Acta Neuropathologica 4, 28--45 (1964)

Departments of Neurology and Pathology, Indiana University Medical Center, Indianapolis, Indiana and Neurology Service, Department of Medicine, Wilford Hall USAF Hospital; Aerospace Medical Division (AFSC), Lackland AFB, Texas

Familial Spasticity, Hyperkinesia and Dementia * Clinieopathologie Observations and Comments on the Nosology of Hallervorden-Spatz Disease By WILLIAM DEMYER~ DONALD H, HARTER and WOLFfiANfl ZEMAN With 8 Figures in the Text

(Received August 8, 1963) While some heredodegenerative diseases, such as h e p a t o l e n t i c u l a r degeneration, H u n t i r t g t o n ' s chorea a n d Pelizaeus-Merzbaeher disease, offer more or less characteristic, easily recognized prototypes, others defy classification, either because t h e y are u n i q u e or because t h e y c o m b i n e features t h a t u s u a l l y occur i n u n r e l a t e d diseases. The f a m i l y described i n this report falls i n the l a t t e r category a n d presents challenging problems i n nosology a n d pathogenesis. A m o n g five generations of the family, three m e m b e r s were afflicted with progressive spasticity, dyskinesia, b r a d y l a l i a a n d d e m e n t i a . As i n d i c a t e d i n Fig. 1, t h e affected m e m b e r s consist of the propositus (IV-4), w h o m we s t u d i e d clinically a n d b y a u t o p s y , his n e p h e w (V-5), w h o m we s t u d i e d clinically, a n d his m o t h e r (III-9), w h o m we k n o w only b y history. Some m e m b e r s of the 4 t h g e n e r a t i o n a n d m o s t of t h e 5 t h are still y o u n g a n d m a y y e t m a n i f e s t the disorder.

Case Report: Patient I (IV-4), the propositus This boy was born in 1940. Although he had failed the second grade in school, he was considered well until the age of 8--9 years. Gradually he became clumsy and began to drop objects. His speech became slurred. He complained of headaches and pain in his legs. After his mother died in 1949 from a disorder similar to his, he was cared for by foster parents, who reported that he was very nervous, unable to sit still and that he masturbated frequently. Examination when he was 10 years old disclosed a small cooperative child with a slightly slurred, nasal speech and moderately brisk myotatic reflexes without extensor toe signs. No involuntary movements were reported by the examiners. His Stanford-Binet I.Q. was 80. On the Wechsler-Bellevue Intelligence Scale for adolescents and adults he had a full scale I.Q. of 92, with a performance score of 98 and a verbal score of 89. An electroencephalogram and skull radiograms were considered normal. No final diagnosis was achieved on the initial evaluation. His disability gradually became more severe. At the age of 12 years he was confined to a state hospital. Examination there disclosed severe dysarthria and drooling, spasticity, ankle clonus, generalized hyperreflexia, bilateral pes cavus, and bilateral extensor toe signs. He could walk with assistance but not alone. He displayed involuntary movements of mild degree, characterized by one observer as "athetoid". The head circumference was 52 cm. When he was 131/2years old his Stanford-Binet I.Q. was 68. Over the next 2 years he continued to deteriorate slowly. * This paper represents the personal viewpoint of the authors and is not to be construed as a statement of official Air Force policy.

Familial spasticity, hyperkinesia and dementia

29

When 15 years old he was examined at Indiana University Medical Center. He was a thin boy who followed simple commands, and exhibited considerable affective lability. His speech was very slow and unintelligible, and he drooled constantly, He moved his eyes through the full range of movements~ and he had no nystagmus, Slit-lamp examination disclosed no Kayser-Fleischer ring and no retinal abnormalities, He had no palsy of the muscles innervated b y the cranial nerves, but ~11 som~tic movements were very slow, r as "dystonic" by one observer and " a t h e t o i d " by a~o%her. He had no cerebeliar signs. He showed generalized hyperreflexia, clonus, and extensor toe signs. Superficial and deep sensory stimuh were normally perceived. Secondary sex characteristics were normM. Routine blood count and urinalysis were normal. Urinary copper excretion was normal. The serum contained 4.1 g-~ of albumin and 2 g-~ of globulin. Liver function tests were normal. The cerebrospinal fluid had 3 white cells per m m s, 45 mg-~ protein, a flat colloidal gold curve, and a negative serological test for syphilis. His E E G was classified as dysrhythmia, grade II, generalized. The alpha r h y t h m was relatively fast, with frequencies of 15 cycles per

aII h "vi'n~,we/Iand oIder than GO/sots oTug0

EXr~ Eyrs

gyrs

~rs

/Oirs 7/rs

/j'ra

7dlrs Ezra Errs 3jirs 2Ulrs

Fig.1. Ge~eaIogb,.Sc!uares ~nclic~e males, circles fen]ales. Crosses indicate deceased individuals. Patient IIL9 was not examined hut was ~etiabty ~po~ed to have clinical features identical with indh,~duais IV-4 and V-5, both of whom we examined clinically. Individual IV-4 indicated by the arrow is the propositus, and was autopsied second, I n addition, frequencies of around 20 CPS were intermixed. A pneumoencephalogram disclosed no abnormalities. A myelogram was thought to show an abnormal prominence of the odontoid process. Because it seemed t h a t cervical cord compression might be contributing to his disability, the dentate ligaments were sectioned. On returning to the state institution, he continued to deteriorate slowly until he was bedfast and helpless. He died four years later at the age of 19, after having been ill for about 10 years. The proscctor recorded t h a t the skull was more t h a n 1 em thick, Review of the available skull radiograms confirmed the unusual thickness of the calvaria, We received the brain already fixed in formalin. The spinal cord was not available. The thoracico-abdominal viscera were either normal grossly and microscopically, or showed only intercurrent or terminal changes. The brain appeared normal externally except for reduction in the size of the brain stem. On coronal section of the brain, the ventricles were minimally dilated. The basal ganglia were small and the eorticofugal systems of the brain stem were reduced in size. :No abnormal coloration was noted. Microscopic observations. 25 samples of the brain stem, cerebellum, and cerebrum were embedded in paraffin, cut in triplicate, and stained by the Nissl, Spielmeyer, and Hortega silver carbonate methods ( D E M Y ~ 1958). 4 coronal sections of a hemisphere were embedded in eelloidin and stained with Nissl, Spielmeyer, Holzer, and Turnbull methods, 15 frozen

30

WILLIAM

DEMYEI~, DONALD

H, HARTE~

and WOLFGAI~!G ZEMAN:

sections were stained with acidified cresyl violet for metachromasia, Oil Red 0, Sudan Black, Hortega silver carbonate, Spielmeyer, a n d Holzer methods. General remarl~s. The cross sectional area of the mid- a n d hind-brain t h r o u g h o u t was considerably reduced. The t e g m e n t u m was relatively well preserved, the major loss being in the basis pedunculi, basis pontis, a n d pyramidal tracts. The medial and lateral ]emnisci, the central tegmental tract, and the medial longitudinal and dorsal longitudinal fasciculi were normal as were all sensory a n d motor cranial nerve and reticular formation nuclei except for a tendency to pallor of perikarya. F a t stains showed no increase of intraneuronal lipids in any p a r t of the brain.

Fig. 2. Cerebellum. myelin stain. Notice the myelin pallor of the deep cerebellar white matter

Cervicomedullary junction. The lowest level available was the caudal limit of the nucleus gracilis, just at the beginning of the pyramidal t r a c t decussation. The pyramidal tracts were severely degenerated as were the olivospinal tracts. The nerve roots stained poorly with hematoxylin. On the other hand, the internal arcuate fibers, substantia reticularis alba, spinocerebellar tracts, fasciculi gracilis a n d cuneatus, a n d the spinal root of the fifth nerve appeared normal in all stains. I n sections stained after HonzER, t h e pyramidal a n d olivospinal systems were conspicuously gliotic. I n Nissl and silver carbonate preparations, the perikarya of t h e reticular, trigeminal, and posterior column nuclei appeared normal, albeit somewhat pallid in Iqissl stains. Throughout the medulla, scattered axonal degeneration could be seen in most tracts. Medulla oblongata at level o/ in/erior olivary nucleus. The medullary pyramids were greatly reduced in cross sectional area, b u t a small percentage of t h i n a n d a few thick fibers appeared i n t a c t in myelin stained and silver impregnated sections. The pyramids contained numerous

Familial spasticity, hyperkinesia and dementia

31

proliferated astrocytes. The medial lemnisci appeared normal. I n the dorso-medial portion of the gliotic pyramidal area, the remaining small axons tended to be more numerous t h a n elsewhere, perhaps representing the homologue of the lemnisco-pyramidal intercalary bundle (DEMYlsl~ and RUSSELL 1963). The olivary amiculum was pallid in myelin stains. The neurons of the inferior olivary nuclei seemed generally well preserved, b u t some were degenerating, as shown b y argyrophilic debris a n d ballooned, tortuous, often vacuolated dendrites. Pons. Corticospinal and corticopontine systems, the pontine gray m a t t e r and the pontoeerebellar fibers were greatly reduced in size. Numerous axons in a stage of irregular swelling and discontinuous granular degeneration were scattered among the nerve cell groups of the basis pontis. Very rarely, a large, deeply argentophilic round body could be found, still retaining continuity with a n axon or axon fragment. The locus caeruleus was well pigmented. Cerebellum. Cortical layers and medullary centers in general were well preserved, except for slight depletion of Purkinje cells, as shown b y e m p t y baskets. A few Purkinje cells contained round or elliptical neuroplasmic swellings in dendrites. Similar bodies occured in the

Fig.3. Caudal level of midbrain, myelin stain. Notice the lack of corticofcgal rathways ~n the basis ICcdt:nculi although the pathways of the tegmentum and rectum are well n:aintained tangential fibers, b u t not in the medullary cores of the folia. No definite "torpedos" were seen in Purkinje cell axons. Degenerative beading and granular discontinuity were fairly common in the mossy and climbing fibers. The deep white m a t t e r surrounding the dentate nuclei was pallid in myelin stains (Fig. 2). Silver impregnated sections showed a definite reduction in the n u m b e r of axons in this region. Mesencephalon. Tectum and t e g m e n t u m greatly overshadowed the basis peduneuli because of the severe a t r o p h y of corticofugal systems (Fig. 3). A few myelinated fibers were randomly scattered t h r o u g h o u t the basis. I n the middle 3/5ths, a few large myelin sheaths were present. The brachium conjunctivum was normal in size a n d well myelinated, b u t some axons were in a stage of fragmentation and unquestionable degeneration. I n the substantia nigra, the zona compaeta contained the normal n u m b e r of neurons which were well pigmented and h a d normal Nissl bodies. The perikarya of the zona reticularis contained normal appearing Nissl bodies, b u t no pigment, and there was no interstitial pigment. I n b o t h zones, some neuroplasmic swellings were found in perikarya, dendrites or axons.

32

WILLIAM DEMYEtr DONALD H, HARTEtr and WOLFG~CG ZEMA~:

Diencephalon and corpus striatum. The gray m a t t e r of the diencephalon and associated regions contained very pallid neurons, as seen in Nissl preparations. Particularly pallid were the neurons of the red nucleus, subthalamie nucleus, globns pallidus, caudate nucleus, and thalamus, although glia, endothelial cells and hypothalamic neurons exhibited the customary degree of chromophilia. I n silver impregnations, neuroplasmie swellings coincided with the fields of Nissl stain pallor, b u t were also seen elsewhere. Caudate Nucleus. Of the deep gray matter, the caudate nuclei exhibited the most severe neuronal depopulation. The ventricular surface of the caudate nucleus was flat or slightly

Fig.4a and b. Caudate nucleus, a Silver carbonate impregllation,showingstatus spongiosusof the tissue adjacent to the subependymal plate, b ~issl stain, showing characteristic "chromatolytic" appearance of large ceils of caudate-putamen. The central homogeneousarea of the neuron sometimes contained an argyrophiiic body, All neurons are very pallid in contrast to the norton1 staining of glial nuclei concave, rather t h a n forming the usual convex bulge into the ventricular lumen. The ependyma and subependymal plate were normal, but the tissue next to the subependymal plate showed a status spongiosus and contained virtually no neurons (Fig. 4). The more laterally placed tissue was less severally affected, b u t throughout the remainder of caudate nucleus and putamen, the overall cellularity was high because of an increase in the number of astrocyiic nuclei per unit of area. The large neurons were all in a state resembling axonal reaction or central chromatolysis. The perikarya were distended, the central protoplasm appeared homogenous, and the nuclei were eccentrically placed. Some large degenerating neurons had very faint cytoplasm and crumpled nuclei. Strewn in the tissue were numerous polymorphic, highly argentophilic

Familial spasticity, hyperkinesia and dementia

33

bodies; some were round, and others were angular, polygonal, elliptical, or asymmetrical. Dendrites and sometimes perikarya contained round or elliptical, deeply argentophilic, neurop]asmic swellings, identical with the bodies illustrated in Fig. 6 and 7 in dendrites of cortical neurons. Similar bodies could be found within axons. Claustrum. The neuronal population seemed reduced, and neuroplasmic swellings were found within dendrites. Globus pallidus. The neurons were so pale in Nissl stain t h a t they could hardly be seen, but their number was not obviously decreased. Some neuroplasmic swellings were present. Very few boutons terminaux could be found around pallidal neurons, although they are always numerous in normal material treated with the same silver carbonate method.

Fig. 5. Pallidum and thalamus, myelin stain. The corticofugal fibers of the internal capsule have virtually disappeared, but the anterior thalamic peduncle is well preserved. Also shown are the severe status dysmyelinisatus of the globus pallidus and ansa lenticularis and the moderate pallor of the external capsule A few pigment laden macrophages had accumulated around the vessels, and some could be found interstitially. No "Pseudokalk" was present. Although the brair~ had been in formalin for months, the Turnbu]l reaction was strongly positive in the pallidum, but not elsewhere. In myelin stained sections, the fields of :Forel were well myelinated as were the stria medullaris and intrinsic hypothalamic and thalamic systems. The myelinated projections of the medial and lateral geniculate bodies were conspicuous because of the moderate myelin pallor of the general hemispheric white matter. In contrast to these normal fiber systems, all capsules, internal, external and extreme, were moderately to severely demyelinated. As shown in Fig. 5, degeneration of the corticofugal pathways of the basis peduneuli extended through the internal c~psule, at least into the eentrum ova]e; however, the thMamic peduncles were preserved. Fig. 5 also illustrates the rather Acta Neuropathologica,Bd. 4

3

34

WILLiaM DEMYEP,, DONALD H . HAI~TEI~ a n d WOLFe;ANO ZEMAN:

s e v e r e s t a t u s d y s m y e l i n i s a t u s o f t h e p a l l i d u m , w h i c h m a y be c o n t r a s t e d w i t h t h e well myelinated anterior commissure, thalamus and corpus callosum.

Fig. 6a and b. Cerebral neocortex, a 3rd layer, silver carbonate impregnation. Typical neuroplasmic swelling in apical dendrite of cortical neuron, b silver carbonate impregnation. Neuroplasmic swelling in a cortical dendrite

Cerebral cortex. 20 s e c t i o n s were p r e p a r e d r e p r e s e n t i n g all m a j o r c y t o a r c h i t e c t u r a l fields, i n c l u d i n g t h e h i p p o e a m p a l f o r m a t i o n . 111 e v e r y section, n e u r o p l a s m i c swellings were p r e s e n t ,

Familial spasticity, hyperkinesia and dementia

35

e i t h e r in d e n d r i t e s or a x o n s , a n d s o m e t i m e s w i t h i n p e r i k a r y a . (Fig. 6 a n d 7). T h e swellings were r e s t r i c t e d to t h e cortex, a n d d i d n o t a p p e a r in t h e h e m i s p h e r i c w h i t e m a t t e r e x c e p t in t h e c a p s u l e s a n d b a s a l ganglia. M o s t cortical a r e a s s h o w e d n e u r o n a l toss as d o c u m e n t e d b y n e u r o n s w i t h g h o s t l i k e outlines, as s e e n b o t h in l~issl a n d silver p r e p a r a t i o n s , a n d e m p t y spaces in t h e cortical l a m i n a e . I t is n o t possible to s a y w h i c h cortical a r e a s were m o s t s e v e r e l y d a m a g e d , b e c a u s e of t h e diffuseness o f t h e process. T h e p r e c e n t r a l g y r u s c o n t a i n e d n o B e t z cells. I n t r a c o r t i c a l m y e l o a r c h i t e c t u r e s e e m e d well preserved. T h e l e p t o m e n i n g e s a p p e a r e d n o r m a l as did t h e blood vessels.

:Fig. 7. Cerebral neocortex, silver carbonate impregnation. Arrows indicate several types of nem'oplasmie swellings in the neocortex. Notice the polygonal, dense body just to the right of the center of the field. :No processes were apparent, the body seeming to be free in the tissue

Case Report: Patient 2 (V-5) T h e s e c o n d p a t i e n t (V-5), w h o is still alive, w a s considered n o r m a l in e v e r y r e s p e c t u n t i l 5 y e a r s of age. H e w a s t h e p r o d u c t of a n o r m a l p r e g n a n c y a n d u n c o m p l i c a t e d delivery. B i r t h w e i g h t w a s 9 lbs. 1 oz. H e c r a w l e d a t 4 m o n t h s , w a l k e d a t 8 m o n t h s a n d b e g a n self-feeding 3*

36

WILLIAM I)EI~/[YEE, DONALD I-I. I-IAB,TER a n d WOLFGANG ZEMAN:

a t 1 year. Intelligible speech was initiated a t 6 months, and toilet training was completed a t 18 m o n t h s of age. W h e n 5 years old, he began to have difficulty in grasping objects. His movem e n t s became awkward, a n d his hands assumed strange postures. A t the same time, his speech became slurred and indistinct. His mother recognized his movements to be similar to those she h a d previously observed in her mother (III-9) a n d her brother, the propositus (IV-4). Because of the speech problem, t h e frenulum of the tongue was divided on two occasions, without improvement. A t the age of 8 years, he became unsteady in walking, a n d he fell frequently. He began to hold his legs stiffly a n d to walk on his toes. Because of poor scholastic performance, he was unable to advance beyond the second grade over a period of 4 years. F r o m ages 6-- 9 years the p a t i e n t was examined b y several physicians who noted athetoid movements of the hands, severe dysarthria, mental subnormality, a n d spasticity of b o t h legs with hyperreflexia and extensor p l a n t a r responses. W h e n he was 61/~ years old, psychometry

trig.8a--d. Show the athetoid movements of individual V-5 showed a full scale I.Q. of 93 (verbal scale I.Q. 91, performance scale I.Q. 97). Hepatolenticular degeneration was excluded b y normal serum and urinary copper levels a n d absence of Kayser-Fleischer ring on slit-lamp examination. Skull radiograms, cerebrcspinal fluid and electroencephalograms were normal. E x c e p t for the neurological difficulties, he has been healthy. He is the eldest of three siblings. His 7 year old sister a n d 1-year old brother are presently free from neurological abnormalities. His striking physical resemblance to his deceased uncle, the propositus (IV-4), causes family acquaintances to mistake his photographs for his uncle's. B o t h of his parents are currently healthy and free from neurological abnormalities. U p o n re-examination at the age of 10 years, he cooperated well. He was oriented in all spheres. His memory seemed unimpaired, and he responded p r o m p t l y to the examiner's requests. A l t h o u g h able to write his rtanle and address a n d to draw simple figures, he was unable to do simple additions or subtractions a n d frequently misspelled simple words. He grimaced frequently. The extraocular movements were normal, without nystagmus. Visual acuity was 20]20 O.U. uncorrected. No abnormalities were found on funduscopic and slit-lamp

Familial spasticity, hyperkinesia and dementia

37

examination. His speech was slow, indistinct and somewhat nasal. Rapid alternating movements of the tongue were poorly performed. Palatal movement and gag reflex were normal. A snout reflex was present. The gait was stiff, with bilateral scissoring and a proclivity to toe walking. He was unable to walk on his heels or tandem. He showed slow, spontaneous, athetoid movements of the fingers of both hands and occasionally at the ankle (Fig. 8). All extremities were hypertenic, the lower more so than the upper. He was unable to dorsiflex or evert either ankle. He had diffuse weakness of the lower extremities, chiefly in the iliopsoas and hamstring muscles. The myotatio reflexes were symmetrical, but pathologically hyperactive with bilateral, well-sustained ankle clonns. Plantar responses were extensor bilaterally. Superficial abdominal reflexes were absent. Touch, pain, position and vibratory stimuli were normally perceived. The following laboratory tests were normal: 1. Blood and serum: routine blood count and red blood cell morphology; iliac crest bone marrow; urea nitrogen; fasting and 2-hour postprandial blood glucose; calcium, phosphorous, cholesterol, total serum lipids, sodium, potassium, calcium, chloride, and COs; bilirubln, thymol turbidity, cephalin flocculation, prothrombin time, alkaline phosphatase, and bromsulphalein excretion; total serum protein, A/G ratio, electrophoresis, and serum ceruloplasmin (350 O.D. units). 2. Urine: routine urinalysis, chromatography for amino aciduria, and heavy metal analysis. 3. Spinal fluid: pressure, color, ceils, total protein, paper strip electrophoresis of proteins, and Kolmer. d. X-rays: Skull, spine and chest radiograms, including views of the odontoid process and foramen magnmn were considered within normal limits, although skull radiograms showed a somewhat thickened calvaria. 5. Electrocardiogram and electroencephalogram. His full scale I.Q. was 75 (verbal scale I.Q. 69, performance I.Q. 85). No abnormalities of chromosome number or shape were seen on examination of 40 cells obtained by peripheral blood culture. Case report: Patient 3 (III-9) This woman was the mother of the propositus. The data regarding her illness were obtained by interviewing her relatives. She was considered to be well until 30 years of age when she began to have speech difficulty and awkward, involuntary movements of both hands. Among the first manifestations of her disease were inability to sing and a tendency to drop objects from her hands. She began to have stiffness of her legs and difficulty walking. She gradually became worse and within 3 years, was bed-ridden. She was admitted to a nursing home where her condition continued to deteriorate, characterized by muscular stiffness, loss of mental faculties, involuntary movements and difficulty in swallowing. She died at the age of 36 years, 6 years after the onset of her illness. Her death certificate records "spastic paralysis." Her daughter (the sister of the propositus and mother of patient two) recognized the similarity of the illness in the three afflicted members of the family.

Discussion Genetic Considerations. Since only a small n u m b e r of people i n one kinship were studied, t h e genetic d a t a are of l i m i t e d significance. Two features require e x p l a n a t i o n : t r a n s m i s s i o n of the disease from m o t h e r to son a n d from m o t h e r to g r a n d s o n t h r o u g h a n a p p a r e n t l y h e a l t h y d a u g h t e r (IV-2). I f the mode of transmission were a u t o s o m a l recessive, all three p a t i e n t s would be homozygous for the defective gene. I n the absence of c o n s a n g u i n i t y , this a s s u m p t i o n is unlikely. I f the mode of t r a n s m i s s i o n were d o m i n a n t , t h e n i n d i v i d u a l IV-2 should be ill. T h e a p p a r e n t discrepancy can be reconciled either b y assuming lack of p e n e t r a n c e or t h a t i n d i v i d u a l IV-2, who is less t h a n 30 years old, m a y y e t m a n i f e s t the disease 1. Clinical considerations. The retrogressive degenerative n a t u r e of the disorder was recognized b y the m a n y clinicians who saw the two boys, a n d the diagnoses i When last examined, in February of 1963, this woman had no neurologie abnormalities.

38

WILLIA~fDE1V~yEI%,DONALDH. HA:~WE~and WOL~GANGZE~A~:

proferred varied from familial spastic paraplegia to ttallervorden-Spatz disease. By giving proper weight to the clinical findings and the genetics of the disorder, the diagnostic possibilities can be reduced to a small number. Most easily eliminated are such exceptionally well-defined heredodegenerations as hepatoleuticular degeneration, Yelizaeus-Merzbacher disease, Friedreich's ataxia and the usually accepted types of leukodystrophy and lipidoses. The apparently dominant hereditary pattern might suggest dystonia musculorum deformans (Z~,M_A~ et al. 1959, i960; and Jotr~so~ et al. 1962), and possibly Huntington's chorea. The early age of onset of the disorder in the boys would argue against Huntington's chorea, b u t would be in keeping with dystonia. The severe spasticity, hyperreflexia, extensor plantar responses and the nature of the abnormal movements make both diagnoses unlikely. In fact the pyramidal tract signs were so prominent that several clinicians entertained the diagnosis of familial spastic paraplegia, which would be a plausible diagnosis were it not for the presence of equally striking dyskinesia and dementia. Of all the diagnoses suggested clinically, Hallervorden-Spatz disease offers the closest similarities. In the original family reported by HALLE~VO~DV,N and SPATZ (1922), five of nine siblings who survived infancy displayed a clinical syndrome that was identical in age of onset to the affection in our two boys and similar in clinical course to all three of our patients. Some degree of dementia as manifested by poor school performance may antedate overt motor features in this disorder. A further similarity is the curious thickening of the calvaria that was observed in our propositus, in the patient described by DwJoNG and S c ~ B ~ o (1952), and in HALLv.~VO~DV.N and SrATZ'S original patient. Our patients did have some clinical features, such as outstanding pyramidal tract signs, which were not prominent in previously reported patients with ttallervorden-Spatz disease. Likewise onset of symptoms in the third decade is unusal. Although M~ss~G (1933) reported the disorder in two generations, the other familial cases have been limited to one generation. In summary, this family has a retrogressive disease, apparently inherited as a Mendelian dominant. It begins in early life with hyperkinesia, spasticity, and dementia and terminates in death after a course of about 10 years. Notably absent were seizures, visual or sensory disturbances, vegetative dysfunction, spinal fluid abnormalities or known metabolic derangements. Despite some discordant features, the clinical picture suggests I-Iallervorden-Spatz disease.

Neuropathologic and l~osologic Considerations The lesions observed in the brain of our patient m a y be listed in order of conspicuousness as follows: 1. Severe symmetrical degeneration of the corticopontine, corticospinal and olivospinal tracts. 2. Atrophy of the caudate nuclei. 3. Diffuse myelin pallor in the centrum ovale and neocerebellar white matter. 4. Status dysmyelinisatus of the globus pallidus w i t h minimal, only microscopically evident pigmentation. 5. Pallor of Nissl substance.

Familial spasticity, hyperkinesia and demengia

39

6. Numerous neuroplasmic swellings, often in dendrites and mainly confined to gray matter.

7. Diffuse, active cerebral, cerebellar and brainstem axonal degeneration with topographic accentuation. 8. Myelin pallor of nerve roots. In their original patient, I-IALLE~VO~DENand SPATZ described the following lesions : the globus pallidus and zona reticularis of the substantia nigra (hereinafter referred to as the pallidal zone) grossly had a striking brown discoloration. Microscopically, the pallidal zone showed polymorphic intra- and extra-cellular accumulations of brown, argentophilic pigment giving a variably positive Prussian blue reaction. Mulberry-shaped "Pseudokalk", staining heavily With hematoxylin, was also conspicuous. Perikarya had pallid Nissl substance, and sometimes increased pigment and lipid. In the pallidal zone, cortex, brainstem and cerebellum, were numerous argentophilic bodies termed "axonal swellings" (Achsenzylinderauftreibungen), because they often retained continuity with axons. The brain was diffusely demyelinated, with accentuation in the pallidal zone, leading to a status dysmyelinisatus of moderate severity. The pyramidal tracts, while not severely degenerated, showed some fiber loss in myelin stains. Cerebral and eerebellar cortices and brainstem nuclei showed diffuse neuronal loss. Some neurons, particularly in the cerebral cortex, had increased amounts of lipid. Gliosis occured in proportion to the degree of parenchymal loss. Since the original report, several autopsied patients have been described (EIcK]s 1957 ; G~oss et al. 1957) who showed all or most of the elinicopathologic syndrome described by HALLEaVO~D~S and SraTz. Yet individual components of the syndrome may be absent in otherwise acceptable cases or may appear in etiologically independent disorders. Thus the disorder has been subject to divergent interpretations. Most authors indicate that the diagnosis should be made only by tissue examination and emphasize two criteria: (1) Pallidonigral hyperpigmentation, (2) "Axonal swellings" (Achsenzylinderauftreibungen) in the basal ganglia. We would wonder, as did Gi~oss et al., whether the "pathognomieity" of these features might have been overestimated and other features unduly neglected. Pallidonigral hyperpigmentation has been associated with whole-body irradiation (HAYMAX~.~ et al. 1958) and with several heredodegenerations such as amaurotic idiocy and neurofibromatosis (JEBws 1952 ; EIC~E 1957 ; ZEMAN and SCAnSELLI1958; MEYE~ 1958; and SEITELBE~G~.~ and SrMMA1962). It was an incidental finding in an otherwise normal brain (patient 2 of NETSXY et a1.1951). The list of hered0dcgenerations with pallidonigral hyperpigmentation might be expanded to include Friedreich's ataxia which appears to be a plausible diagnosis for patient 1 (NETsKu et al.) who also had cardiac myopathy characteristic of that disorder (JAMES and FISCH 1963). Cardiac myopathy has otherwise not been reported in the pallidM degenerations. Evidently pallidonigral hyperpigmentation results from a variety of exogenous and endogenous causes as does pallidM hypercalcinosis (NEu3~ANN 1963). The tendency to equate a lesion, pallidal hyperpigmentation, with tIa,llervorden-Spatz disease may have hampered progress toward accepting what otherwise is a fairly

40

WILLIAMDEMYER, DONALDH. HARTERand WOLFGANGZEMAI'~:

cohesive clinicopathological syndrome. I t is instructive to speculate on the consequences for nosology ff fate had presented HAZLERVORDEN and SrATZ with a grossly non-pigmented pallidum, as in the patient of WINKELMAN (1932) or GRoss et al. We were impressed, as were others (HALLERVORDENand SPATZ;SEITELBERGER and GRoss 1957; GRoss et al. ; SEITELB~,RGER1957) by the extensive, variegated neuronal degeneration, manifested not only by neuroplasmic swellings and axonal fragmentation, but also by pallor of Nissl substance in brain stem nuclei and cerebellum. When looked for, neuroplasmie swellings have been found in virtually every patient with Hallervorden-Spatz desease (EIcKV,; SEITELBERGER and GROSS; GRoss et al. ; SEITELB]~RGER). Previous observers have not stressed the dendritic location of the swellings, although suggesting this possibility (GRoss et al.). Detection of these lesions will depend on the diligence of the observer and on the quality of the silver impregnation method used. In aniline dye stains they are unimpressive, difficult t o appreciate, and may be overlooked or confused with corpora amylacea. The neuroplasmie swellings are thought to consist of mueoproteid (SEITELBERGER and GRoss ; RABINOWICZ and W~DI 1955), leading SEITELBERGERto call Hallervorden-Spatz disease a "neuro-axonal mucoproteid dystrophy". Under the term "Infantile neuraxonal dystrophy", COWEN and OLMSTEAD have recently described another patient with widespread neuroplasmic swellings, sometimes in dendrites. From the arguments advanced by SEITELBERGER and COWEN and OLMSTEAD, the neuroplasmic swellings become the focal point of the disease. All authors, however, have raised some question as to the specificity of the swellings because they occur under various conditions in man (GRoss et al. ; SEITELBERGER, WOLTER and LIss 1957; P~TSCHEW and SCHWARZ 1962), and in vitamin E deficient rats (PE~TSCHEW and SCHWARZ). Whether the neuroplasmic swellings in lower mammals have the same pathogenesis as in man is unknown, but it is interesting to note their association with malnutrition. By discarding gross pallidal pigmentation as an indispensable criterion for Hallervorden-Spatz disease, our patients might fit the descriptive definitions of this entity. In stressing the extra-pallidal lesions, as do GRoss et al. and SEITELBERGER and G~oss, we return to the original emphasis of H~LERVORD~.~ and SPATZ, and would demur from the suggestion that "lesions outside the pallidum and substantia nigra have little importance in respect to the characterization of the disease." (EICKE). Because of the conspicuous pyramidal tract degeneration in our patient's brain, the diagnosis of familial spastic paraplegia must be considered. We would agree with SCHWARTZand Lr~ (1956) who stated, "Perhaps a more rigid clinical designation of cases to be included in this group in the future might obviate some of the present inconsistencies in the pathologic data." Since the pyramidal tracts are vulnerable to any number of pathogens, neither clinical nor morphologic evidence of pyramidal tract involvement against a background of generalized brain lesions justifies the diagnosis of familial spastic paraplegia or of its linkage with other heredodegenerations. In accepting the arguments of SCHWARTZ and LIU, one excludes patients, such as ours, who have hyperkinesia and dementia.

Familial spasticity, hyperkinesia and dementia

41

Previous authors having patients similar to ours and not wishing to classify them as Hallervorden-Spatz disease have taken one of two alternatives. Either the patients were considered to have a unique disorder and were called pallidal or pallido-pyramidal degeneration (HuN~ 1917; VAN BOGA~T 1946; TITECA and vA~ BOGAE~T 1946; DAWSO~ 1954; DAVISON and GOO~HA~T 1938 and B ~ D A 1949), or the patients were considered to have a variant of leukodystrophy (Pos]~ et al. 1957; VAN BOGA~T et a1.1961). In the family reported by Pos~i~ et al. were 4 affected brothers. Two became ill in their late teens, having a clinical picture of fairly pure spastic quadriplegia, but with "a slight extra-pyramidal overtone evidenced by spasmodic laughing and c r y i n g . . . " . The other two brothers manifested the disorder around the age of 5 years, and showed a mixture of spastic quadriparesis, involuntary movements, ataxia, and the late onset of dementia. Brain lesions in one of the younger brothers consisted of diffuse demylination, degeneration (but not gross pigmentation) of the pallidum and other brain stem nuclei, degeneration of olivocerebellar and long spinal tracts, and demyelination of spinal nerve roots. These lesions are reminiscent of those in our patient, except that no neuroplasmie swellings were reported. Although seizures and malnutrition complicated the patient's illness, the authors propose that his brain lesions and somatic deformities were all the result of different genetic faults. Thus, the case is offered as a montage of heredodegenerations such as leukodystrophy and systematized degeneration of the spinocerebellar, pyramidal, and pallidal types. To support their all-encompassing Hnkage theory, the authors offer several contestable assumptions. They consider the emotional incontinence as the result of "extrapyramidal involvement" and the pes eavus as the result of a different genetic fault than the brain lesions, but a more parsimonious explanation would relate both to the retrogressive spastic quadriparesis. The cerebellar degeneration could be explained as seizure-induced (Sc~oLz 1959), and the atypical "leukodystrophy" may reflect either the effects of malnutrition, or may represent secondary degeneration following an inconspicuous loss of neurons. One has misgivings about designating myelin pallor as "leukodystrophy" and then equating the process with "leukodystrophy" as it occurs in metachromatic leukodystrophy or in Krabbe's disease. We hesitate to consider the lesion in our patient's brain as leukodystrophy because even in areas without demyelination, axonal degeneration was obvious. This fact combined with the virtual absence of macrophages or myelin catabolic products in the dcmyelinated fields, suggests that the neuronal decay, occurring very indolently over the years, was the primary lesion. While we would not dogmatically claim that our interpretations are correct, we do suggest that there are plausible alternatives to the leukodystrophy linkage theory of P o s e r et al., and in fact, this theory is no longer stressed in the later paper of VAN BOGAW~T et al. (1961) dealing with a very similar family. Despite the arguments which have been presented, the proper classification of the disorder we have described and the similar ones in the literature remains unresolved. Of all the known heredodegenerative diseases, the disorder most closely approximates Hallervorden-Spatz disease. Its several atypical features m a y indicate that the clinical and pathological spectrum of/-Iallervorden-Spatz disease is wider than has been accepted. We would suggest that among the heredo-

42

WILLI~_W*DEMY~, DONALD H. HARTEI% and WOLFGAWO Z~MA~:

degenerative diseases there is a fairlyhomogeneous group of patients clinicallycharacterized by slowly retrogressive spastieity, hyperklnesia, and dementia. Visual and sensory disturbances, seizures, and spinal fluid abnormalities are usnally not prominent. The disease typically manifests itselfin childhood or even as late as the 3rd or 4th decade. Morphologically, it is characterized by diffuse, but topographically accentuated neuronal degeneration with various types of neuroplasmic swellings in dendrites, perikarya and axons; diffuse pallor of myelin; Nissl stain pallor of perikarya, and quantitatively variable pallidal pigmentation. W e would fully agree with Cowv.N and 0LI~ST~AD that this group of disorders is most likely to have neuronal dysmetabolism as the pathogenic basis and that final classification of these disorders must await knowledge of the metabolic defect.

Summary A mother, her son, and grandson had an apparently dominantly inherited, slowly retrogressive, syndrome of spastieity, hyperkinesia, and dementia. The boys manifested the disorder between 5--8 years of age, the woman at 30 years of age. Paper chromatography for amino aciduria, paper strip electrophoresis of the cerebrospinal fluid, and the karyotype of the grandson disclosed no abnormalities. The mother died after 6 years of illness. The grandson is still living. The son died at the age of 20 years, 12 years after the onset of his illness. His brain had diffuse but topographically accentuated neuronal degeneration manifested by fiber loss, neuroplasmic swellings, axonal fragmentation, and pallor of perikarya in lNisslstain.Cerebral and eerebellarwhite matter was somewhat pale in myelin stains, especially in the pallidum and around the dentate nuclei. The caudate nuclei were atrophic. The paflidum had small quantities of interstitial pigment and gave a positive Prussian blue reaction. Corticopontine, corticospinal, and olivospinal tracts were severely degenerated. Virtually no evidence could be found of active myelin disintegration such as fat-laden macrophages or myelin catabolic products. In the areas of myelin pallor the axonal population was always reduced, and scattered axonal degeneration occurred in areas in which myelin was well stained. The disorder is tentatively considered to be Hallervorden-Spatz disease although similar cases have been classified by some as a "linkage" syndrome of systematized abiotrophy and leukodystrophy, and by others as pallidal or pallidopyramidal degeneration sui generis. The relationship to infanbfle neuraxonal dystrophy remains to be clarified. We suggest that in tIallervorden-Spatz disease the intensity and topographic accentuation of the degenerative processes, such as neuroplasmic swellings, pallidal pigmentation, and tract involvement, are rather variable and may depend to some extent on exogenous factors like malnutrition. Final classification of these similar clinicopathologic syndromes must await knowledge of the metabolic defect, l~eanwhile, the question remains open as to whether these syndromes represent one disease or a number of diseases with only superficial slmilarities. Zusammenfassung Eine Frau, ihr Sohn und ihr Enkel litten an einem Syndrom, das offensiehtlich dominant vererbt, und dutch fortschreitende, ascendiercnde Spastik, Hyperkinesen und Demenz gekennzeichnet war. Die beiden m~nnlichen Patienten

Familial spastieity, hyperkinesia and dementia

43

zeigten die ersten Krankheitserseheinungen im Alter yon 5 und 8 Jahren, die Frau abet erst mit 30. Papierehromatographisehe Untersuehungen des Urins auf Aminos~uren, Papierelektrophorese des Liquors und Bestimmtmg der Karyotypen beim Enkel waren normal. Die Mutter starb naeh 6j~hriger Krankheitsdauer, der Enkel lebt noeh. Der Sohn starb nach 12j/~hrigem Leiden im Alter von 20 Jahren. I n seinem makroskopiseh leieht atrophisehen Gehirn fanden sieh weitverbreitete, topographiseh akzentuierte Parenehymausfs und -degenerationen. Die letzteren bestanden in argentolohilen Sehwellungen in Dendriten, Perikarya und Achseneylindern und in einer Abblassung der Ganglienzellen, besonders in Basalganglien und im Kleinhirn. Die weige Substanz des Grog- und I~einhirns war in Markseheidenpr/~paraten nur sehwaeh angef/irbt. Der Verlust an Markseheiden war besonders stark im Gebiet der Pallida und der Zahnkerne. Der Caudatumkopf war beidseits atrophiseh. I n den Pallida fanden sieh mikroskopiseh geringe Mengen yon Pigment, vornehmlieh in perivaseul/~rer LokaHsation. Die Eisenreaktion war bier positiv. Die eortieopontinen, eortieospinalen und olivospinalen Bahnen waren stark geliehtet ohne Zeiehen eines aktiven Markabbaues. Die Zahl der Aehsenzylinder war allgemein reduziert, selbst in Gebieten mit normaler F/~rbbarkeit der Markseheiden. Das Syndrom wird, mit gewissen Vorbehalten, als Itallervorden-Spatzsehe Krankheit gedeutet, obwohl ghnliehe Beobaehtungen bisher als Kombination yon Systemdegeneration mit Leukodystrophie, oder als Pallidum- oder pallidopyramidale Degeneration bezeiehnet worden sind. Die nosologisehen Beziehungen unserer Beobaehtung zur sp~tinfantilen neuroaxonalen Dystrophie (S~IT~LBERate) bleiben ungekl/~rt. Es wird darauf hingewiesen, dab Intensit&t und Verteilungsmodus der Pigmentst6rungen und der neuronalen Degenerationserseheinungen bei der Hallervorden-Spatzsehen Krankheit augerordentlieh weehselnd sind und dab dies m6glieherweise auf exogene Faktoren, z. B. Mangelern/ihrung, zurfiekgeftihrt werden kann. Die endgiiltige Klassifizierung der hier diskutierten Krankheiten bleibt fragwtirdig, solange nieht der urs/ichliehe Stoffweehseldefekt aufgedeekt ist. Daher kann aueh nieht entsehieden werden, ob es sieh bei dem besehriebenen Syndrom und bei den anderen zitierten Beobaehtungen um dieselbe Krankheit oder nut um kliniseh und morphologiseh /~hnliehe, aber gtiologiseh versehiedene Prozesse handelt. A clcnowIedgment We wish to thank Capt. J o ~ W. FOFT, USAF, MC, Pathology Department, USAF School of Aerospace Medicine, Brooks AFB, Texas, who performed the chromosome studies on our patient. References BENDA, C.E.: Chronic rheumatic encephalitis, torsion dystonia and ttallervorden-Spatz disease. Arch. Neurol. Psychiat. (Chic.) 61, 137--163 (1949). Cow~, D., and E.M. OLMSTEAD: Infantile Neuraxonal Dystrophy. J. Neuropath. exp. Neurol. 22, 175--236 (1963). DAvIso~, C. : Pallido-pyramidal disease. J. Neuropath. exp. Neurol. 18, 50--59 (1954). --, and S. P. GOOD,ART: Dystonia musculorum deformans. Arch. Neurol. Psyehiat. (Chic.) 89, 939--972 (1938). DEJO~G, 1%.,and K. SCtr~t~ENBERG:The syndrome of tIallervorden ~nd Spitz. Trans. Amer. Neurol. Ass. 67, 83--87 (1952).

44

WILLIAMDE~u

DONALDH. HARTERand WOLFGANOZE~AN:

DE!~/IYER,W. : Impregnation of axons and terminal buttons in routine paraffin or frozen sections of central and peripheral nervous tissue. Amer. J. din. Path. 29, 449--454 (1958). --, and J. RUSSELL: The lemnisco-pyramidal intercalary bundle: A hitherto unrecognized bundle of axons located between the medial lemniseus and the eorticospinal tracts in Macaca rhesus. Neurology 13: 793--796, 1963). EmKE, W. J. : Die Hallervorden-Spatz-Krankheit. pp. 836--850 in Handbuch der speziellen pathologischen Anatomic and Histologie, 13/1. Berlin, GSttingen, Heidelberg: Springer 1957. GROSS, H., E. KALTENBACK,and B. UIBER~ACK: ~ber einc sp~tinfantile Form der Hallervorden-Spatzsehen Krankheit. I. Mitteilung: Klinisch-anatomische Befunde. Dtsch. Z. Nervenheilk. 176, 77--103 (1957). HALLERu J., and H. SPATZ:Eigenartige Erkrankung im extrapyramidalen System mit besonderer Beteiligung des Globus pallidus und der Substantia nigra. Ein Beitrag zu den Beziehungen zwischen diesen beiden Zcntren. Z. ges. Neurol. Psychiat. 79, 254--302 (1922). HAYlVs W., H. SttIRAKI, S. MATSUOKA, S. TAKEYA, K. KorA~o, M. ARxv~i, Y. UCBI~rRX, M. MIYAXE, C. T~AGAWA, S. AMINO, and W. W. AVRES: Joint report. Effects of atomic radiation on the brain in man. (A study of the brains of 49 Hiroshima and Nagasaki casualties). J. Neuropath. exp. Neurol. 17, 79--137 (1958). Hu~T, J. R.: Progressive atrophy of the globus pallidus (primary atrophy of the pallidal system). Brain 40, 50--148 (1917). J ~ E S , T. N., and C. FISCH: Observations on the cardiovascular involvement in Friedreich's ataxia. Amer. Heart J. 66: 164--175, 1963. JERVIS, G.A.: Hallervorden-Spatz disease associated with atypical amaurotic idiocy. J. Neuropath. exp. Neurol. 11, 4--18 (1952). JOHNSON, W., G. SCmTC~_~Tz,and A. B~!=~REAU:Studies on dystonia musculorum deformans. Arch. Neurol. (Chic.) 7, 301--313 (1962). MESSING,Z. : Choroba Hallervordena-Spatza. Roczn. Psychjatryczny. $1, 261--275 (1933). M~ER, A. : Neuropathology. Edited by GREENFIELD. London: J. G. Arnold 1958. NETSKY, 1VI., D. S~IRO, and H. ZIMMER~AN: Hallervorden-Spatz disease and dystonia. J. Neuropath. exp. Neurol. 10, 125--141 (1951). NEUMANN,M.: Iron and calcium dysmetabolism in the brain. J. Neuropath. exp. Neurol. 22, 148--163 (1963). PENTSCHEW,A., and K. SCnWARZ:Systemic axonal dystrophy in vitamin E-deficient adult rats. Acta Neuropath. (Berl.) 1, 313--334 (1962). POSER, C., A. DEWULF, and L. VAN BOGAERT: Atypical cerebellar degeneration associated with leucodystrophy. A study of the relationship between dissimilar degenerative processes. J. Neuropath. exp. Neurol. 16, 209--237 (1957). RARn~OWIEZ,T., and E. W~DI: Spastic amaurotie axonaI idiocy, pp. 34--47 in Cerebral Lipidoses. Springfield, Ill. : Ch. C. Thomas 1957. SCHOLZ,W.: The contribution of patho-anatomical research to the problem of epilepsy. Epilepsia (Amst.) 1, 36--55 (1959). Sc~r162 G. A., and CHAN-NAOLIU: Hereditary (Familial) spastic paraplegia. Further clinical and pathologic observations. Arch. Neurol. Psychiat. (Chic.) 75, 144--162 (1956). SEITELBERGER,F . : Zur Morphologie und Histochemie der degenerativen Axonveranderungen im Zentralnervensystem.I I I Congr~s International de Neuropathologie, p. 127--147 (1957). - - , u . H. GRoss: tJTber eine spatinfantile Form ~er tIallervorden-Spatzschen Krank_heit. II. Mitteilung: Histochemische Befunde. ErSrterung der Nosologie. Dtsch. Z. Nervenheflk. 176, 104--125 (1957). --, and K. SI~L~: On the pigment variant of amaurotic idiocy. I n Cerebral Sphingolipidoses, p. 29--47. New York and London: Academic press 1962. TITECA,J., and L. v a n BOaAERT" Heredo-degenerative hemibaI1/smus. Brain 69, 251--263 (1946).

Familial spasticity, hyperkinesia and dementia

45

L.: Aspects cliniques et patho]ogiques des atrophies pallidales et pallidoluysiennes progressives. J. Neurol. Neurosurg. Psychiatry 9, 124--157 (1946). -- G . W . F . EDGAR, and D. KA~CHE~: Type orthochromatique (~ substance soudanophile) diffuse de la leucodystrophie familiale. (Famille Huys). Acta neuropath. (BEE.) 1, 289--307 (1961). WI~K~LMA~,N. W. : Progressive pallida] degeneration, a new elinicopathologieal syndrome. Arch. Neurol. Psyehiat. (Chic.) ~7, 1--21 (1932). WOLT~a, J. R., and L. Llss: The evolution of hyaline corpuscles (cytoid bodies) in the human optic nerve. Amer. J. Opthal. 43, 885--892 (1957). ZE~A~, W., and D. G. SCARI~ELLI: The non-specific lesions of Hallervorden-Spatz disease. J. Neuropath. exp. Neurol. 17, 622--630 (1958). - - l~. K A E L B L I ~ G , and B. PASAMANICK:Idiopathic Dystonia museulorum deformans. I. The hereditary pattern. Amer. J. hum. Genet.ll, 188--202 (1959). - - - --: Idiopathic Dystonia musculorum deformans. II. The formes frustes. Neurology (Minneap.) 10, 1068--1075 (1960). VAN BOGAERT,

Dr. WILLI~ DEMYEIa, Indiana University, Medical Center, II00 West Michigan Street, Indianapolis 7, Indiana (U.S.)