve this. Ployssuch as singing or tapping the glass of the lamp wereused to keep the child still and quiet when necessary.Simultaneous bilateral eye stimulation was alwayscarried out and, ifa unilateral problem was suspected,monocular stimulation was achieved by holding apad over the other eye. Many patients, especiallyyoung ones, had repeat studies to check maturationand progression of any disorder.The electroretinogram was always recorded

simultaneously with the flash visual evoked potential(derived from the mid occipital and right and leftposterior temporal regions, also referred to thevertex). All signals were amplified using a Grasselectroencephalograph machine with bandwidth of0-3-100 Hz. Averaging was carried out using a PDP11/40 general purpose computer with in houseprograms. At least 100 responses were averagedover a 250 ms epoch and repeated several times toensure consistent findings. All patients had anelectroencephalogram immediately before theelectroretinogram and visual evoked potentialinvestigations.

Results

NORMAL PARAMETERSThe averaged electoretinogram in response to aflash stimulus was recorded as a negative/positivecomplex ('a' and 'b' waves) of similar waveformthough approximately one 10th the amplitude ofthat recorded with a corneal electrode using thesame intensity stimulus. The amplitude and durationof the components of the electroretinogram atdifferent ages with the eyes open (bilateral stimula-

Table 1 Normal parameters of electroretinogram at different ages

Age Mean (2SD) Mean (2SD) Mean (2SD) Mean (2SD)(n=30) amplitude 'a' duration 'a' amplitude 'alb' duration 'alb'

(uV) (ms) (uV) (ms)

0-4 Weeks 4-0 (3-20) 27-5 (7-64) 8-0 (6-54) 54-0 (17-58)5-12 Weeks 6-0 (4-54) 25-0 (7-94) 12-5 (8-98) 48-0 (14-72)3-5 Months 8-7 (5-22) 25-0 (7-26) 17-0 (9-06) 48-7 (18-60)6-11 Months 10-0 (5-36) 25-0 (5-46) 21-7 (11-42) 46-5 (11-86)12-23 Months 11-4 (4-22) 25-0 (6-30) 25-0 (11-72) 43-3 (7-90)2-4 Years 13-0 (7-32) 25-0 (4-74) 25-0 (11-72) 43-3 (7-90)5-10 Years 13-5 (7-28) 24-8 (4-80) 31-7 (17-92) 44-9 (13-6)11-17 Years 13-3 (9-46) 24-5 (4-80) 29-3 (16-90) 44-1 (11-70)



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1082 Harden, Adams, and Taylor

tion) are listed in table 1. It can be seen that in thefirst month of life the electroretinogram is recordablewith this technique, though the response is of verysmall amplitude and somewhat long duration.The amplitude progressively increases and theduration decreases and by 1-2 years of age are ofrelatively constant values (similar to those previously

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reported'). There is quite a wide individual variationin amplitude, however, especially in the older childas can be seen from the standard deviations given intable 1.

Representative electroretinographic records(bilateral stimulation) at different ages are shown infig 1. The electroretinographic response from thesame electrode with monocular stimulation isapproximately half the size seen with bilateral

Age 2months

Both eyesf A -

W.S14

10 years

Right eye

Left eye P

V

Right eye |I

Left eye

L pV

t L. r t02550 75 100 0 25

(Ims) (Ims)Fig 1 Examples ofnormal electroretinographicfindings atdifferent ages with bilateral stimulation. Note the increase inamplitude ofthe 'a/b' complex, occurring over the first50 ms after theflash stimulus (arrow), up to the age of12 months.

Age 2 years q

Eyes openk

fV

f1iV1111.

Age 4 months

Eyes held open / A

Age 5weeks Xl

Eyes open

t t~~~0 250 75 1000 25 5075 100

(Ims) (Ims)Fig 2 Comparison ofthe electroretinogram with bilateralstimulation and monocular stimulation (covering one eye)in a young infant and child. Note the reduced amplitude ofthe 'alb' complex with monocular stimulation but similaritybetween responsesfrom each eye.

Eyes shut 4

Eyes shut

Eyes shut

t t0 25 50 75 160 06 5 S0 75 100

(ins) (ins)Fig 3 Comparison ofelectroretinograms recorded with eyes open and eyes closed in three infants of different ages. There isan appreciable degradation ofthe response when the eyes are closed. In the sleeping state it is often possible to hold the eyesopen and record the electroretinogram satisfactorily.

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Electroretinogrcm Visual evcpotential

L10.V

The electroretinogram

oked

II

,-\1/Joubert's syndromeAge 9 months

Juvenile Batten's diseaseAge 8 years

Bilateral retinoblastomaAge 14 months

Leber's amaurosisAge 2 years

0 S0 160 150 200(Ims)

tI ; IIoI I I Ir0 50 100 150 200

(ms)

Fig 4 Four children with an absent electroretinogram related to different conditions. Note the different visual evokedpotentialfindings with a normal visual evoked potential seen in the infant with Joubert's syndrome and loss ofmain earlynegative component in the juvenile Batten's and retinoblastoma patients. The visual evoked potential is absent in the patientwith Leber's amaurosis. The visual evoked potentialfindings may vary in all these conditions.

stimulation (fig 2). If the eyes are shut a smaller andmore prolonged response is recorded (fig 3) andideally the response is recorded with the eyes openeven if held open during the sleeping state (fig 3).

ABNORMAL FINDINGSThe 332 cases in whom the electroretinographicresponse was absent or appreciably reduced inamplitude have been somewhat arbitrarily dividedinto primarily ocular disease (table 2), neuro-degenerative disorders (table 3), and various syn-dromes (table 4). Some examples of combinedelectroretinograph and visual evoked potentialfindings in some of these disorders are shown infig 4.

Discussion

The technique for recording the flash electroretino-gram as described has proved simple and reliableeven in patients unable to cooperate. Some otherworkers have preferred to use skin electrodes placed

under each eye that enables recording a separateelectroretinogram from each eye. In our experience,however, these electrodes are not so well toleratedby the child who is young or retarded, or both, as asingle electrode on the bridge of the nose. Althoughthe electroretinogram thus recorded is the summedresponse from both eyes, abnormalities in most ofthe conditions described affect the retina of botheyes. A reduced amplitude electroretinographicresponse with bilateral stimulation will often suggesta monocular retinal disorder. If a unilateral retinalproblem is suspected, it is more useful to cover oneeye and not only record the monocular response butalso the monocular cortical visual evoked potential.As the optic pathways from each eye pass to thevisual cortex of both hemispheres, monocular stimu-lation is necessary if the integrity of the visualpathways from each eye to the brain is to beassessed.Most patients with abnormalities on electroretino-

graphy show some fundus changes suggestive of a

retinopathy and the fundal appearance of retinitis

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Table 2 Ocular disorders

No ofpatients

Dystrophies:Leber's amaurosis'Retinal dystrophy'Rod/cone dystrophyRetinitis pigmentosaStargardt's diseaseGyrate atrophyChoroideraemia

Malformations:Microphthalmos (with or without other)ColobomaPersistent hyperplastic primary vitreousRetinal fold and hyaloid remnant

Retinal detachmentRetinopathy of prematurityRetinitis/chorioretinitis:

CongenitalAcquired

CytomegalovirusChickenpoxAIDSUnknown

RetinoblastomaVascular:

Retinal haemorrhageInjury

PostsurgicalOsteopetrosisUndiagnosed:With cataractsOthers

Total

601911911

23531

1121

2

21113

431

195

pigmentosa is well known. This is not always thecase, however, most notably in the young patientwith Leber's amaurosis.5 Conversely some retino-pathies-for example, rubella-do not show abnor-malities on electroretinography and visual functionis not always compromised.6 In patients who aredifficult to examine clinically, the presence of anormal electroretinogram is some reassurance thatthere is no appreciable loss of function of outerretinal layers. In the presence of cataract, fundusexamination may be limited. In our experience theflash electroretinogram is normal in most patientswith cataracts unless retinal pathology is present andan abnormally reduced or absent electroretinographic.response in the presence of cataract is indicative ofretinal pathology. The few cases of cataracts withabnormal findings listed in table 2 are presumed tohave other unidentified ocular disease. Nystagmuswas a very common symptom in many patients, withor without retinal pathology, and has not beenconsidered as a separate entity.The flash electroretinogram is mainly derived

from peripheral photoreceptors and its absence does

Table 3 Neurodegenerative disorders

No ofpatients

Batten's disease:InfantileLate infantileJuvenileVariant forms

Mucopolysaccharidoses:SanfilippoScheieHurlerUnknown

Mucolipidoses type IVHallervorden-Spatz diseaseMitochondrial cytopathyPeroxisome disorders:

Infantile RefsumZellweger syndrome

Spinocerebellar degenerationsUndiagnosed

Total

16328

2

11

2

13

7

22513

94

Table 4 Syndromes

No ofpatients

Aicardi 1CHARGE association 1Cockayne 1Ellis-van Creveld 1Jeune 1Joubert 2Laurence-Moon-Biedl 9Norrie's disease 6Senior 4Sjogren-Larssen 1Usher 3Walker-Warburg (HARD±E) 2Undiagnosed 11

Total 43

not necessarily imply that all retinal function hasbeen lost. As the flash visual evoked potential is amainly macular response, the combined recording ofan electroretinogram and visual evoked potentialmay be helpful in distinguishing between peripheraland macular retinal problems. Thus an absentelectroretinographic response can be associated witha normal visual evoked potential in patients withsome preservation of macular function (fig 4) and isusually associated with reasonable vision.The commonest diagnosis in the primary ocular

group was a retinal dystrophy. The diagnosis ofunclassified retinal dystrophy can only be made byexclusion of other known causes for reduced visionand retinopathy by biochemical screening (amino



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acids, phytanic acid, urine osmolality, creatinineclearance, mucopolysaccharides, blood lipids). Thecone/rod dystrophies are considered as a distinctsubgroup. In this study the electroretinogram hasbeen recorded under photopic conditions and,although, even with a non-corneal electrode, rodand cone responses can be distinguished usingflicker fusion or varying spectral frequencies ofstimulation, this has not been routinely carried out.The most commonly diagnosed retinal dystrophy

was Leber's amaurosis, first described by Leber in1869,7 in infants who before the age of 1 year showappreciably reduced vision, nystagmus, and poorpupillary reactions. It is regarded as having an

autosomal recessive mode of inheritance. In 1954Franceschetti and Dieterle added an absent or

appreciably reduced electroretinographic responseto the diagnostic criteria.8 The fundus appearancevaries from normal to a retinal dystrophy likepicture. The disease can have systemic associationssuch as renal and neurological disease.9 Because ofthe varied presenting clinical signs and differingfundus appearances, the electroretinographic find-ings have been considered crucial in making thecorrect diagnosis. "'

As the electroretinogram shows a mass retinalresponse to light stimulation, it is obvious that anycondition that destroys a large amount of retina suchas gyrate atrophy and choroideraemia as well as a

large retinoblastoma will affect the response. Incoloboma of the eye there is thought to be defectiveclosure of the fetal fissure, leaving a defect which inthe retina is replaced by glial and fibrous tissue.Depending on the size of the coloboma and thereforethe amount of retina affected, the electroretinogrammay or may not be reduced. Bilateral maculardysplasia ('colobomata') has been described inassociation with retinal dystrophy," with the retinalresponses disproportionately small to the size of thecoloboma.

In the more severe forms of retinopathy ofprematurity in which there is an abnormal vascula-risation of the retina, the retina becomes detachedand the electroretinographic response is appreciablyreduced. The retina may also became detached inpersistent hyperplastic primary vitreous and soreduce the electroretinogram. In severe microph-thalmia the retina is poorly developed, especially asit is frequently associated with a coloboma, explain-ing both the poor vision and the reduced electro-retinogram. In primarily macular disorders such as

Stargardt's disease, enough peripheral retina may beaffected to reduce the response. Surgical proceduresincluding resection of an optic nerve glioma may

compromise the ocular circulation and thus accountfor electroretinographic abnormalities in such cases.


Hoyt and Billson first described a small or absentelectroretinogram in three patients with the infantileform of osteopetrosis (an abnormal response hasonly been found in one of six patients we haveexamined), despite a normal fundus appearance.'2They suggested that visual loss in these patients maybe the result of retinal degeneration rather thansolely due to optic atrophy, although the reason forany retinal pathology is not clear.

In our series by far the largest group of neuro-degenerative disorders showing electroretinographicabnormalities were the various types of Batten'sdisease (neuronal ceroid lipofuscinosis). Diagnosiscan be confirmed by histological examination only(as no biochemical defect has been identified) andcombined clinical neurophysiological assessment hasproved of considerable value in suggesting thediagnosis. 13 In all types of Batten's disease theelectroretinogram is affected at a relatively earlystage, particularly in the juvenile form which usuallypresents at 5 to 6 years of age with visual problems.It should be noted that the flash electroretinogram isnot affected in the various types of gangliosidoses asonly the ganglion cell layer of the retina is involvedin these disorders.'4 While the electroretinographicfindings may not be important in the diagnosis of themucopolysaccharidoses, it may often be worthwhilecarrying out electroretinographic studies to monitorany progression of retinal dysfunction especially inthe presence ol zataracts. Reduction of the electro-retinographic response, however, may be helpful inthe diagnosis of rarer disorders such as mucolipidosistype IV15 and Hallervorden-Spatz disease, and inour experience progressive changes may occur overa number of years in both these diseases. In thenewly recognised peroxisome disorders'6 it seemsthat electroretinographic abnormalities may bepresent from an early age,17 as we have found ininfantile Refsum's disease and some cases of Zell-weger's syndrome. An absent electroretinogram hasbeen reported in infantile adrenoleucodystrophy,'8although as yet we have not seen any cases with thisdiagnosis.The diagnosis of a syndrome is based on the

recognition of a pattern of associated anomalies. Insome of the syndromes listed in table 4 there is anassociated pigmentary retinopathgy as for example,Laurence-Moon-Biedl, Senior's1 and Joubert's20syndromes. There are also causes for a reducedresponse other than in a retinopathy as for example,coloboma in CHARGE syndrome,2' chorioretinallacunae in Aicardi's syndrome,22 retinal malforma-tions in Norrie's disease,23 and retinal dysplasia inWalker-Warburg's syndrome. 24

In the progressive neurological disorders and inmany of the syndromes listed, the electroretino-



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gram is progressively reduced in amplitude over thecourse of months or years, usually parallelingchanges in vision (and also in visual evoked poten-tials). In conditions such as eye injury (includingnon-accidental injuries) and retinal haemorrhages(secondary to for example, hypertension or leukae-mia), the extent of retinal abnormality is variableand determines whether or not the electroretino-gram is affected. This is also the case in infectionswhether congenital, such as toxoplasmosis orcytomegalovirus, or acquired (seen mainly inimmunosuppressed patients in our series). It shouldalso be noted that in most of the syndromesdescribed, retinal involvement (and consequentelectroretinographic abnormality) is not invariable.In a disorder such as mitochondrial cytopathy,which has such a very variable clinical expression, itis not surprising that less than half the cases we haveseen show electroretinographic abnormalities.25Associated deafness may occur in mitochondrialcytopathy and in some other conditions as forexample, Usher's and Senior's syndromes and infan-tile Refsum's disease among others.26 The auditoryproblem can be documented using brain stemauditory evoked potentials in the very young oruncooperative child, and the combination of abnor-malities found on electroretinography and brainstem auditory evoked potentials may be importantin delineating some of these disorders. In additionthe presence and type of any electroencephalo-graphic abnormalities may also be important insuggesting the nature of any associated cerebralinvolvement in some of the conditions describedespecially in some of the neurodegenerative dis-orders.

Recording of the flash electroretinogram appearsto have been a somewhat neglected investigation,especially in children, perhaps because it has generallybeen believed that it is only possible to carry outusing corneal electrodes under general anaesthesia.As outlined in this study, however, reliable recordingscan be obtained as a routine procedure in thewaking state, without any need for cooperation, andavoiding anaesthetic risks. Most departments ofclinical neurophysiology now have averaging equip-ment available and recording the electroretinogramfrom skin electrodes is quite feasible using averagingtechniques. There are advantages in electroretino-graphy being carried out in clinical neurophysiologyunits where evoked potential studies and electro-encephalography can also be carried out as appro-priate. The integrated reults often give much moreinformation than any one test alone, especially indisorders that may involve the brain or auditorypathways, or both.

It is appreciated that the disorders discussed in

this survey do not comprise an exhaustive list of allpaediatric conditions in which the electroretinogrammay be affected. Furthermore over the 10 yearperiod of this survey the diagnostic categories havewidened and some patients seen in the earlier yearsand, in particular, patients diagnosed as Leber'samaurosis would now be given a different diagnosticlabel as awareness of conditions such as Joubert'ssyndrome, cone dystrophies, and congenital sta-tionary night blindness have been appreciated.While it is not claimed that the flash electroretinogramrecorded with this technique can detect subtle orearly retinal involvement, the results show that thefinding of a reduced or absent response is oftenessential in the diagnosis of a wide variety of notonly ocular problems but also some neurodegenera-tive conditions and is a pointer towards the identifi-cation of some syndromes. As there are geneticimplications in a number of these disorders, theimportance of a correct and early diagnosis cannotbe over emphasised.We are grateful to the physicians and surgeons for referringpatients for these studies, in particular the neurologists Dr J Wilsonand Dr E Brett. It is a pleasure to acknowledge the help of thetechnicians whose patience and skills made these recordingspossible.

References

Harden A. Non-corneal electroretinogram: parameters innormal children. BrJ Ophthalmol 1974;58:811-6.

2 Harden A. Maturation of the visual evoked potentials. In:Chiarenza GA, Papakostopoulos D, eds. Clinical applications ofcerebral evoked potentials in paediatric medicine. Amsterdam:Excerpta Medica, 1982:41-59.

3Harden A, Pampiglione G. Neurophysiological approach todisorders of vision. Lancet 1970;i:805-9.

4 Harden A. Electrodiagnostic assessment in infancy. In: Wybar K,Taylor D, eds. Pediatric ophthalmology. New York: MarcelDekker, 1983:11-8.

5Francois J. Leber's congenital tapetoretinal degeneration. IntOphthalmol Clin 1968;8:929-47.

h Krill AE. Retinal disease of rubella. Arch Ophthalmol 1967;77:445-9.

7Leber T. Uber Retinitis pigmentosa und angeborene Amaurose.Albrecht von Graefes Archiv fdr Ophthalmologie 1869;15:1-25.

8 Franceschetti A, Dieterle P. Importance diagnostique de l'dlectro-retinogramme (ERG) dans les degenerescences tapeto-retiennesavec retrecissement du champs visuel et hemeralopie. ConfiniaNeurologica 1954;14:184-6.Vaizey MJ, Sanders MD, Wybar KC, Wilson J. Neurologicalabnormalities in congenital amaurosis of Leber: review of 30cases. Arch Dis Child 1977;52:399-402.

"' Schroeder R, Mets MB, Maunemee IH. Leber's congenitalamaurosis: retrospective review of 43 cases and a new fundusfinding in two cases. Arch Ophthalmol 1987;105:356-9.

" Moore AT, Taylor DS, Harden A. Bilateral macular dysplasia('colobomata') and congenital retinal dystrophy. BrJ Ophthalmol1985;69:691-9.

2 Hoyt CS, Billson FA. Visual loss in osteopetrosis. Am J DisChild 1979;133:955-8.

'3 Pampiglione G, Harden A. So-called neuronal ceroid lipo-fuscinosis. Neurological studies in 60 children. J Neurol Neuro-surg Psychiatry 1977;40:323-30.



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4 Pampiglione G, Harden A. Neurophysiological investigations inGM1 and GM2 gangliosidoses. Neuropediatrics [Suppli 1984;15:74-84.

'5 Amir N, Ziotogora I, Bach G. Mucolipidosis type IV. Clinicalaspects and natural history. Pediatrics 1987;79:953-9.

16 Schutgens RBH, Heymans HSA, Wanders RJA, Bosch HUD,Tager JM. Perioxisomal disorders: a newly recognised group ofgenetic diseases. Eur J Pediatr 1986;144:430-40.

7 Zellweger H. The cerebro-hepato-renal (Zellweger) syndromeand other peroxisomal disorders. Dev Med Child Neurol1987;29:821-9.

'8 Verma NP, Hart ZH, Nigro M. Electrophysiologic studies inneonatal adrenoleucodystrophy. Electroencephalogr Clin Neuro-physiol 1985;60:7-15.

'9 Senior B, Friedman Al, Braude JL. Juvenile familial nephro-pathy with tapetoretinal degeneration. Am J Ophthalmol1961;52:625-33.

211 King MD, Dudgeon J, Stephenson JBP. Joubert's syndromewith retinal dysplasia: a neonatal tachypnoea as the clue to agenetic brain-eye malformation. Arch Dis Child 1984;59:709-18.

21 Pagon RA, Graham JM, Zonana J, Young SL. Coloboma,congenital heart disease, and choanal atresia with multipleanomalies: CHARGE association. J Pediatr 1981;99:223-7.

22 Chevrie JJ, Aicardi J. The Aicardi syndrome. In: Pedley TA,Meldrum BS, eds. Recent advances in epilepsy 3. Edinburgh:Churchill Livingstone, 1986:189-210.

23 Hansen AC. Norrie's disease. Am J Ophthalmol 1968;66:328-32.

24 Pagon RA, Chandler JW, Collie WR, et al. Hydrocephalus,,agyria, retinal dysplasia, encephalocele (HARD±E) syndrome:an autosomal recessive condition. Birth Defects 1978;14:233-41.

25 Harden A, Pampiglione G, Battaglia A. 'Mitochondrial myo-pathy' or mitochondrial disease? EEG, ERG, VEP studies in 13children. J Neurol Neurosurg Psychiatry 1982;45:627-32.

26 Mills RP, Calver DM. Retinitis pigmentosa and deafness. J RSoc Med 1987;80:17-20.

Correspondence to Dr A Harden, Department of Clinical Neuro-physiology, The Hospital for Sick Children, Great Ormond Street,London WC1N 3JH.



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