neuropathological dysautonomia - bmj · the pars distalis of the pituitary gland was congested. the...

J. Neurol. Neurosurg. Psychiat., 1964, 27, 131

A neuropathological study of familial dysautonomia(Riley-Day syndrome) in siblings

W. JANN BROWN, J. A. BEAUCHEMIN, AND LEONARD M. LINDE

From the Departments of Pathology (Division of Neuropathology) and Paediatrics,University of California, School of Medicine, Los Angeles, California

Riley, Day, Greeley, and Langford (1949) describedthe clinical features of a disturbance of the auto-nomic nervous system manifested by skin blotching,fluctuations in blood pressure, erratic temperaturecontrol, disturbances of the swallowing reflex, hyper-hidrosis, and diminished or absent lacrimation. Ad-ditional signs of neurological involvement includedincoordination, relative insensitivity to pain, dimin-ished deep tendon reflexes, emotional lability, anddisturbances of the gastrointestinal tract withepisodes of severe vomiting.

While this widespread involvement of the nervoussystem was evident clinically, attempts to elucidatethe histopathology and pharmacopathology havemet with only partial success. The aetiology andpathogenesis of this condition remains obscure.Aring and Engel (1945a, 1945b) reported clinical

and pathological studies in a patient who had'hypothalamic attacks' and at necropsy an oldcystic lesion was found in the thalamus. Theseauthors postulated repeated paroxysms of hypo-thalamic overactivity because of disruption ofcorticohypothalamic association tracts described byMagoun (1939) which coursed through a cysticdegenerative lesion of the dorsomedial and lateralnuclei of the right thalamus. The clinical descriptionsof the 'hypothalamic attacks' are those of dysauto-nomia.

In a more recent necropsy study of a typical caseof dysautonomia, Cohen and Solomon (1955) foundthe pons and medulla grossly smaller than normaldue to alterations in the reticular formation. Noaetiological clues could be found. These authorsbelieved that the pathological changes had occurredin tracts similar to those described by Magoun (1939)in cats. These tracts arise in the lateral hypothalamusand descend to preganglionic sympathetic neuronsof the spinal cord. In the medulla, these tracts aresituated largely in the lateral reticular formation.

Recently Riley (1957) presented a comprehensivereview of this condition. He reviewed t'1ree newcases. In one case there were multiple brain abscesses,presumably secondary to an aspiration type pneu-

monia. In the other cases abnormalities of the centralnervous system were sought using the Cohen andSolomon (1955) criteria. but none were found. Nonote was made of any examination of the peripheralnervous system.The two cases in siblings reported here are

significant in that the abnormalities described byCohen and Solomon (1955), and to some extent byAring and Engel (1945a), were present. In addition,changes in the dorsal longitudinal bundle in thebrain-stem, spino-thalamic tracts of the cord andmedulla, ascending dorsal columns, and spino-cerebellar tracts were found. Also included in thereport is a detailed study of significant changes inautonomic ganglia and peripheral nerves.

MATERIALS AND METHODS

The brains of both cases and the spinal cord of case 1were fixed in 10% neutral formalin. Other tissues werefixed in both Zenker's solution and 10% neutral formalin.An extensive dissection was carried out on case I andeyes, muscles, lacrimal glands, tongue, vagus, peroneal,femoral nerves, brachial plexus, and autonomic nervechains were all sampled and placed in both fixatives.Autonomic ganglia from the coeliac plexus and thethoracic and pelvic regions were taken. The brain incase 2 was coronally sectioned and embedded in bothcelloidin and paraffin. The brain and spinal cord in case 1were similarly cut and embedded only in paraffin. Thebrains and cord were sectioned subserially and stainedusing multiple histopathological techniques (Weil,haematoxylin and eosin, Holzer, Nile blue sulphate,Luxol fast blue, Bielschowsky, and Bodian preparations).Tests for melanin, iron, lipofuscin and periodic acid-Schiff (P.A.S.)-positive materials were done on tissuesections of autonomic ganglia using methods describedby Pearse (1960).

CASE REPORTS

CASE 1 The clinical details of this case have been exten-sively treated in another context by Linde (1956). Thefollowing is only a brief clinical abstract:

J.S., a 2-year-old Jewish girl, was noted on the secondday of life to have hypotonia, hypertension, poor colour,

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FIG. 1. Caselat2lyearsofage.Noteextremelossoftissue.

FIG. 2. Pons in case 1. Note enlargedfourth ventricle, lackof abnormality of cortico-spinal tracts, and slight spongyappearance of reticular formation in insert. Weil x 8.

poor feeding, and defective swallowing. 'Dysautonomia'was diagnosed and she was placed in a nursing home bythe parents. During her stay in hospital she consistentlyfailed to gain weight and died after a 'progressive down-hill course'. The baby never produced tears and wasinsensitive to pain. She had recurrent aspiration pneu-monia. The terminal episode was related to aspiration.The mother had cancer of the thyroid and had beentreated by local irradiation some time before conception.Necropsy revealed an emaciated 2-year-old white

female (Fig. 1) who measured 58 cm. from crown to heel;head circumference was 38 cm. The total body weightwas 2,600 g. Both corneas were opaque. There weremultiple deformities and fibrotic scars in the tongue. Theupper teeth were intact, but only one tooth was presentin the lower jaw. The skeletal muscle was thin andatrophic. There was bronchopneumonia and focalatelectasis. The oesophagus and colon were moderatelydilated. The adrenals weighed 2-0 g. together. Micro-scopically extensive fibrous scarring of the tongue andserous atrophy of body fat were noted. In the focalatelectatic regions the alveoli contained foamy fat-filled macrophages and occasional giant cells. The zonareticularis of the small adrenals contained copiousamounts of golden-brown pigment. The lacrimal glandepithelium was slightly atrophic and cells contained a fewvacuoles, but neural elements of the gland were normal.Numerous small capillaries in the iris beneath the pig-ment layer, as well as focal parakeratosis of cornealepithelium, were noted in sections of the eyes.

Neuropathological findings The neuropathologicalfindings included, on gross examination, several smallgyri in the frontal and posterior parietal lobes and en-largement of the fourth ventricle (Fig. 2). The contour ofthe spinal cord appeared normal. On microscopicexamination the veins and capillaries of the lepto-meninx, cortical and subcortical white matter wereengorged. Sharply defined enlarged perivascular spaceswere noted. Cortical lamination was distinct, but manyneurones of the third, fifth, and sixth layers of the frontallobes were poorly stained, had vacuoles, and little Nisslsubstance. Subcortical myelination was not completebut its extent was consistent with the child's age. Mye-linated tracts and fibres in the basal ganglia appearednormal, but there were a few scattered petechiae andoccasional vacuolated neurones. No pathological altera-tions of the tracts and nuclei of the thalamus were found.Infantile multilayered ependymal cells were still presentalong the edges of the lateral ventricles. The cell popu-lation and general architecture in both anterior andposterior segments of the hypothalamus were normal.The pars distalis of the pituitary gland was congested.The substantia nigra was not pigmented. The myelinsheaths of the lower and mid-pontine reticular formationwere sparse (Fig. 3a). In longitudinal sections 'digestionchambers' could be seen, along with variously shapedswellings along the myelin sheaths. Only an occasionalsmall sheath could be seen in some regions that normallycontained a large amount of myelin. Phagocytic activitywas not seen. There was, however, a slight increase inthe number of astrocytes present. The pontine nuclei andbrachium conjunctivum appeared normal. The spino-

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FIG. 3a FIG. 3bFIG. 3a. Note absent and distorted myelin sheaths in reticularformation ofpons takenfrom insert ofFigure 2. There areoccasional astrocytes present, but no oligodendroglia. Note lack of reactive cell response. Compare density of the sheathswith similar region ofreticularformation in normalpons. Weil x 460.FIG. 3b. Reticular formation from normal pons. Note compact dense fascicles of myelin sheaths with scattered oligon-dendroglia. Weil x 460.

FIG. 4. Note swollen, ballooned,and degenerated myelin sheaths incross section of ascending posteriorcolumns of cervical spinal cord incase 1. The fasciculus gracilis is shownbut both fascicles were involved.Weil x 300.

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thalamic fasciculus was partially demyelinated and noreactive cells were present in and around the tract. Themyelin of the dorsolongitudinal fasciculus was distortedand more sparse than that of normal tracts. There werescattered irregular sheaths in the mesencephalic tract ofthe fifth nerve in the mesencephalon and pons. In thecerebellum there were a few scattered foci of primitiveneuroblasts in the molecular layer and occasional lostPurkinje cells, but there were no changes in the supportingglia or granular cell layer. The cranial nerves and nucleiof the medulla appeared normal. A few fibres along thelateral edges of the medial lemniscus were distorted. Thechange in the nearby reticular formation was pronounced.Sheaths were lost, some distorted, others were merelyghosts, but neither phagocytic response nor free fat wasfound. The neuron population of the reticular formationwas less than normal, but this change was not striking.There was no evident demyelination of the inferior olivesor restiform bodies. Spongy forms and irregular enlarged'digestion chambers' were noted in the myelin sheaths atall levels of the fasciculus gracilus and cuneatus, butthe change was most pronounced in the former (Fig. 4).The spinothalamic tracts, both lateral and ventral, and toa lesser extent, the spinocerebellar tracts, showed myelinand axis cylinder alterations similar to those of theposterior columns. The lateral and ventral corticospinal

tracts appeared normal for this age, as did theventral roots.Numerous segments of the peroneal and femoral

nerves, as well as elements of the brachial plexus, wereexamined, and only an occasional sheath was d:myeli-nated. Posterior roots, on the other hand, did haveirregular loss of myelin sheaths, as well as scatteredballooned and spongy alterations in sheaths (Fig. 5).Sympathetic fibres of the thoracic and cervical chainsand vagus nerves in general had normal axon cylinders,but there were scattered irregular enlargements, and lostfibres were replaced by proliferated fibrocytes. Roundvacuoles of various sizes were noted in the cytoplasm ofganglion cells of the sympathetic chains. Fat stains,P.A.S. preparations, iron and protein stains, all failed tocharacterize the vacuoles. Some of the ganglion cells ofthe coeliac plexus and pelvic ganglia (Fig. 6) containeddense masses of material in the cytoplasm which re-sembled lipochrome. Bodian and Masson Fontana pre-parations showed the argyrophilic nature of this material.The Gomori silver methenamine test failed to show anyreducing properties in the cytoplasmic granules. Ingeneral, the argyrophilic material was finely divided andsprinkled near the nucleas of t.ie cell. Though myentericplexuses were prominent throughout the oesophagus,stomach,. pyloric junction, small bowel, and vermiformappendix, the ganglion cells had a bright eosinophilic

FIG. 5. Ganglion cells in coeliac plexus of case 1. Note degenerated, irregular cells with masses of silverdeposited in cytoplasm and obscuring the nucleus. Also note discrete granules in cytoplasm of other cells.Bodian preparation. x 200.

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FIG. 6. Swollen, bulging myelin sheaths from posteriorroot of case 1. Note large bubbles in 'digestion chambers'ofsome sheaths contributing to transparency of the sheath.Weil x 2,070.

cytoplasm but lacked the argyrophilic masses similar tothose of the coeliac plexus ganglia.

CASE 2 S.S., an 8-year-old boy, died after his fifteenthadmission to hospital. The details of his extensive andcomplicated clinical history have been reported byLinde (1956). In summary, the numerous admissionswere for various combinations of autonomic and neuro-

logical dysfunction which included aspiration pneumonia,atelectasis, cyanosis, apnoea, vomiting, fever, abdominaldistention, cough, flaccidity, arreflexia, incoordination,deficient lacrimation, indifference to pain in relation totraumatic ulceration of the tongue, anorexia, convulsions,dehydration and acidosis, choking spells, disorientation,hysteria, and, finally, shock and coma in relation todehydration and vomiting.

Necropsy revealed an undersized boy with markedlydiminished body fat and poorly formed pale musculature.The trachea and major bronchi bilaterally contained a

considerable amount of mucopurulent bloody fluid. Thelung parenchyma contained foci of consolidation and

irregular patches of atelectasis. The left ventricle of theheart was hypertrophied. The liver and kidneys wereatrophic. The adrenals weighed 7 g. (normal, 12-5 g.).

Microscopic examination revealed bronchiolitis, focalfibrosis with calcinosis, and some giant cells in thepulmonary alveoli. The mucosa of the lower oesophaguswas extensively ulcerated and overlay a thickened,fibrotic lamina propria.

Neuropathological findings The neuropathologicalfindings included a gross brain weight of 1,039 g. (normal,1,273 g.) which on section revealed an enlarged fourthventricle and atrophy of the brain-stem (Fig. 7). Thespinal cord, peripheral nerves, and sympathetic gangliawere not examined. The cerebrum was similar to that ofcase 1 except that the myelination was more advanced.The nuclei of the hypothalamus were normal. There wereneither fibre changes nor neurone losses in the thalamus.The limbic system, mesencephalon, and choroid plexuseswere severely congested and oedematous. There wassome pigmentation of the substantia nigra.The myelin sheaths of the reticular formation at the

ponto-mesencephalic level of the brain-stem were swollenin a fusiform fashion with scattered focal balloons(Fig. 8). The lateral portions of the reticular formationat this level and in the pons and medulla had a greatlydecreased incidence of myelin sheaths, although outlinesof fascicles of sheaths could be seen. The sheaths of thegrey portions of the reticular formation were also alteredand diminished in number. The changes appeared bothold and progressive. The recently altered fibres did notexcite any phagocytic reaction, nor was any free fatfound, but there were more astroglial nuclei in thereticular formation than in comparable control sections.At the mid-pontine level, the dorsal longitudinal tract ofSchutz contained scattered enlarged degenerated myelintubes amidst its sparsely myelinated fibres (Fig. 9).There were similar changes in the contour of myelin

sheaths of the mesencephalic tract of the fifth nerve.Structures of the medulla, exclusive of the reticularformation and including the medial lemniscus, mediallongitudinal fasciculus, olives, seventh, eighth, ninth,tenth, eleventh, and twelfth cranial nerves and nuclei,all appeared without abnormality.The medullary spino-thalamic tracts had lost many

myelin sheaths and, in addition, contained sheaths invarious stages of degeneration (Fig. 10). The restiformbodies were smaller than normal, but there were only afew sheaths that were changed. There were, however,neurones lost from both the dentate nucleus and thegranular layer of the cerebellum. The granular cell losswas irregularly distributed, chronic and, again, hadexcited no reactive cell infiltration. The cortico-spinaltracts appeared normal at all levels. The myentericplexuses of Auerbach and Meissner were normally dis-tributed but both types contained cytoplasmic vacuolesin ganglion cells. Histochemical tests on these vacuoles,similar to those used in case 1, showed no reaction.

DISCUSSION

The two cases presented here were siblings of Jewishextraction. The Jewish and sibling relationship hasbeen observed in dysautonomia by Hutchison and

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A neuropathological study of familial dysautonomia (Riley-Day syndrome) in siblings

TABLEPATHOLOGICAL FEATURES OF PRESENT CASES COMPARED WITH PREVIOUSLY REPORTED NECROPSIED CASES

Age and PeripheralSex Autonomic Nervous

System

Pertinent Systemic Distribution ofLesions in CentralFindings Nervous System

Aring and Engel 18 yr.(1945a, b) M

Not stated Severe physical Cystic malacia dorsomedial thalamicretardation nucleus, internal medullary lamina,

lateral nucleus, thalamus; petechiaedorsal motor nucleus, vagus, and dorso-longitudinal fasciculus; lateral reticu-lar formation pons and medullademyelination; reduction cervicalanterior horn cells and upper dorsalsegments spinal cord; loss of myelinin posterior columns

Acute necrosis liver;glomerulonephritis,chronic bronchialasthma, acutebronchopneumonia

Cohen and Solomon 34 yr.(1955) M

Riley (1957)

Hutchison and 15 mtb.Hamilton (1962) F

Not stated

Not statedNot statedNot stated

Not stated

Pes cavus,physical retarda-tion

Physical re-tardation

Demyelination reticular formation,medulla, and lower pons; loss neuronesof cranial nerve nuclei floor of fourthventricle; some atrophy restiform body

Case I Multiple brain abscessesCase 2 No lesions notedCase 3 No lesions noted

Case 1 No anatomical abnormalitiesnoted

Haematemesis andfebrile episode

Aspiration pneu-monia

Bronchopneumonia

Present case 1 2 yr. Degenerative pig-F mentary changes

ganglion cells,coeliac plexus,thoracic and pelvicsympathetic ganglia

Present case 2 8 yr. Vacuoles in my-M enteric plexuses

(complete dissectionnot done)

Hamilton (1962). The Table summarizes the knownfacts relative to necropsied cases thus far reportedin addition to the present case reports. Clinically,death in the present siblings was due to vomitingwith numerous episodes of aspiration broncho-pneumonia. In view of the physical state of thesepatients, it is difficult to rule out some overlay ofchanges in the nervous system due to malnutrition.Some of the lesions in the central nervous systemin the two cases are in many respects similar indistribution and nature to thecase reported by Cohenand Solomon (1955) but there are new findings inthese cases that warrant comment. Essentially focalold and slowly progressive demyelination and orfailure of development of myelin in the reticularformation was noted in the lower pons and medullain both cases. Neurones, too, appeared to be de-creased in the grey reticular formation, but moststriking was loss of myelinated fibres within thegrey substance, as well as in the lateral portion ofthe formation. The brain-stem of both cases wasmarkedly decreased in size with concomitantenlargement of the fourth ventricle. The loss of

Cachexia, Reticular formation, bilateral demye- Aspiration pneu-physical retarda- lination medulla and pons, atrophy moniation brain-stem, enlargement fourth ventricle;

focal myelin loss dorso-longitudinalfasciculus; loss of sheaths ascendingposterior columns, spinothalamic tracts,posterior roots and spinocerebellartracts; fibrosis cornea

Physical retarda- Bilateral loss of myelin from reticular Vomiting, dehydra-tion, ulceration formation, medulla, and pons, dorsal tion, aspirationof tongue longitudinal tracts, and spino- pneumonia, ulcera-

thalamic tracts of medulla tive oesophagitis,shock

reticular formation and dorsolongitudinal fasciculusportions of the tegmentum were responsible for theincrease in size of the fourth ventricle.

Histologically, the significant changes in themyelin sheaths of the reticular formation were notas obvious as those found in the case described byCohen and Solomon (1955). For instance, although'digestion chambers' and other distortions of thesheath were noted in the reticular formation, therewas no great profusion of such sheaths; rather, ageneral decrease in the staining was noted in the in-volved regions where sheaths appeared to be absent.In addition, no phagocytosis of degenerated myelinby gitter cells was noted nor were any extracellularfragments of these structures found. Fat stains oftissue from the reticular formation did not revealany free fat. Moreover, there was little gliosis in thebrain-stem. These features motivated against anacute or rapidly progressive demyelination in thebrain-stem.

In the case study of Cohen and Solomon (1955)the focal demyelination of the reticular formationhad a moderate phagocytic reaction with fat-

Cause of Death

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positive gitter cells present, which indicated someprogressive activity. The present cases had no suchreaction at the time of death. It is entirely possiblethat relapsing episodes occur in the pathogenesis orthat some of the changes represent failure of myelindevelopment of small fascicles of sheaths from birthrather than degeneration. In both instances, at anyone period, phagocytosis might be absent.Cohen and Solomon (1955) did not mention

changes in the dorso-longitudinal tract of Schutz,but in the present two cases, when compared withcontrol preparations (age, sex, and stain), sheathsand fibres of this tract were decreased and/ordistorted. In the detailed presentation of Aring andEngel (1945b), changes in this fasciculus are alsodescribed. Interruptions or degeneration of thedorso-longitudinal fasciculus, which is believed tocarry impulses from hypothalamic centres to auto-nomic nuclei of the brain-stem, combined withabnormalities of descending hypothalamic tractswhich course through the lateral reticular substance,may explain much of the autonomic dysfunctionwhich appears to originate from brain-stem nuclei.The thalamus was extensively studied because of

the cystic lesion described by Aring and Engel(1945b) which had destroyed portions of the dorso-medial nucleus, the internal medullary lamina, andthe lateral nucleus of the right thalamus, and alsobecause of the presence of the sensory componentof the Riley-Day syndrome. One side of the reticularformation in their case was affected also. The cystmay have been a coincidental lesion, possibly ofvascular origin. If autonomic dysfunction can resultfrom such a cyst, then there is a possibility ofsecondary dysautonomia. Lesions in this positionhave been noted, however, many times, and clinicaldysautonomia as a result is certainly rare. Theirpatient undoubtedly had clinical dysautonomia alongwith a unilateral lesion in the diencephalon. Theseinvestigators found no abnormalities of the hypo-thalamus. We failed also to reveal any changes inthe nuclei of either anterior or posterior segments ofthe hypothalamus or other parts of the diencephalon.

In both of our cases, there are abnormalities whichunderlie the sensory disturbances in these patients.Case 1, for instance, had loss of fibres of both thelateral and ventral spinothalamic tracts. There wereno spinal cord sections in case 2, hence we could notbe sure of the findings in that portion of the neuraxis,but there were changes in the spino-thalamic tractsof the medulla and in all probability similar changeswere present in the spinal cord. Loss of these tractshelps to explain the relative indifference to pain inthese patients.Absence of sheaths and/or sheath alterations in

the mesencephalic tract of the fifth nerve may

account for the lack of sensory response to stimu-lation of the fifth nerve and, in addition, the opacityand ulceration of the cornea.The abnormal proprioceptive responses in the

form of imbalance, ataxia, irregular hypotonia, and,in some cases, absent deep tendon reflexes, arelargely due to abnormalities of both the ascendingposterior columns and spino-cerebellar tracts, in theabsence of cerebellar changes. It will be noted in theTable that Aring and Engel (1945b) also found lossof myelin sheaths in ascending columns of thegracilus and cuneatus, and Cohen and Solomon(1955) found, in addition, atrophy of the restiformbody.

In a preliminary note, Linde and Westover (1962)have suggested that the ganglion cells and myentericplexuses of the gastrointestinal tract of children withfamilial dysautonomia are normal. In the presentstudy this was not strictly true, since abnormalities ofthe coeliac plexus, pelvic ganglia, and thoracic sympa-thetic ganglia were found. The black masses notedin the distorted ganglion cell cytoplasm are con-sidered to be significant, although non-specific,silver deposits. The vacuoles and focal cloudiness ofthe discrete structures of the cytoplasm imply thatsome of the ganglia are actually undergoing dis-solution. There was no phagocytic reaction present.In case 2, similar autonomic ganglia were notavailable for study, but nonetheless there werevacuoles in some ganglia of the bowel wall.

It is certainly evident from the above descriptionthat the anatomical substrate of this disorder is awidespread involvement of the nervous system, bothcentral and peripheral, with unequivocal involvementof the tracts of the reticular formation. Althoughthe anatomical lesions may help to explain manyclinical features of the disorder, ideas concerningtheir pathogenesis are still conjectural.The changes noted in peripheral autonomic

ganglia certainly merit further histochemical study,and though Riley (1957) has reported effects ofsympathectomy in these patients, no reports onpathological anatomy or microhistochemistry havebeen made. That such studies may be highly signi-ficant is indicated by the work of Smith, Taylor, andWortis (1963) who found evidence of abnormal cate-cholamine metabolism in familial dysautonomia. Intheir patients, the mean excretion rate of homo-vanillic acid (derived from dopamine, a pressor amineprecursor) was shown to be twice that of controls.Loss of critical regulation of catechol secretion fromautonomic ganglia by central abnormalities and/orexcesses of acetylcholine, as suggested by Hutchisonand Hamilton (1962), could readily account for bothmassive catechol discharge as well as for periods oflow catechol output.

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The argyrophilic masses noted in the peripheralautonomic ganglia of case 1 were first thought torepresent abnormal ripening or poorly controlledstorage of either catechol or catechol precursor-containing granules. Preliminary histochemical testsdone on this material, however, showed that bothSchmorl's reaction and Gomori's silver nmethenaminetest were negative, indicating the unlikely phenolicnature of the cytoplasmic pigment. It is postulated,therefore, that the abnormal accumulation ofargyrophilic material in a 3-year-old child representsexcessive deposition of ganglion cell pigment.

SUMMARY

Pathological studies of familial dysautonomia in twoJewish siblings revealed a combination of medullary,pontine reticular formation, and dorso-longitudinaltract demyelination; degeneration, pigmentation,and loss of ganglion cells of the coeliac plexus,thoracic and pelvic sympathetic ganglia, all of whichcould account for clinical dysautonomia.

Alterations of spino-thalamic tracts, ascendingposterior columns, posterior roots, spinocerebellar

tracts, and mesencephalic tracts of the fifth nervemay serve to explain abnormal sensory responsesand corneal changes in these patients.

All changes appeared slowly progressive with littleor no phagocytic response. These changes are dis-cussed in relation to previously reported studies,and attention is directed to the necessity for histo-chemical investigation of catechol amine storageand release in this condition.

Dr. A. Miller, presently pathologist St. Catherine'sHospital, Helena, Montana, did the necropsy on case 1.

REFERENCES

Aring, C. D., and Engel, G. L. (1945a). Arch. Neurol. Psychiat.(Chic.), 54, 37.

-, , (1945b). Ibid. 54, 44.Cohen, P., and Solomon, N. H. (1955). J. Pediat., 46, 663.Hutchison, J. H., and Hamilton, W. (1962). Lancet, 1, 1216.Linde, L. M. (1956). Pediatrics, 18, 692.-, and Westover, J. L., (1962). Ibid., 29, 303.Magoun, H. W. (1939). Res. Publ. Ass. nerv. Ment. Dis., 20, 270.Pearse, A. G. E. (1960). Histochemistry, 2nd ed., Churchill, London.Riley, C. M., Day, R. L., Greeley, D. McL., and Langford, W. S.

(1949). Pediatrics, 3, 468.(1957). Advanc. Pediat., 9, 157.

Smith, A. A., Taylor, T., and Wortis, S. B. (1963). New Engl. J.Med., 268. 705.

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