pontocerebellar hypoplasia in infants - Journal of Neurology ...

Journal ofNeurology, Neurosurgery, and Psychiatry, 1977, 40, 370-378

Anterior horn cell disease associated withpontocerebellar hypoplasia in infantsFRANCOISE GOUTIERES, JEAN AICARDI, AND EDITH FARKAS

From the Laboratoire de Neuropathologie, Hopital Saint Vincent de Paul, andInstitut National de la Sante' et de la Recherche Medicale, Paris, France

S UMMAR Y Three sibs presented with an identical clinical picture of severe mental retardation,cortical blindness, and extensive peripheral paralysis of lower motor neurone type, and died beforeone year of age. In the one necropsied case, spinal cord lesions, indistinguishable from those ofWerdnig-Hoffmann disease, were associated with extreme hypoplasia and atrophy of the cerebellum,and with atrophy of the ventral part ofthe pons. No prominent abnormalities were found in the nervessampled despite gross reduction of motor and sensory conduction velocities in two infants. It is pro-

posed that this familial disorder is distinct from Werdnig-Hoffmann disease, and represents a furthersubtype in the heterogeneous group of the infantile muscular atrophies.

Supraspinal and suprabulbar lesions have long beenrecognised in Werdnig-Hoffmann disease (Brandt,1950; Radermecker, 1951, 1953; Thieffry et al.,1955; Miranda-Nieves and Campos-Castello, 1970).In a few cases, gross abnormalities of the cerebellumhave been reported in association with the character-istic changes ofinfantile spinal amyotrophy (Norman,1961; Norman and Kay, 1965; Weinberg and Kirk-patrick, 1975). These were considered atypical casesof Werdnig-Hoffmann disease, although the clinicalpicture was quite unusual with mental retardationand spasticity as prominent features. In this paper, wereport a familial case of associated cerebellar hypo-plasia and spinal anterior horn cell disease, anddiscuss the nosological situation of this, and of pre-viously reported similar cases, with reference to themore classical spinal amyotrophies of infancy andchildhood, and to other forms of cerebellar hypo-plasia and atrophy.

Case reports

Case 1, LV, a girl, the third child of healthy unrelatedparents, was born at term in breech presentation,weighing 2325 g. The Apgar score at one minute was2, on account of severe hypotonia and poor respira-tory movement. On admission at 10 days, multiplejoint contractures were evident. The lower limbs were

Address for reprint requests: Francoise Goutieres, H6pital SaintVincent de Paul, 74 avenue Denfert Rochereau, 75674 Paris C6dex 14,France.Accepted 2 November 1976

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fixed in extension and rotated 900 on the truncal axisThe head was turned laterally to the opposite direction(Fig. 1). Hip abduction was limited to 200 on bothsides. The thumbs and third fingers were permanentlyflexed. A severe degree of diffuse muscular atrophywas evident with very little spontaneous movement.Tendon reflexes could not be found. BilateralBabinski and Rossolimo signs, however, were elicited.Intercostal muscles were paralysed, the diaphragmappearing normal. There was marked retrognathism,and the tongue was atrophic and fasciculating.Suction was weak, and no gag reflex was found. Aright facial palsy was evident. The cry was bitonal onaccount of a partial abductor paralysis as shown bylaryngoscopy. Ocular jerks of a large amplitude werenoted, and the child did not follow objects. Photo-motor responses were preserved. The child had nointerest in her surroundings, and mental developmentremained quite limited until her death, at age 3months, from respiratory insufficiency. Cranial cir-cumference was 36.5 cm at 6 weeks (-1 .8 SD).

SPECIAL INVESTIGATIONSThe CSF, fundi, and electroretinogram were normal.Visual evoked potentials were of an immature typewith delayed positive deflection. Pneumoencephalo-graphy revealed slight enlargement of the lateralventricles with large cisterna magna and prepontinecisterna. The brainstem appeared abnormally thin.Electromyography of the quadriceps, deltoids andtibialis anterior muscles displayed intermediatetracings with high amplitude potentials, interpreted

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Anterior horn cell disease associated with pontocerebellar hypoplasia in infants

_---- nique for neurones, Loyez's technique for myelin, andHoizer's technique for fibrillary glia. Serial sections ofPons and medulla were available. The femoral nervewas stained by haematoxylin-eosin and Massontrichrome. Frozen sections were stained by Oil Red 0and Sudan Black.

After fixation, the brain weighed 475 g (mean forage 516 g). The cerebellum and brain stem wereextremely small (Fig. 2), weighing together 8 g. Thecerebellar hemispheres were tiny and flattened, thevermis being relatively better preserved. Due to theminute size of the cerebellum, however, it was notpossible to make out the various parts. The size of thebrain stem was about half that of a control of thesame age. The spinal cord was grossly normal. Theanterior nerve roots, however, were abnormally thin.On coronal section the lateral ventricles were slightlydilated. Horizontal sections through the brain stemshowed that the ventral portions of the pons andmedulla were more affected than the dorsal parts(Fig. 3).

Microscopically, the most remarkable lesions werefound in the cerebellum, pons, medulla oblongata,and spinal cord. Cerebellar hypoplasia was especially

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Fig. 1 Abnormalposition oflower limbs, permanentflexion of thumbs, and retrognathism.

as typically neurogenic. Motor nerve conductionvelocity (right peroneal nerve) was 8 m/s. Sensorynerve conduction velocity was 15 m/s (median nerve)and 16 m/s (sural nerve).

POSTMORTEM EXAMINATION

Except for terminal bronchopneumonia, significantabnormalities were limited to the nervous system.The material received for examination consisted of thebrain, the spinal cord, and a sample of the cruralnerve, fixed in formol saline. Paraffin and celloidin-embedded sections of the central nervous system Fig. 2 Extreme hypoplasia of cerebellum and brainwere stained with haematoxylin-eosin, Nissl's tech- stem.

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Fig. 3 Pons. Horizontal section. Luxolfast blue. Marked atrophy ofpes pontis.

marked in the hemispheres which consisted of only afew broad and simplified folia (Figs. 4 and 5). Thegranule cell and Purkinje cell layers were extremelythin, having entirely disappeared in some places. Thevermis was more easily identifiable; it contained anouter granular layer. The dentate nuclei were hardlydistinct. They were poorly convoluted, the neuronesforming rounded clusters in several places. The whitematter was markedly gliotic, and its myelination wassomewhat poor. The pes pontis was severely atrophic.Only a few neurones remained in the pontine nuclei,and gliosis was marked. Gliosis was also severe in themiddle cerebellar peduncles with only a few myelinsheaths. In the medulla, the inferior olives were ex-tremely atrophic and poorly convoluted. Only a fewneurones were present, some ofthem with a balloonedcytoplasm and eccentric nucleus. The nucleus am-biguus was not identifiable. Loss of cells was evident

in the XIIh nerve nucleus which contained someswollen and chromatolytic neurones in axonalreaction. In the spinal cord, mostly in its lumbarportion, the number of anterior horn cells was re-duced, as compared with a control of the same age(Fig. 6). Several neurones were small and retracted.Others displayed eccentric nuclei and ballooned,chromatolytic cytoplasm (Fig. 7). Myelin sheaths inthe anterior nerve roots were sparse and thin, and thenumber of axons was reduced. No abnormalitieswere found in the thalami, cerebral peduncles, sub-stantia nigra, red nuclei, and nuclei of the IlIrd, IV',VIth, and VIIth nerves. The cortex was not affected.Myelination of the cerebral hemispheres, pyramidaltracts, and tracts of the spinal cord appeared normalas did the posterior nerve roots. In the lenticularnuclei, a few chromatolytic cells were seen. In thefemoral nerve, the number of myelin sheaths seemed

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Fig. 4 Horizontal section through cerebellum. Luxolfast blue. Extremtie atrophy ofhemispheres with poorlyconvolutedfolia. Less marked involvement of vermis.

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to be diminished with several empty endoneuralsheaths. This finding was deemed compatible withWallerian degeneration but the technique used wasinsufficient for complete assessment.

Case 2, EV, a boy, the older brother of case 1, was thesecond child of the family. He was born at termweighing 3140 g. From birth, he was hypotonic,breathing movements were poor, and the cry was

Fig. 5 Cerebellar cortex. Nissl( x 90). Alteration of internalgranular cells layer whichdisappears totally in some places.

weak. Limb mobility was extremely limited. Thefacies was expressionless with retrognathism, andswallowing was impaired. On admission at age Imonth, there was diffuse muscular atrophy and para-lysis involving also the intercostal muscles. His crywas very much like his sister's, and similar joint con-tractures were noted. Tendon reflexes were brisk. Theplantar responses were extensor, and there weredefinite bilateral Rossolimo signs. Cranial circum-

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ference was 35.5 cm (-1.2 SD). When admittedagain at 4 months of age, limb paralysis was com-

plete, with severe muscular atrophy predominatingproximally. Tendon jerks were no longer obtainablein the lower limbs but still present in the arms. Painsensitivity was grossly preserved. Mental retardationwas now evident as were coarse ocular jerks. Therewas facial diplegia. Cranial circumference was 39.3cm (-1.9 SD). He died at 7- months. There was no

necropsy examination.

SPECIAL INVESTIGATIONSCSF protein concentration was 0.72 g/l at 1 month,and 0.56 g/l at 5 months. Pneumoencephalographyshowed normal sized ventricles with a very large

cisterna magna and large prepontine cisternae.Electromyography of the tibialis anterior disclosedfibrillation activity, and polyphasic motor unitpotentials. Motor nerve conduction velocity (mediannerve) was 13 m/s, and sensory nerve conductionvelocity (right median nerve) 17 m/s at 1 month. At 4months motor nerve conduction velocity could no

longer be estimated as stimulation produced no

muscle response. Muscle biopsy of the vastuslateralis at 6 weeks of age was interpreted as normal.Biopsy of the sural nerve revealed no abnormality on

histological and ultramicroscopic examination. Ahistogram of nerve fibre diameter was normal for theage. Teasing showed no major anomalies of the nervefibres. Internodal distances were, however, excessively

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variable for fibres of similar diameters, especiallyso in the smallest ones. The significance of this isuncertain.

Case 3, CV, the oldest brother of cases 1 and 2, wasborn at term weighing 2200 g. The parents statedthat hypotonia, respiratory paralysis, and joint con-tractures were noticed from birth. Tendon reflexeswere not found. The cry was weak and swallowingwas impaired. He seemed mentally retarded and diedat 6 weeks of age from respiratory complications. Noinvestigations were done, and no necropsy wasperformed.

Comments

The unusual picture of central and lower motorneurone involvement in three sibs, with almost iden-tical clinical features and course, leaves little doubtthat all three infants were affected with thesame illness.In the one pathologically verified case, an extremedegree of cerebellar hypoplasia was associated withdegenerative changes in the spinal anterior horn cellsand brain stem nuclei, indistinguishable from thoserecorded in Werdnig-Hoffmann's disease.The same-or a closely similar-association of

cerebellar hypoplasia and atrophy with anterior horncell abiotrophy, has been reported previously in twopatients (Norman, 1961; Weinberg and Kirkpatrick,1975). In all three necropsied patients (Table), therewas a conspicuous loss of large anterior horn cellswith several greatly inflated chromatolytic perikarya.Several brain stem nuclei were similarly affected, andthe thalami were involved in one patient (Norman,1961). In every case, the cerebellum was very much

Fig. 7 Spinal cord: anteriorhorn. Nissl ( x 220). One neuronewith ballooned cytoplasm andeccentric nucleus.

reduced in size, the hemispheres being even morecompromised than the vermis. The cerebellar lesionswere mixed in type, with both atrophy of apparentlypreviously normally formed structures and hypo-plasia of a malformative type, with reduction in thenumber of convolutions and abnormal disposition ofthe cellular layers. The dentate nuclei were atrophicand malformed with rounded groups of cells presentin two cases. The pons, especially in its ventral part,was severely affected, the nuclei pontis and transversefibres being greatly reduced in number, in associationwith a severe gliosis. The inferior olive also had minormalformations in Norman's case and in our case 1.The clinical picture was one of severe, and perhaps

progressive, mental retardation, spasticity and con-tractures, and diffuse peripheral paralysis of the trunkand limbs with hypotonia. In at least two cases thepharyngolaryngeal musculature was affected and, inall patients, respiratory failure was evident. Allinfants died before the end of their first year. Inaddition to these general features, several interestingpoints emerged in our patients in whom far moreclinical data are available than the scanty informationexisting on the two previous infants. Thus, we havebeen able to document the peripheral character of theparalysis, with loss of deep tendon reflexes andelectrical signs of denervation. Additional features,not previously recorded, include microcephaly,cortical blindness with abnormal eye movements,laryngeal involvement with a peculiar cry, pyramidaltract signs, intercostal muscles paralysis, anddefinite lowering of motor and sensory nerve con-duction velocity. The progressive course of the dis-order was illustrated in case 2, where tendon reflexes,initially present, were no longei found at 4 months of

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Table Summary offindings in six reported cases

Case Sex Age at Clinicalfindings Family Age at Neuropathologicalfindingsonset death

Norman M birth Hypotonia. Adductor spasms. 0 6 mo. Spinal cord: WH* changes.(1961) Mental deterioration. Medulla: neuronal loss in

Respiratory failure. inferior olives and cranial nuclei.Impairment of swallowing. Pons: atrophy and gliosis of the

pes. Cerebellum: poorly develoredfolia, loss of granular andPurkinje cells, atrophy of nucleusdentatus. Normal vermis.Thalamus: neuronal loss.

Weinberg and M birth Hypotonia. Absent tendon I normal 4 d Spinal cord: WH changes.Kirkpatrick jerks. Respiratory failure. half-sibling Medulla: neuronal loss in(1975) Impairment of swallowing. inferior olives. Gliosis. Pons:

Muscle biopsy: neurogenic severe reduction of pontineatrophy. nuclei. Cerebellum: poorly

developed folia mostly inhemispheres. Atrophy of deepnuclei

Present cases F birth Hypotonia; muscular atrophy; + 3 mo Spinial cord: WH changes.I paralysis of limbs and sister of cases Medulla: atrophy of inferior

respiratory muscles. Absent 2 and 3 olives and cranial nuclei. Poas:tendon jerks; pyramidal tract gliosis of pes; neuronal loss ofsigns; cranial nerve intrinsic nuclei. Cerebellum:involvement. Mental poorly developed folia; loss ofretardation. Low conduction granules and Purkinje cells;velocity. severe atrophy of nucleus

dentatus; vermis partially spared.

2 M birth Hypotonia; muscular atrophy; + 7j mo NEtdisappearance of tendon jerks; brother of casesparalysis of limbs and inter- I and 3costal muscles; pyramidal tractsigns; cranial nerve involvement;mental retardation; low conductionvelocity of nerves.

3 M birth Hypotonia; absent tendon + 1 mo NEjsrks; limb contractures; brother of casescranial nerve involvement; I and 2mental retardation.

Norman and F ? Hypertonic lower limbs; + 22 mo Spinal cord: WH changes; poorKay first seen increased tendon reflexes left I brother similarly myelination of posterior and(1965) at 11 mo Babinski; mental retardation. affected died at lateral fasciculi; gliosis.

11 mo Medulla: neuronal loss of cranialnuclei. Pons: normal.Cerebellum: loss of granular andPurkinje cells in hemispheresand vermis; gliosis; atrophicchanges of cells of dentate nucleus.Thalamus: extreme atrophy andgliosis.

*WH =changes of Werdnig-Hoffmann disease.tNE=not examined.

age. In none of the patients were cerebellar signsrecorded.Although some of the clinical symptoms and signs

are readily explainable in view of the pathologicallesions-for example, peripheral paralysis, absentreflexes, and cranial nerve palsies-no satisfactoryaccount can be given in any of the cases for the mentaldefect, blindness, spasticity, and lack of cerebellarsigns. The latter, however, is quite common in con-genital malformations of the cerebellum (Greenfield,1954), and the young age at death might have pre-

vented their appearance. The slow nerve conductionvelocity repeatedly found in two of our infants ispuzzling, since no major myelin sheath abnormalitieswere found in the nerves sampled, and since theslowing was much more marked than that occasion-ally mentioned in lower motor neurone disease(Gamstorp, 1967; Raimbault and Laget, 1972). Inthe face of the pathological findings, however, we donot think that a diagnosis of primary nerve disorderis warranted, unless the normal aspect resulted from asampling error.

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The clinicopathological picture present in the threecompletely documented cases and, in all probability,in our two other patients, is probably to be regardedas a specific morbid entity, distinct from Werdnig-Hoffmann disease. Although the two previously re-ported patients were considered as cases of Werdnig-Hoffmann disease with unusually extensive supra-spinal involvement, the chance association of twouncommon central nervous system anomalies inseveral infants is highly unlikely, and the occurrenceof this symptom complex in three sibs makes thishypothesis even less tenable. The most likely hypo-thesis is that of a genetic, probably recessive, dis-order, resulting from the action of a single mutantgene.The infantile spinal atrophies have recently been

shown to encompass several disorders with distinctclinical and genetic features (Zellweger et al., 1969;White and Blaw, 1971; Van Wijngaarden andBethlem, 1973; Bundey and Lovelace, 1975), and it isconceivable that the cases here described constituteone further rare subtype within this group. Otherhypotheses, such as a viral disorder resembling thatwhich occurs in cats infected with feline panleuco-penia virus and other viral agents (Kilham et al., 1971;Brown et al., 1973; Monjan et al., 1973), seem lesslikely in view of the degenerative type of the cordlesions, and the lack of inflammatory changes in thecord despite the postnatal progression of the disorder.The relationship of our cases and those of Norman

(1961), and Weinberg and Kirkpatrick (1975), with afew other related cases deserves some comment.Norman and Kay (1965) have reported the cases oftwo siblings affected with a disorder which they con-sidered to be an unusual variant of Werdnig-Hoffmann disease, featuringcerebellar degeneration inaddition to spinal, brain stem, and thalamic involve-ment. In the one pathologically documented case(Table) cerebellar lesions were of a purely degenera-tive character without evidence of malformation, andthe degree of atrophy was far less severe. The pespontis was normal as were the inferior olives. Theclinical picture was predominantly one of spasticitywith brisk reflexes and mental retardation leading todeath at 22 months of age. Whether these patientswere affected with a milder form of the disease herereported is impossible to state, in spite of clinical andpathological resemblances. There were no malforma-tions of the cerebellum or brain stem, suggesting thatthe noxious agent had been active later than in thepresent patients, and the authors considered thesecases distinct from the case of cerebello-spinal dis-order they had reported previously.On the other hand, the cases of cerebello-pontine

hypoplasia described by Norman and Urich (1958)as hypoplasia pontoneocerebellaris, are certainly

different from the present cases since, in spite of thesimilarity of the cerebellar and olivo-pontine lesions,the spinal cord was not involved.

Addendum

Since submission of this paper we have been in-formed by Dr P. Procopis (Sydney, NSW, Australia)that he has observed a family in which siblings hadbeen affected with the same disorder. Pathologicalfindings in two of these children were identical tothose in our case 1.

References

Brandt, S. (1950). Werdnig-Hoffnmann's Infantile Progress-ive Muscular Atrophy. Munskgaard: Copenhagen.

Brown, T. T., Delahunte, A., Scott, F. W., Kahrs, R. F.,McEntee, K., and Gillespie, J. H. (1973). Virus inducedcongenital anomalies of the bovine fetus. II Histo-pathology of cerebellar degeneration (hypoplasia)induced by the virus of bovine viral diarrhea-mucosaldisease. Cornell Veterinarian, 63, 561-578.

Bundey, S., and Lovelace, R. E. (1975). A clinical andgenetic study of chronic proximal spinal muscularatrophy. Brain, 98, 455-472.

Gamstorp, I. (1967). Progressive spinal muscular atrophywith onset in infancy or early childhood. Acta Paediat-rica Scandinavica, 56, 408-423.

Greenfield, J. G. (1954). The Spinocerebellar Degenera-tions. Blackwell: Oxford.

Kilham, L., Margolis, G., and Colby, E. D. (1971).Cerebellar ataxia and its congenital transmission incats by feline panleukopenia virus. Journal ofAmericanVeterinary Association, 158 (Suppl. 2), 888.

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Norman, R. M. (1961). Cerebellar hypoplasia in Werdnig-Hoffmann disease. Archives of Disease in Childhood.36, 96-101.

Norman, R. M. and Kay, J. M. (1965). Cerebello-thalamo-spinal degeneration in infancy: an unusual variant ofWerdnig-Hoffmann disease. Archives of Disease inChildhood, 40, 302-308.

Norman, R. M. and Urich, H. (1958). Cerebellar hypo-plasia associated with systemic degeneration in earlylife. Journal ofNeurology, Neurosurgery, and Psychiatry,21, 159-166.

Radermecker, J. (1951). L'amyotrophie spinale del'enfance (Werdnig-Hoffmann) comme heredo-degenerescence. Revue Neurologique, 84, 14-31.

Radermecker, J. (1953). Sur les lesions supra-

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spinobulbaires dans l'amyotrophie de Werdnig-Hoffmann. Revue Neurologique, 89, 368-370.

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Thieffry, S., Arthuis, M., and Bargeton, E. (1955).Quarante cas de maladie de Werdnig-Hoffmann aveconze examens anatomiques. Revue Neurologique, 93,621-644.

Weinberg, A. G. and Kirkpatrick, J. B. (1975). Cerebellar

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White, N. R. and Blaw, M. E. (1971). An unusual in-heritance pattern for spinal muscular atrophy. Develop-mental Medicine and Child Neurology, 13, 621-624.

Wijngaarden, G. K. Van and Bethlem, J. (1973). Benigninfantile spinal muscular atrophy. A prospective study.Brain, 96, 163-170.

Zellweger, H., Schneider, H. J., Schuldt, D. R., andMergner, W. (1969). Heritable spinal muscularatrophies. Helvetica Paediatrica Acta, 24, 92-105.

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