11. Walker AE: Dilation of the vertebral canal abnormalities presenting with mirror move- terior enteric remnants and spinal malforma- associated with congenital anomalies of the spi- ments in a patient with Klippel-Feil : tions: The splint notocord syndrome. Arch Dis nal cord. AJR 1944;52:571-582. Case report. J Neurosurg 1983;59:891-894. Child 1960;35:76-86. 12. Gunderson CH, Solitare GB: Mirror move- 17. Levine RS, Geremia GK, McNeill TW: CT 23. Matson DD, Woods RP, Campbell JB, et al: ments in patients with the Klippel-Feil syn- demonstration of cervical diastematomyelia. Diastematomyelia (congenital clefts of the spinal drome. Arch Neurol 1968;18:675-679. J Comput Assist Tomogr 1985;9:592-594. cord): Diagnosis and surgical treatment. Pediat- 13. Mackenzie NG, Emery JL: Deformities of 18. Herren RY, Edwards JE: Diplomyelia (du- rics 1950;6:98-112. the cervical cord children with neurospinal dys- plication of the spinal cord). Arch Pathol Lab 24. Paget DH: Neuroschisis and human raphisms. Dev Med Child Neurol 1971;13(suppl Med 1940;30;1203-1214. embryonic maldevelopment: New evidence on 25):58-67. 19. Emery JL, Lender RG: The cord lesion in anencephaly, spina bifida and diverse mammali- 14. Giordano GB, Davidovits P, Cerisoli M, et neurospinal dysraphism (meningomyelocele). an defects. J Neuropathol Exp Neurol 1970; al: Cervical diplomyelia revealed by computed J Pathol 1973;110:83-96. 29:192-216. tomography (CT). Neuropediatrics 1982;13:93\x=req-\ 20. James JCC, Lassaman LP: Diastemato- 25. Thompson JS, Thompson M: Patterns of 94. myelia: A critical review of 24 cases submitted to transmission of single gene traits, in Thompson 15. Naidich TP, McLone DG, Fulling KH: The laminectomy. Arch Dis Child 1964;39:125-130. JS, Thompson M (eds): Genetics in Medicine. Chiari II malformation: IV. The hindbrain defor- 21. Reynolds AF: Cervical diastematomyelia. Philadelphia, WB Saunders Co, 1980, p 78. mity. Neuroradiology 1983;25:179-197. Neurosurgery 1985;17:1014. 16. Whittle IR, Besser M: Congenital neural 22. Bently JFR, Smith JR: Developmental pos-

Abnormal Neuroanatomy in a Nonretarded Person With Autism Unusual Findings With Magnetic Resonance Imaging Eric Courchesne, PhD; John R. Hesselink, MD; Terry L. Jernigan, PhD; Rachel Yeung-Courchesne

\s=b\Recent studies of infantile autism "infantile autism is a neural disorder or which conditions are associated using computed tomographic scanning that severely affects social, lan¬ specifically with autism, it is neces¬ emphasized the importance of studying guage, and cognitive development.14 sary to study individuals who do not cases of classic autism (Kanner's syn- The etiology of infantile autism is have concurrent conditions that may drome) without complicating conditions unknown. The neuroanatomical sub¬ significantly contribute to observed such as mental retardation. Computed strates associated with this disorder abnormalities above and beyond those tomographic scan studies of such have not been firmly established. due to autism alone. patients reported no evidence of anatom- While there have been computed Computed tomographic scan studies ical abnormalities of cerebral hemi-$ tomographic (CT) scan reports that of such classic cases of autism have spheres or of subcortical structures, subgroups of autistic persons have found no evidence of anatomical which are defined by landmarks such as anomalous cerebral asymmetries abnormalities of cerebral hemi¬ the lateral ventricles and lentiform nuclei. (right parieto-occipital regions wider spheres or of subcortical structures Examination of the was not than left5) or abnormalities of the that are defined by landmarks such as mentioned. The most recent postmortem ventricular system,6·7 there have also the lateral ventricles and lentiform neuropathologic study reported signifi- been reports that these structures are nuclei.10·15 cant cerebellar abnormality, but the study clinically normal in most autistic per¬ Examination of the cerebellum has was of a severely retarded autistic indi- sons8 or are similar in autistic and not been mentioned in the CT scan vidual. Using magnetic resonance imag- matched control groups.9 It has been reports on classic cases of autism, have ing, we found in vivo evidence of a argued that mental retardation has and, in fact, there are no in vivo or significant and unusual cerebellar malfor- been a complicating factor in some CT postmortem reports examining the mation in a person with the classic form of scan studies and that CT abnormali¬ cerebellum in such classic cases. How¬ autism uncomplicated by mental retarda- ties could just as well be related to ever, with regard to retarded autistic tion = (current nonverbal IQ 112), epilep- mental retardation as they are to cases, significant pathologic features sy, history of drug use, postnatal trauma, autism.10 of the cerebellum were found in five of or disease. The finding showed hypopla- Recently, therefore, emphasis has a total of eight cases in three sia of the declive, folium, and tuber in been placed on the importance of reports.1618 All eight individuals posterior vermis, but not of the anterior studying patients with classic autism studied were severely retarded, and vermis, and hypoplasia of only the medial (Kanner's syndrome) uncomplicated had a wide variety of complicating of each aspect cerebellar hemisphere. by concurrent conditions such as men¬ disorders and traumas, including phe- The right posterior cerebral hemisphere tal retardation.3·1114 According to this nylketonuria, severe concussions, and also showed pathologic findings. view, to determine which conditions epilepsy. In one of these reports, Bau¬ (Arch Neurol 1987;44:335-341) must be present for autism to develop man and Kemper18 found, in the post¬ mortem of a retarded Accepted for publication Nov 10, 1986. Jolla; and the Psychiatry Department, Veterans study severely From the Neuropsychology Research Labora- Administration Medical Center, San Diego (Dr man, marked loss in the tory, Children's Hospital Research Center, San Jernigan). neocerebellum, as well as cell loss in Diego (Dr Courchesne and Mrs Yeung-Cour- Reprint requests to Neuropsychology Research several cerebellar chesne); the of Neurosciences Children's Research Cen- deep nuclei—fastig- Departments (Dr Laboratory, Hospital and emboliform. In a sec¬ Courchesne), Radiology (Drs Hesselink and Jer- ter, 8001 Frost St, San Diego, CA 92123 (Dr ial, globose, nigan), and Psychiatry (Dr Jernigan), University Courchesne). ond report,17 CT scans of all three of California at San Diego School of Medicine, La severely retarded "autistic" children

Downloaded From: http://archneur.jamanetwork.com/ by a University of California - San Diego User on 04/25/2016 Fig 1.—Magnetic resonance images of midline sagittal section in normal subject (left) and midline sagittal (center) and axial (right; 7.5 mm above fourth ventricle) sections in nonretarded patient with infantile autism. In latter, hypoplasia of superior posterior vermis (pv), which includes declive, folium, and tuber, and of medial aspect of cerebellar hemispheres (m) is evident. Folia of pv are incompletely formed. Cisterna magna (cm) is enlarged. Other midline structures, including fourth ventricle (IV), stem, diencephalon, corpus collosum (cc), and medial cortical areas (eg, cingulate gyrus [ci]), appear normal.

studied showed of the cere¬ with but without hyoplasia ing person autism The patient's first words were helicopter bellum, especially in the vermal por¬ complicating . and cookie at 18 months. tion. The three children ranged in age his third and fourth of REPORT OF A CASE During years life, from 20 to 44 months, and their intel¬ the parents observed that he was socially lectual developmental level ranged A 21-year-old right-handed man meets isolated and that he was not initiating from 2 to 6 months. In a third report the Diagnostic and Statistical Manual of social contact or showing any evidence of of individuals with autisticlike behav¬ Mental Disorders, ed 3 (DSM-III), diagnos¬ social communication. He preferred to play tic criteria for autism. He does not have alone in his room and would become ior,16 marked Purkinje cell loss was other or disor¬ upset if he was dur¬ in one of four cases studied. any neurologic psychiatric extremely interrupted reported der and has no history of taking neurologic ing his repetitive play with objects. He had Of the three cases for whom there was or psychiatric medications. no playmates and would not ask questions no one report of cerebellar pathology, The patient's mother recalls an unevent¬ or state his needs other than to hold some¬ showed evidence of phenylketonuria. ful pregnancy, with the exception of a viral one's hand and use that person's hand to Another suffered a cerebral concus¬ cold contracted during the end of the first point at something. He still did not speak sion during the fourth year of life and trimester. The patient was born at full two-word phrases. He spent hours spin¬ showed no learning for almost 18 term without complications. He was the ning tops and records and flushing the months thereafter, but he did develop third child born to his parents. The toilet to watch the spinning water. bonds of attachment with his mother. patient's one younger and two older sib¬ Between the ages of 3 and 4 years, he are normal. and received examina¬ The third was a who showed lings Throughout infancy thorough neurologic girl to tions at two medical centers normal the first childhood, the patient is reported have separate (one development during been healthy, except for the usual occa¬ was The Johns Hopkins Medical Center, 18 and a months then progressive sional colds that were readily resolved by Baltimore); both concluded that there was degeneration of function, including medication. His height and weight have no detectable neurologic abnormality. hand wringing, posturing of the upper been within normal limits from birth Electroencephalography at that time was extremities, and grimacing. The clini¬ onward. The patient achieved motor devel¬ normal. Medical examinations since then cal picture of this third child is sug¬ opmental milestones on a normal schedule have continued to reveal no detectable Brain-stem audito¬ gestive of Rett's syndrome." In sum¬ as follows: rolling over at 3 months of age, neurologic syndromes. cerebellar anatomical sitting independently at 6 to 7 months, ry evoked response audiometrie testing at mary, then, 20 abnormalities have been found in crawling at 7 to 8 months, standing unsup¬ age years was also normal (see reference only ported at 9 to 10 months, and walking 8 for details of testing procedure used). autistic with severe mental persons at 15 months. The After the age of 4 years, he was placed in and of independently patient's retardation epilepsy—either father, a physician, reported that during special education and speech classes for which may be correlated with cerebel¬ infancy and childhood the patient's "fine autistic and aphasie children. From 8 years lar pathologic findings. motor coordination appeared normal, as of age onward, he was also in a socializa¬ Currently, the brain imaging tech¬ judged by his excellent manual dexterity tion therapy group for nonretarded autis¬ nology that yields the most anatomi¬ and his skill in gross motor activities tic children. cal detail is magnetic resonance imag¬ (walking on narrow walls, tree climbing, By 6 years of age, he still did not say "I" In MRI is much bicycle riding, etc)." or "me." At this time, he was placed in a ing (MRI). particular, to With superior to CT technology in imaging The parents judged the infant be "talking typewriter program." this, the cerebellum and the of healthy and bright; he cooed and his inter¬ he began to learn the alphabet and to read. periphery active play with parents during infancy He began to speak echolalically, first with the brain. In the MRI present report, was normal. However, both parents words, then phrases. By the age of 13 years, was used to examine the cerebellum, observed that the infant tended to be he still had difficulty with mixing up the , and subcortical struc¬ quieter than their two older children. He pronouns /and you and referred to himself tures in a nonretarded, high-function- had not spoken any words by 12 months. in the third person. However, by this age,

Downloaded From: http://archneur.jamanetwork.com/ by a University of California - San Diego User on 04/25/2016 the patient performed within normal lim¬ its on speech and language tests of syntax, semantics, morphology, and phonology. However, his comprehension and use of language remained peculiar and severely impaired. He spoke idiosyncratic phrases, such as saying "get pigged" for "get dressed." He referred to himself using several peculiar names, such as "Mole," "Pack," and "Alexander Wakefield Apple- gate." Whether alone in his room or with others in class, he often carried on loud conversations with himself; the other "per¬ son" in the conversation was "Panda," a stuffed bear he received as a young child. He once told a teacher, "I like talking to myself or Panda because that is grown-up talk. To me, talking to other people and saying words like Hi is toddler talk." His scores on the Comprehension sub- test of the Wechsler Intelligence Scales over a ten-year period (8 to 18 years of age) have averaged 2.5 SDs below normal. From age 8 to 9 years onward, he became a prolific writer of lists—lists of time, dates, holidays, and programs on television and radio. He became absorbed in memorizing maps and their lists of "places of interest." His long-term memory for details of sub¬ jects that interest him is somewhat above normal. Currently, he works in a bicycle shop putting together new bicycles but does not know how to repair them. He is an avid bicycle rider and has been since early childhood. He continues to show little spontaneity, especially in social situations. He remains self-contained and socially iso¬ lated and is virtually indifferent about other autistic persons he has known for more than ten years through a weekly socialization therapy group. He knows 2.—Cortical and subcortical structures in axial sections levels of third many social rules that are appropriate for Fig at (top left), classrooms, churches, buses, and the like, ventricle (top right), lateral ventricles (bottom left), and centrum semiovale (bottom right) in same nonretarded autistic as in 1. c indicates and . but he follows the rules in an almost patient Fig caudate; p, putamen; t, mechanical, rote fashion. He continues to be unaware of the social and personal scores (100, 109, and 107, respectively). placed. The tone of his voice has a tinny, needs of others, speaks with others as little Nonetheless, recent tests also show his hollow, and mechanical quality. as possible, and takes no initiative to make speaking vocabulary to be more than 1 SD Recent examinations of motor function friends. He is, however, aware that he has below normal, although his speaking confirm that the patient does not have a handicap called autism and that he dif¬ grammar and reading vocabulary are nor¬ major or debilitating motor impairment; fers from others, and he appears to feel mal. The patient has normal performance there is no evidence of , and he badly about this. on the Bender test of visual-motor ability has good dexterity and visual-motor coor¬ Psychometric testing has been per¬ and has an above-average Memory Quo¬ dination. He did, however, have significant formed several times. Between 8 and 21 tient of 120 on the Wechsler Memory difficulty keeping his balance when his years of age, the patient received tests of Scale. eyes were closed, and, when asked to per¬ nonverbal IQ, including the Leiter and the The pattern of his scores on Wechsler form motor sequences that were new to Performance subtests of the Wechsler Intelligence Scales has remained constant him, he could not do so with the facility Intelligence Scale for Children, Revised across six test sessions over a ten-year expected of normal functioning. (WISC-R), and Wechsler Adult Intelli¬ period since he was 8 years old; the nonver¬ After obtaining informed consent from gence Scale, Revised (WAIS-R). Results bal subtests Block Design and Object the patient and his parents, we conducted show nonverbal IQs of 113, 108, 121, and, Assembly have been consistently between an MRI scan of this patient's brain. A most recently, 112. At the age of 4 years, 2 and 3 SDs above the verbal subtests 1.5-tesla whole-body imager (Signa) was his IQ was 63, as measured by the Stan- Vocabulary and Comprehension. This pat¬ used. Three multisection sequences were ford-Binet; this IQ principally reflects the tern of extreme disparity between these performed: (1) a multisection spin-echo patient's severe language impairment at nonverbal and verbal subtests is similar to sequence (TR-2000, TE-25, 70 ms) in the that time. Between 8 and 21 years of age, the pattern found by Rutter20 and others axial plane from the foramen magnum to there has been a steady increase in verbal (A. J. Lincoln, PhD, E. Courchesne, PhD, vertex; (2) a multisection spin-echo ability. Results of the Verbal subtests of B. A. Kilman, et al, unpublished observa¬ sequence (TR-2000, TE-25, 70 ms) in the the Wechsler Intelligence Scales have been tions, 1986) in large samples of high-func¬ coronal plane through the brain; and (3) a 72, 82, and, most recently, 96. His language tioning, nonretarded autistic persons. multisection Tl-weighted sequence (TR- quotient, based on the Test of Adolescent The quality of the patient's speech is 600, TE-25) in the sagittal plane near the Language, is 89, which is in the low normal distinctly dysprosodic. It is arrhythmic, midline. Sections were 5 mm in thickness, range. Recent tests of reading, spelling, clipped, and hesitant. His voice is typically and there were 2.5-mm gaps between adja¬ and arithmetic with the Wide-Range monotonie, and any changes in tone and cent sections. Achievement Test (WRAT) reveal normal loudness are abrupt and inappropriately As seen in Fig 1, specific regions in the

Downloaded From: http://archneur.jamanetwork.com/ by a University of California - San Diego User on 04/25/2016 with his severe language deficit, par¬ ticularly during the first six years of his life (the relative contributions to his language deficit of his cerebellar pathologic condition and the function¬ ing in other language areas of his brain cannot be determined). Such a speculation, however, may not be war¬ ranted for several reasons; for exam¬ ple, the possibility remains that the right hemisphere enlargement was secondary to right posterior ventricu¬ lar enlargement, rather than to left hemisphere maldevelopment or un- deruse. Furthermore, the pathologic data in our patient points to the right cerebral not the left. Our Fig 3.—Views at two axial levels (right axial section is 7.5 mm superior to left axial section) of hemisphere, same autistic patient as in Fig 1 show sulcal widening in right posterior hemisphere and patient's neuropathologic findings abnormally enlarged posterior horn of lateral ventricle in right hemisphere. R101 indicates right remind us that a larger cerebral hemi¬ side; L99, left side. sphere is not necessarily better. In addition to the cerebral patho¬ logic findings, an unusual and medial neocerebellar hemi¬ tal trauma, or disease. pathologic condition was found, which spheres of our patient are abnormally The right posterior cerebral hemi¬ appears to be decreased or arrested small, and the cisterna magna is enlarged. sphere appears to be abnormal in this development of the declive, folium, Within the posterior vermis only, the classic case of autism. In particular, and tuber in the superior posterior and tuber neocerebellar declive, folium, (ie, the right posterior cerebral hemi¬ vermis, as well as the medial aspect of vermal lobules VI and are VII) particularly has an overall size that is the cerebellar The and incompletely formed. sphere hemispheres. hypo- maldeveloped area on in these three of The remainder of the vermis (ie, anterior larger than its corresponding plasia regions the vermis, pyramis, nodulus, and uvula- the left hemisphere, which is atypical superior posterior vermis, which con¬ all nonneocerebellar lobules) appears of normal adult men,21 and it has an stitute neocerebellar vermis, is brack¬ normal in size (midline section; Fig 1, cen¬ abnormally large ventricle and a eted on either side by normal-sized ter). The fourth ventricle, folia of the slight increase in sulcal width. These anterior vermis and by apparently cerebellar hemispheres, and anterior ver¬ findings are not in general agreement normal-sized pyramis, nodular, and mal sulci are normal in size. This pattern with the CT scan data from other uvular of the inferior fea¬ regions posteri¬ of abnormal and normal cerebellar nonretarded autistic and or vermis. tures indicates that the abnormalities of persons,1015 raise the of whether the the same structures in the declive, folium, and tuber in the poste¬ they question Very nearly rior vermis and of the medial neocerebellar greater anatomical detail provided by the rat have only just recently been MRI reveal further of shown be essential for form of hemispheres are attributable to hypopla- may evidence to one sia. The dentate nuclei appear to be normal cerebral abnormalities in autism. learning and memory—long-term ha- in size. The significance of these right pos¬ bituation of the acoustic startle The right posterior horn of the lateral terior cerebral findings is unclear at response.24 It is an important experi¬ ventricle is abnormally large, and the right this time. With anatomical abnormal¬ mental question as to whether our posterior cerebral hemisphere appears to ities of the right posterior cerebral patient will show an analogous deficit than the left 2 and be larger (Figs 3). Also, hemisphere, one would predict lower- in long-term habituation. in the right posterior cerebral hemisphere than-normal nonverbal intellectual Such noticeable (parieto-occipital cortex), there is a slight readily pathologic our has increase in the sulcal width. Otherwise, ability. Paradoxically, patient findings in the cerebellum of our cortical structures, including gyral and /it^/ier-than-normal nonverbal IQ. patient do not rule out the possible sulcal landmarks, and cortical thickness The evidence that the right posteri¬ presence of other pathologic condi¬ appear to be normal (Figs 2 and 3). No or hemisphere is larger than the left tions at the microanatomical or phys- abnormalities were found in the anterior in our patient is reminiscent of some iochemical level that are transparent or medial temporal lobes, frontal and CT scan reports, which indicate that to the MRI technique. Also, this dis¬ medial cortical areas, corpus callosum, some retarded autistic persons have tinctive single case cannot be used to basal or brain stem thalamus, ganglia, (Fig anomalous asymmetries in the pari- establish a direct causal link between 2). There are no foci of abnormal signal Goldman-Rakic the cerebellum and autism. and no evidence of intracranial eto-occipital region.5 intensity Rakic22 have shown Most lesions (Figs 1 through 3). The lateral and that removal importantly, however, this (with the exception of the right posterior of one cortical area may result in case alerts us to the possibility that horn) and third ventricles are normal in hypertrophy of the homologous con¬ the chronology of cerebellar hypopla- size (Figs 2 and 3). tralateral cortical area, and Gesch¬ sias in autism may serve as one sign¬ wind and Galaburda23 have to the of the COMMENT speculated post pointing chronology that poorer development or slowed critical neural maldevelopment in With the use of MRI, we have found growth of one cortical area could also autism. For example, the concurrence in vivo evidence of both cerebral and result in hypertrophy of the homolo¬ in our patient of a neuropathologic cerebellar abnormalities in a person gous area. One might speculate that condition—cerebellar hypoplasia— with a "pure" case of the classic form the enlarged right posterior hemi¬ and a neuropsychopathologic condi¬ of infantile autism. This case was sphere in our patient is the result of tion—autism—presents the possibili¬ uncomplicated by mental retardation, abnormally reduced growth of left ty that both pathologic conditions epilepsy, history of drug use, postna- hemisphere speech areas associated may have resulted from the same

Downloaded From: http://archneur.jamanetwork.com/ by a University of California - San Diego User on 04/25/2016 genetically or environmentally medi¬ and migration in the cerebellum neocerebellum without concurrently ated disruption to his brain during its occurs throughout the first two years producing overt cerebellar motor dys¬ development. Because of the nature of of postnatal life.34 The declive, folium, function. our patient's limited gross pathologic and tuber receive their final full com¬ Genetic mutations in mice may pro¬ findings, we can hypothesize critical plement of granule cells after the vide insights. Postnatal loss of Pur¬ neurodevelopmental periods during anterior vermis and the inferior pos¬ kinje cells in mice is caused by two which this pathologic condition could terior vermis.35 If the brain was genetic mutations, one called the have occurred. exposed to teratogenic agents during "nervous" mouse and the other the There are several possibilities, the final stages of granule cell genesis "PCD" (Purkinje cell degeneration) three of which will be noted. First, in and migration, depletion of granule mouse.41 Such postnatal Purkinje cell the rat on developmental day E14, the cells in the declive, folium, and tuber loss might be expected to produce first Purkinje cells to be generated could occur, but anterior vermis and macroscopic cerebellar hypoplasia. are destined for the vermal wedge inferior posterior vermis would be Both mouse mutations also cause (eventually the posterior vermis) and much less affected. Given sufficient photoreceptor degeneration. This pat¬ for portions of the cerebellar hemi¬ granule cell depletion, the macroscop¬ tern of pathologic findings—postnatal spheres (the lobus simplex and crura I ic appearance on MRI scans could be Purkinje cell loss and photoreceptor and II)25—regions similar to those similar to the hypoplasia of the degeneration—is distinctive of these that are hypoplastic in our patient. A declive, folium, and tuber seen in our genetic mutations. Although our genetically or environmentally medi¬ patient. patient exhibits macroscopic hypopla¬ ated disruption at that time might In light of the maternal history, the sia, we do not know whether he also simultaneously disturb the cytogene- patient's history, and the appearance has photoreceptor degeneration. sis of these Purkinje cells as well as of the vermal sulci, a number of The Purkinje cells of the cerebellar other neurons whose peak day of neu- potential causes of his cerebellar cortex are among the most sensitive rogenesis is also E14. These latter pathologic condition can be ruled out, in the central nervous system to the include neurons of the nucleus reticu- including postnatal trauma, epilepsy, effects of anoxia.42 It is conceivable laris thalami and of the most superfi¬ nutritional deficiency, maternal use that anoxia during early development, cial layer of cortex.26 Nucleus reticu- of medications, alcohol or smoking, including postnatal development, laris thalami gates interactions and maternal endocrine disorders. could result in an abnormally small among cortex, thalamus, and mesen- This patient's abnormal neuroanato- cerebellum. However, the medical his¬ cephalic reticular system and is my also differs from known cerebellar tories of the mother during pregnancy involved in modulating awareness, developmental anomalies and known and of the patient as an infant show attention, and sensory transmis¬ degenerative cerebellar diseases.36"40 no significant event that could cause sion.2730 Behavioral attention and For example, his pathologic condition such a condition. The only wrinkle in arousal trigger excitatory input to the does not present with pontine dysgen- the history of the pregnancy was an most superficial layers of cortex as esis typical of pontoneocerebellar ordinary cold that the mother had at part of the first stage of cortical acti¬ hypoplasia. Also, in contrast to the end of the first trimester, and the vation.31·32 Down's syndrome, the Dandy-Walker only one in the postnatal period was a As a second example, in the rat, the syndrome, the Arnold-Chiari defor¬ three-day cold with a temperature of migrations of Purkinje neurons to mity, and the Joubert syndrome, our 39.4°C that the patient had at 22 posterior and anterior vermis occur in patient's pathologic condition occurs months of age. waves, which are separated in time in the absence of the major malforma¬ Dysprosody may result from cere¬ from each other; they migrate first to tions of other neuroanatomical and bellar damage in adulthood, particu¬ the posterior vermis (completing their nonneural structures found in these larly to the left superior paravermal migration from days E17 through syndromes and in the absence of clini¬ cerebellum43 (for a review, see refer¬ E19), and then later to the anterior cally significant deficits in gross ence 37). In global cerebellar hypopla¬ vermis (completing their migration motor functioning. For instance, the sia, speech typically fails to devel¬ from days E20 through E22).25 These Dandy-Walker syndrome includes not op,39·40 and, when it does, it has been migrations occur in a relatively brief only vermal hypoplasia but also described as hesitant, stammering, time (at the end of the first trimester enlargement of the fourth ventricle; and explosive in character.39 It seems in the human33). A brief disruption at commonly associated abnormalities likely that our patient's dysprosody is the time of the migration of Purkinje include agenesis of the corpus callo- a consequence of his regional cerebel¬ neurons to the posterior vermis could sum, anomalies of cortical gyri, lar hypoplasia. If that were so, one leave it (and the adjacent medial cere¬ dolichocephaly, polydactyly, and cleft may speculate that cerebellar mecha¬ bellar hemisphere) hypoplastic, as in palate. In congenital cerebellar hypo¬ nisms are crucial to the development our patient; it might also simulta¬ plasia, the cerebellum is typically uni¬ of speech and that neural plasticity is neously affect other neural systems formly small. This is a rare autosomal insufficient to fully compensate for that are undergoing critical develop¬ recessive disorder in which there is some speech deficits resulting from a ment during that time. In the rat, severe reduction in the number of cerebellar pathologic condition in¬ systems undergoing cytogenesis dur¬ granule cells throughout the cerebel¬ curred early in development—in con¬ ing this period include the subiculum, lum and neuronal loss in the hippo¬ tradistinction to the Kennard princi¬ CAI and CA3 of the hippocampal for¬ campus; patients have hypotonia, poor ple, which states that there is greater mation, portions of the septum, and coordination, and delay in motor recovery or sparing of function follow¬ the amygdalohippocampal area of the development—symptoms not seen in ing lesions incurred early in develop¬ corticomedial complex of the amygda¬ our patient.38"40 At present, we cannot ment compared with those incurred la26; these neural systems are involved completely rule out some other yet- later.44·45 In contrast to speech, it is in memory and emotional behavior. to-be-described postnatal mechanism curious and noteworthy that the cere¬ As a third and final example, in that principally affects only portions bellar pathologic features in our humans, granule cell neurogenesis of the posterior vermis and medial patient were not associated with

Downloaded From: http://archneur.jamanetwork.com/ by a University of California - San Diego User on 04/25/2016 impairment of other aspects of motor grant 5-R01-NS19855 from the National Insti¬ 19. Hagberg B, Aicardi J, Dias K, et al: A development. tute of Neurological and Communicative Disor¬ progressive syndrome of autism, dementia, atax- ders and Stroke and 1-RO1-MH36840 from and loss of hand use in Rett's our an grant ia, purposeful girls: Thus, patient represents the National Institute of Mental Health, Nation¬ syndrome: Report of 35 cases. Ann Neurol unusual case of regional cerebellar al Institutes of Health, Bethesda, Md (Dr Cour¬ 1983;14:471-479. hypoplasia. Patients with global cere¬ chesne). 20. Rutter M: Language disorder and infantile bellar exhibit Valuable assistance has also been provided by autism, in Rutter M, Schopler E (eds): Autism: A hypoplasia usually glob¬ the Magnetic Resonance Institute of the Medical and Treatment. New al or Reappraisal of Concepts cognitive impairment, delays Center of the University of California at San York, Plenum Publishing Corp, 1978. failure to develop speech, hesitant and Diego and by the San Diego Regional Center for 21. Zatz LM, Jernigan TL, Ahumada AJ: explosive speech, and the following the Developmentally Disabled. We extend special Changes on computed cranial tomography with motor abnormalities: substan¬ thanks to Sara Wells, Alan J. Lincoln, PhD, and aging: Intracranial fluid volume. Am J Neurora- major Beverly A. Kilman, PhD. diol tial in or or 1982;3:1-11. delays failure to sit, stand, 22. Goldman-Rakic P, Rakic P: Experimental walk; hypotonia; incoordination (eg, References modification of gyral patterns, in Geschwind N, , dyssynergia, and titubation); Galaburda AM (eds): Cerebral Dominance: The and abnormal ocular movements (eg, 1. Kanner L: Autistic disturbances of affective Biological Foundations. Cambridge, Mass, Har- fixation In contact. Nerv Child 1943;2:217-250. vard University Press, 1984, pp 179-192. nystagmus).39·40 compari¬ 2. Cohen DJ, Caparulo B, Shaywitz B: Primary 23. Geschwind N, Galaburda AM: Cerebral son, our patient has partial cognitive childhood and childhood autism: Clini- lateralization: Biological mechanisms, associa- impairment, was delayed in speech cal, biological and conceptual observations. J Am tions, and pathology: II. A hypothesis and a has hesitant and Acad Child Psychiatry 1976;15:604-645. program for research. Arch Neurol 1985;42:521\x=req-\ development, explo¬ Rutter M: sive did not have motor 3. Language, cognition, and autism, 552. speech, major in Katzman R (ed): Congenital and Acquired 24. Leaton RN, Supple WF: Cerebellar vermis: abnormalities beyond dysprosody and Cognitive Disorders. New York, Raven Press, Essential for long-term habituation of the acous- poor balance with eyes closed, and has 1979, pp 247-264. tic startle response. Science 1986;232:513-515. autism. 4. DeMyer MK, Hingtgen JN, Jackson RK: 25. Altman J, Bayer SA: Embryonic develop- The cerebellar Infantile autism reviewed: A decade of research. ment of the rat cerebellum: III. Regional differ- pathologic findings Schizophr Bull 1981;7:388-451. ences in the time of origin, migration, and set- in our nonretarded patient are consis¬ 5. Hier DB, LeMay M, Rosenberger PB: tling of Purkinje cells. J Comp Neurol 1985; tent with previous CT as well as post¬ Autism and unfavorable left-right asymmetries 231:42-65. mortem neuropathologic data from of the brain. J Autism Dev Disord 1979;9:153\x=req-\ 26. Bayer SA, Altman J: Directions in neuro- several retarded 159. genetic gradients and patterns of anatomical severely autistic per¬ 6. Campbell M, Rosenbloom S, Perry R, et al: connections in the telencephalon. Prog- Neuro- sons.17·18 A question raised by these Computerized axial tomographic scans in young biol, in press. findings is whether cerebellar ana¬ autistic children. Am J Psychiatry 1982;139:510\x=req-\ 27. Scheibel AB: Anatomical and physiological tomical now 512. substrates of arousal: A veiw from the bridge, in abnormalities, having 7. Damasio Maurer Damasio et al: Hobson Brazier MAB The Reticular been found in retarded and nonre¬ H, RG, AR, JA, (eds): Computerized tomographic scan findings in Formation Revisited. New York, Plenum Pub- tarded autistic individuals alike, may patients with autistic behavior. Arch Neurol lishing Corp, 1980, pp 55-66. be found in a significant subpopula¬ 1980;37:504-510. 28. Watson RT, Valenstein E, Heilman KM: tion of autistic persons in general. 8. Caparulo BK, Cohen DJ, Rothman SL, et al: Thalamic neglect: Possible role of the medial Another is the Computed tomographic brain scanning in chil- thalamus and nucleus reticularis in behavior. question part played dren with developmental neuropsychiatric disor- Arch Neurol 1981;38:501-506. by anatomical abnormalities of the ders. J Am Acad Child Psychiatry 1981;20:338\x=req-\ 29. Skinner JE, Yingling CD: Regulation of cerebellum when it does occur in per¬ 357. slow potential shifts in nucleus reticularis tha- sons with autism. It has been sug¬ 9. Tsai L, Jacoby C, Stewart M, et al: Unfavor- lami by the mescencephalic reticular formation that these cerebellar able left-right asymmetries of the brain and and the frontal granular cortex. Electroencepha- gested abnormal autism: A question of methodology. Biol Psychi- logr Clin Neurophysiol 1976;40:288-296. anatomical and physiologic conditions atry 1983;18:317-327. 30. Singer W: Control of thalamic transmis- might significantly disrupt the func¬ 10. Prior MR, Tress B, Hoffman WL, et al: sion by corticofugal and ascending reticular tioning of attentional mechanisms,46 Computed tomographic study of children with pathways in the visual system. Physiol Rev the limbic and the classic autism. Arch Neurol 1984;41:482-484. 1977;57:386-420. system,47 acquisi¬ 11. Prior M: Learning abilities and disabilities 31. Inubushi S, Kobayashi T, Oshima T, et al: tion and execution of skilled mental as in childhood autism: A review. J Abnorm Child Intracellular recordings from the motor cortex well as motor operations.48 Recently, Psychol 1979;7:357-380. during EEG arousal in unanesthetized brain the cerebellum has been shown to be 12. Hoffman W, Prior M: Neuropsychological preparations of the cat. Jpn J Neurophysiol dimensions of autism in children: A test of the an essential location for certain forms 1978;28:669-688. hemispheric dysfunction hypothesis. J Clin Neu- 32. Inubushi S, Kobayashi T, Oshima T, et al: of learning and memory.24·49 For ropsychol 1982;4:27-42. An intracellular analysis of EEG arousal in cat instance, might anatomical abnormal¬ 13. Rumsey JM, Grimes AM, Pikus AM, et al: motor cortex. Jpn J Neurophysiol 1978;28:689\x=req-\ ities in the vermis in autism affect Auditory responses in pervasive 708. acoustic developmental disorders. Biol Psychiatry 33. Rakic P, Sidman RL: Histogenesis of corti- long-term habituation of the 1984;19:1403-1418. cal layers in human cerebellum, particularly the startle response as it does in rats,24 or 14. Courchesne E, Yeung-Courchesne R, Hicks lamina dissecans. J Comp Neurol 1970;139:473\x=req-\ might anatomical abnormalities of G, et al: Functioning of the brainstem auditory 500. the cerebellar hemispheres in autism pathway in non-retarded autistic individuals. 34. Raaf J, Kernohan JW: A study of the Clin Neurophysiol external in the cerebellum. Am J affect associative as it does Electroencephalogr 1985; granular layer learning 61:491-501. Anat 1944;75:151-172. in rats?49 15. Creasey H, Rumsey JM, Schwartz M, et al: 35. Altman J: Autoradiographic and histologi- The answer to these questions will Brain morphometry, as measured by quantita- cal studies of postnatal neurogenesis: III. Dating require MRI studies of larger samples tive CT scanning, in autistic men. Arch Neurol the time of production and onset of differentia- of retarded and autistic 1986;43:669-672. tion of cerebellar microneurons in rats. J Comp nonretarded 16. Williams RS, Hauser SL, Purpura DP, et Neurol 1969;136:269-294. persons, and comparing subjects with al: Autism and mental retardation: Neuropatho- 36. Malamud N, Hirano A: Atlas of Neuropath- major cerebellar pathologic findings, logic studies performed in four retarded persons ology. Berkeley, University of California Press, with autistic behavior. Arch Neurol as seen in MRI data, with those with¬ 1980;37:749\x=req-\ 1974. out discernible in 753. 37. Gilman S, Bloedel J, Lechtenberg R: Disor- pathologic findings 17. Jaeken J, van den Berghe G: An infantile ders of the Cerebellum. Philadelphia, FA Davis detailed neurophysiologic, neuro- autistic syndrome characterized by the presence Co Publishers, 1981. chemical, and behavioral studies. of succinylpurines in body fluids. Lancet 38. Chaves E, Frank LM: Disorders of basal 1984;1:1058-1059. ganglia, cerebellum, brain stem, and cranial 18. Bauman M, Kemper TL: Histoanatomic nerves, in Farmer TW (ed): Pediatric Neurology. This research was supported by Children's observations of the brain in early infantile New York, Harper & Row Publishers Inc, 1983, Hospital Research Center, San Diego, and by autism. Neurology 1985;35:866-874. pp 605-648.

Downloaded From: http://archneur.jamanetwork.com/ by a University of California - San Diego User on 04/25/2016 39. Jervis GA: Early familiar cerebellar 290. Neurobiological Issues in Autism. New York, degeneration. J Nerv Ment Dis 1950;111:398\x=req-\ 44. Simons D, Finger S: Some factors affecting Plenum Publishing Corp, 1986. 407. behavior after brain damage early in life, in 47. Heath R, Dempsey CW, Fontana CJ, et al: 40. Sarnat HB, Alcala H: Human cerebellar Finger S, Almli CR (eds): Early Brain Damage. Feedback loop between cerebellum and septal-$ hypoplasia: A syndrome of diverse causes. Arch Orlando, Fla, Academic Press Inc, 1984, vol 2: hippocampal sites: Its role in emotion and epilep- Neurol 1980;37:300-305. Neurobiology and Behavior, pp 327-347. sy. Biol Psychiatry 1980;15:541-556. 41. Caviness VS Jr, Rakic P: Mechanisms of 45. Will B, Eclander F: Early brain damage 48. Leiner HC, Leiner AL, Dow RS: Does the cortical development: A view from mutations in and early environment, in Finger S, Almli CR cerebellum contribute to mental skills? Behav mice. Ann Rev Neurosci 1978;1:297-326. (eds): Early Brain Damage. Orlando, Fla, Aca- Neurosci 1986;100:443-454. 42. Margerison JH, Corsellis JAN: Epilepsy demic Press Inc, 1984, vol 2: Neurobiology and 49. McCormick DA, Thompson RF: Cerebel- and the temporal lobes. Brain 1966;89:499-530. Behavior, pp 349-367. lum; Essential involvement in the classically 43. Lechtenberg R, Gilman S: Speech disorders 46. Courchesne E: A neurophysiological view conditioned eyelid response. Science 1984; in cerebellar disease. Ann Neurol 1978;3:285\x=req-\ of autism, in Schopler E, Mesibov GB (eds): 223:296-299.

Sporadic Case Resembling Autosomal-Dominant Motor System Degeneration (Azorean Disease Complex) Barbara A. McQuinn, MD, Thomas L. Kemper, MD

\s=b\We describe a case of an adult-onset sponses, and variable cranial nerve dysesthesias due to a left C6-C7 cervical progressive with external oph- abnormalities. At autopsy, affected radiculopathy, and the recent onset of a thalmoplegia, occurring in a black man members exhibited consistent leftward torticollis. Severe athetosis of the family limbs that could be either without a family history of neurologic dis- neuronal loss in the anterior horns provoked by movements or emotion orders. Neuropathologic examination and Clarke's column in the voluntary by strong spinal was noted. The extraocular movement demonstrated neuronal loss and gliosis in cranial nerve motor nuclei cord, the findings were unchanged. A mild left facial the anterior horn and Clarke's column in concerned with extraocular motility, paresis and myokymia over the left eyelid the nuclei of cranial spinal cord, nerves III, hypoglossal nucleus, vestibular com¬ and corner of the mouth was apparent. VI, X, and XII, vestibular complex, lateral plex, and substantia nigra in the brain Strength, cognitive function, perception of cuneate nucleus, lower pontine tegmen- stem, and in the dentate nucleus of pinprick, light touch, and vibration were tum, red nucleus, substantia nigra, and the cerebellum (Table). We describe normal. Muscle tone was now decreased, dentate nucleus. The cerebral cortex, cor- herein the clinical features and neuro- and his speech had become hypophonic. Plantar were recorded as flexor. pus striatum, basis pontis, inferior olives, of what is the to our responses pathology first, An evaluation demon¬ and cerebellum were spared. The clinical case of the dis¬ electrodiagnostic knowledge, sporadic strated a diffuse and mild, peripheral neuropa¬ pathologic findings closely resemble ease. thy. autosomal-dominant motor system de- In the next five the REPORT OF A CASE years, patient's generation or "Azorean disease," with- external ophthalmoplegia had progressed out, however, demonstrable familial A 38-year-old black man, born and to such a degree that no eye movements in transmission. In addition to the absence raised in Barbados, died of aspiration any direction could be elicited either volun¬ of a family history, unique features of the pneumonia following a protracted and pro¬ tarily or by oculovestibular testing maneu¬ case include the presence of Alzheimer gressive neurologic illness. His difficulties vers. Bilateral ptosis was present and the to The type II glial cells in the red nucleus and an began at age 21 years, when his sister first pupils reacted sluggishly light. gag an and of his reflex was absent. The was unexplained persistent elevated concen- noted unsteady gait buckling patient's speech left knee. At age 23 years, he to unintelligible although he was able to fol¬ tration of serum amylase. began move¬ low complex commands. Reflexes were Neurol experience involuntary writhing (Arch 1987;44:341-344) ments of the limbs and trunk, necessitat¬ brisk bilaterally and his plantar reflexes ing his confinement to a wheelchair by age were again extensor. The patient suffered 25 years. At age 30 years, a neurologic a respiratory arrest and died 17 years after Autosomal-dominant motor system examination demonstrated slurred speech, the onset of symptoms. is a disease (ADMSD) dominantly truncal ataxia, mild in the left Pharmacologie therapy was attempted and unremit¬ inherited, progressive, arm on finger-to-nose testing, and left repeatedly during the course of his illness. ting disorder, originally described in hemiparesis. He was admitted later that Levodopa/carbidopa, baclofen, amantidine patients of Portuguese Azorean year to another hospital for evaluation of hydrochloride, and several anticholinergic descent15; hence, the term Azorean abdominal pain. Neurologic evaluation dis¬ agents were ineffective in alleviating his disease of the nervous system. It has closed further progression of his disease, dystonia. been described in at least four Portu¬ with limitation of upgaze, nystagmus on The family history, obtained from old lateral gaze in either direction, mild ptosis, hospital records and available family guese families, two black families, and saccadic of visual members, was negative for or one The clinical pursuit stimuli, general¬ neurologic Japanese family.69 vermiform move¬ illness. The relatives manifestations include ized choreoathetosis, psychiatric patient's dystonia and/ ments of the tongue, and increased tone denied a history of either known consan¬ or rigidity, ataxia, progressive exter¬ with bilateral extensor plantar responses. guinity or Azorean ancestry. His mother nal ophthalmoplegia, dysarthria, His abdominal pain resolved spontaneous¬ died at age 53 years while still in Barbados, amyotrophy, extensor plantar re- ly. A thorough gastrointestinal work-up reportedly from complications of diabetes was unremarkable except for an elevated mellitus. His father is alive and well at age serum concentration Somo- 70 None of the for Oct 1986. amylase (234 years. patient's family Accepted publication 20, in of From the Neurological Unit, Boston City Hos- gyi U/dL [433 U/L]), which persisted reported any history neurologic prob¬ pital, Boston. this range throughout the rest of his life. lems, gait trouble, tremors, or early death Reprint requests to 2832 Summit St, Oakland, Three years later, the patient was ad¬ in themselves or other relatives, although CA 94609 (Dr McQuinn). mitted for spontaneous left arm and hand diabetes mellitus was common on the

Downloaded From: http://archneur.jamanetwork.com/ by a University of California - San Diego User on 04/25/2016