Muscular Alteration in Agyria with Pyramidal Tract Anomaly

Akira Hori, MD, Attila Bardosi, MD, Hans H. Goebel, MD

and U ros Roessmann, MD

A 4-year-old boy with a history of muscular hypotonia, mental retardation, microcephaly, and generalized convulsions was found at autopsy to have agy ria, agenesis of the anterior commissure and posterior corpus callosum as well as an abnormal decussation of pyramidal tracts which de­scended in the spinal dorsal columns. Postmortem muscular alterations included type lIe fiber hypertrophy and type I fiber grouping, variably expressed in individual muscles and intramuscular fascicles. This may represent a developmental delay compatible with a gestational age between the 34th and 40th week. These studies also indicate the importance of examining (a) multiple samples of postmortem muscles and (b) muscles from patients afflicted with cerebral malformations.

Hori A , Bardosi A, Goebel HH, Roessmann U. Muscular alteration in agyria with pyramidal tract anomaly. Brain Dev 1986;8:624-30

Muscle pathology associated with central ner­vous system (CNS) malformations is scantily documented. Myopathologic data provided in this context should increase the spectrum of combined CNS developmental defects and muscle pathology amongst which congenital muscular dystrophy combined with cerebral lesions has previously been observed. However,

From the Department of Neuropathology, University of Goettingen (AH, AB); Department of Neuropa­thology, University ofMainz (HHG), Federal Republic of Germany; and Department of Pathology, Case Western University, Cleveland, USA (UR).

Received for publication: February 24 , 1986 . Accepted for publication: June 18, 1986.

Key words: Abnormal pyramidal tracts, agyrio, brain malformation, muscle changes in brain malformation, postmortem muscle histochemistry.

Correspondence address: Dr. A. Hori , Department of Neuropathology, University of Goettingen, Robert­Koch-Str. 40,0-3400 Goettingen, Federal Republic of Germany.

the nosological significance of these observa­tions is not always clear.

Case Report Clinical and neuropathological evaluation of this case has been reported elsewhere [1] ; these findings are only briefly repeated here.

The patient was a 4-year-old boy born after an uncomplicated pregnancy. The delivery was prolonged. He had a normal chromosomal pat­tern . Microcephaly and micrognathia were the only craniofacial anomalies. He failed to thrive and had diffuse muscular hypotonia with slight­ly increased tendon reflexes bilaterally. His weakness was progressive, particularly in the lower extremities. He showed severe mental retardation and generalized convulsions which were poorly controlled by medication. He died at 4 years of age after repeated bouts of bronchopneumonia . There were no similarly affected family members.

Neuropathological Findings

The cerebrum was completely agyric. The

Fig 1 Histochemical features of muscles. Generally, type I fibers (darkly stained in all pictures but B) are small in diameter and type IIc fibers (lightly stained in all pictures but B) are hypertrophic. Note that there are no regular mosaic pattern of uniform fiber size and no type grouping present. A & B from left gastrocnemius, C & D from right biceps, E from right quadriceps and F from left gastrocnemius muscles. ATPase (pH 4.3) except B: menadione-linked alpha-glycerophosphate dehydrogenase. Photomicrographs obtained by differential interference contrast/Nomarski, xl06 (A,B,D,E&F) and x42 (C).

cortex was diffusely thickened and showed a simplified structure consisting of molecular, large neuronal and small neuronal layers. Nei­ances. No gliomesenchymal proliferates were seen on the surface of the brain. The internal capsules were present but the cerebral pedun­cles were hypoplastic . Cortical disorganization was seen in the vermis (i.e. archicerebellum). Further brain anomalies consisted of agenesis of the anterior commissure and of the posterior part of the corpus callosum, and of small heterotopic neuronal nests in the cerebellar white matter. The pyramidal crossing consisted of multiple small bundles. The fibers crossed

ther the precentral gyrus nor Betz cells were identified. There were no cerebral heterotopic neuronal nests suggesting migratory disturb­into the dorsal columns, respectively , in which they descended throughout the spinal cord. The distribution of the anterior horn cells was very irregular with focally reduced numbers of nerve cells. Existing spinal nerve roots were normal. The eyes showed no pathological changes.

Muscle Findings

At necropsy, tissue was obtained from bilateral

Hori et al: Muscular alteraction in agyria 625

H~ ~ f F:fOU (H CY lUI EI

H~S ffii:f.OUI:.HCY 7. ElIiJ

LT. BICEpS

TYPE I

TYPE . lie

u ~:eU+-.-~--~~"""-J.+ • ..J."""'.L...""""~"""-"':7:-:.-;"

"IJS FI,OU'HCY III e

HBS ffl'(OUEtiCY 38 ee

~ .u+-_...::JL..... • 08.

LI. QUADRICEPS

TYPE I

TYPE lie

. I :;. I .

)5 •• 78 88

~ ~ ~ ~~~ ~ Uf~C'!' 7 ~ ~u

3:> UO

.. l; -;' J J:[QlH . H CY

"HI 0-:'

BT. BICEpS

TYPE I

TYPE lie

II ~ ~ ito+' .-. • --L--L...J.......J..-I.-J> ......... ...J.L..L-........ -'-........ ~-7-.-;O.

Hl;i $ flJ([OU[HC Y

7. '.1 I

I

RT. GASIAOCN .

TYPE I

" "·1

;; .. ,.~ IL.....L-L...L..~I----..L..j u "".,

.:ItS fR[QU[HC"I 1. iltll

,. .. I '0 •• j I

uo .1 ·11 I,

TYPE lit

o ue 35 88 ,

70 eo

Fig 2 Number and diameter of muscle fibers of type [ and type [Ie from various muscles of the patient. On ver· tical axis numbers of fibers and on horizontal axis fiber diameter in JJ111. Counted and calculated by computer "Videoplan"@ (KontronJ.

biceps brachii, quadriceps femoris, and gastIO­cnemius muscles and processed according to

626 Brain & Development, Vol 8, No 6, 1986

routine procedures. Histologically , there was no evidence of dystrophy, neurogenic atrophy, nor

inflammation. There was variability in fiber size. Histochemically, isolated type I fiber grouping was recognized in the gastrocnemius muscle (Fig la, b). Regionally, there was type I predominance. The average percentage of each fiber type was 50:2-15:30-50 (I:IIc:IIa + b). Although fiber type distribution varied considerably in different muscles and in various fascicles of the same muscle (Fig Ic-f), there was no statistically significant difference be­tween right and left when many fascicles were examined.

Quantitative analysis of fiber diameters showed marked differences in size of type I fibers among examined muscles and in each section of one muscle, but many fibers were small. In the upper extremities, mean diameters of type I fibers varied between 23 and 26 pm and those of type lIc fibers between 37 and 39 pm, indicating marked type IIc hypertrophy (Table 1, Fig 2). In the lower extremities, the diameters were 23 to 28 pm for type I fibers and 22 to 24 pm for type IIc fibers (Table 1). Generally, type IIa + b fibers also showed hypertrophy.

1_ . __ . __ ._ ..... _.~. _!,' •

10

'" 10

!IO

10

!IO

10

o

"'t. \

\ , \. , ,

lie \ \ ,

, " , , , , ,

, ., J '.

• II.

.. ,

• II.

\ . . " ' ......

l' 11 JO U at at z. JO J2 lfill 11 40 U '*

Discussion

Little information is available on changes in skeletal muscles of patients afflicted with cerebral malformations. Brooke and Engel [2] have reported that the mean diameter of the type II fibers in such patients is smaller than usual, but that the fiber distribution is highly variable. This information is difficult to correla­te because clinical data on their patients were limitedly reported, the number of cases ex­amined was small and the patients' mobility was not clearly dealt with.

Considerable attention has recently been given to a group of diseases which entail

Table 1 Fiber diameters of Type I and lIe in present case (mean ± standard deviation in pm)

lIe

lIe

It. biceps

23.94 ± 5.07

39.63 ± 7.40 lIe

rt. gastroen.

23.98 ± 6.35

24.33 ± 5.32 lIe

IbvlRle!,s too, • ........................... _- ...... ...a.,.

• ...... j ....

10

'" 10

!IO

10

'\, , , , , , , , , ,

lie " ,

o •

rt. biceps

26.66 ± 7.82

37.93 ± 11.36

1 t. quadriceps

28.29 ± 5.91

22.97 ± 5.24

• II.

\ , ..

I' l' :Ie) U 24 21 21 !IO J2 ,. ,. ,,. 10 U ...

F~ 3 Histochemical differentiation of normal fetal muscle jibers. Modified from Kumagai et al. (9). Vertical aXIs: percentage; horizontal axis: gestational wks.

Han et al: Muscular alteractian in agyria 627

.; . .- <:: ... 0 >. .­OIl .... o '" ... ... u "' .§ ::E

o :;ti 0_

.::: '" .<;:: E ~ >.

.~ -5 ... <:: ~~ oj "' - E ~ 0

.0;.::1

"' OIl ... 0 ~Z

.~ ~ >.

"0 0. o t; . .- <:: ~ .§ ~'" >. ... .:::~ u ._ oj-0.0 '-' ... _0.

~<;I .0 E ~ >. "'.::: uu

>. OIl o "0 -5 '" Co o ... :;

"' Z

on

~ '" .::: u

"' >.

"' o Z

628 Brain & Development, Vol 8, No 6,1986

congenital muscular dystrophy of the Fuku­yama type (FCMD) [3] and cerebro-ocular dysplasia-muscular dystrophy syndrome (COD­MD) of Towfighi et al [4]. Some other forms of the brain-eye-muscle syndrome, sporadically reported [5-7] should be classified as variants of COD-MD of Towfighi et al [4], who describ­ed the nosological details excellently. As the names imply, these are multi-system syndromes characterized by a nonspecific muscular dystro­phy which, in some instances, also shows an inflammatory myopathic component associated with cerebral lesions.

The major findings in these brains are de­scribed as polymicrogyria, pachygyria, or agyria-lissencephaly (Table 2). In several such patients, extensive glial heterotopia in the arachnoid - "gliomesenchymal dysplasia" - was noted. In our patient, the brain lesion consists of agyria without any polymicrogyric com­ponent or gliomesenchymal dysplasia, apparent­ly different from "agyria" of the Walker type [8] .

In FCMD and COD-MD, cerebellar cortical disorganization similar to that seen in our patient has been consistently described, but mislabelled as "cerebellar micropolygyria"; this latter finding is, however, frequently and nonspecificaily present and is found in more superficial hemispheric areas than in deep cortical regions. In our patient, this lesion was restricted to the cerebellar vermis, the archi­cerebellum. Furthermore, there were no ocular changes in our patient.

The muscle fmdings in our patient differed very significantly from those described in the above cited disease complexes and we were unable to find comparable changes in the litera­ture. No dystrophic or inflammatory features were present, only abnormalities in fiber size and fiber type distribution. Normal differentia­tion of muscle fibers in the fetus was studied by Kumagai et al [9] and is presented in Fig 3. Ac­cording to Kumagai et al [9], the proportional number of type IIc fibers normally decreases after the 30th week and the number of type I fibers increases at the same time, suggesting that immature type lIe fibers differentiate into type I fibers. When the two curves intersect or shortly thereafter, type IIa and lIb fibers appear (Fig 3). The fiber type distribution in our 4-year-old child was similar to that of a fetus between the gestational ages of 34 to 40

weeks, with the exception that all fibers, espe­cially the IIc fibers, in our patient achieved larger diameters than those exhibited by normal fetuses. The fiber diameters of our patient, compared with those of normal children [2], corresponded to those of 3-year-old children except type IIc fibers of the upper extremities in our patient, corresponding to the diameters of 7 to 9-year-old children.

Reporting on seven children with cerebral hypotonia of possibly different though largely unidentified causes, Fenichel et al [10] inter­preted certain muscle biopsy findings in these children as indicating delayed maturation of muscle development or regression from already attained maturity. However, as no precise quantitative data on distribution of type I and type II myofibers and diameter spectra of normal pre- and postnatal muscles were included in this study [10], the aspects of selective fiber type hypo- and hypertrophy, respectively, as observed in our patient's patho­logic muscles, were not further canvassed.

The regional irregular pattern of type I fibers in our patient's muscles suggests an unbalanced development of muscle fibers and faulty in­nervation or lack of trophic factors of type I fibers. And type IIc fibers, which did not dif­ferentiate further into type I fibers, might have compensatorily grown hypertrophic. Sarnat [11] hypothesized that the motor unit is capable of developing normally without suprasegmental influence, but that an abnormal balance of descending impulses may alter histo­chemical differentation of fetal muscles. That is, minor "subcorticospinal" pathways arising in the brain stem are more influential than the pyramidal tract in histochemical differentiation of muscle and differential growth of fiber types. In our case, the uppermost pyramidal tract (precentral area) was severely malformed, but anomaly of the pyramidal tract at the brain stem level was minimal, while the cerebello­cortical malformation was also prominent. Anterior horn hypoplasia of the spinal cord might correlate with the anomaly of the upper motor neuron system.

In conclusion, our fmdings indicate develop­mental aberration in muscle morphology, pos­sibly related to the developmental anomalies of the CNS. Whether the muscle changes are relat­ed to the agyria or to the abnormality of the pyramidal tracts and hypoplasia of anterior

horn cells is still not clear. Thus, the nosologic position of our patient's eNS and muscle dis­order differs from those described previously [5-7], and whether similar muscle pathology patterns are associated with our patient's spec­trum of CNS malformations or not remains to be elucidated by future studies. Our muscle examination showed variability of findings in each muscle. This underlines the necessity to examine several muscles, at necropsy easily performed in contrast to surgical biopsy. Sys­tematic examination of muscles in patients with different brain malformations can thus be accomplished, providing new information on muscle pathology, especially on the relation between pyramidal tract anomalies and muscle abnormalities. Our report emphasizes the need for more systematic investigations and the possible correlation of their respective individu­al findings.

References l. Roessmann U, Hori A. Agyria (lissencephaly)

with anomalous pyramidal crossing. Case report and review of literature. J Neurol Sci 1985 ;69: 357-64

2. Brooke M, Engel WK. The histographic analysis of human muscle biopsies with regard to fiber types. 4. Children's biopsies. Neurology 1969; 19:591-605

3. Fukuyama Y, Osawa M, Suzuki H. Congenital progressive muscular dystrophy of the Fukuyama type-Clinical, genetic and pathological conside­rations-. Brain Dev (Tokyo) 1981;3: 1-29

4. Towfighi J, Sassani JW, Suzuki K, Ladda RL. Cerebro-ocular dysplasia-muscular dystrophy (COD-MD) syndrome. Acta Neuropathol. (Berl) 1984;65: 110-23

5. Santavuori P, Leisti J, Kruus S, Raitta CH. Muscle, eye and brain disease: a new syndrome. Doc Ophthalmol Proc Series 1978; 17: 393-6

6. Korinthenberg R, Palm D, Schlake W, Klein J. Congenital muscular dystrophy, brain malforma­tion and ocular problems (muscle, eye and brain disease) in two German families. Eur J Pediatr 1984; 142:64-8

7. Dambska M, Wisniewski K, Sher J, Solish G. Cerebro-oculo-muscular syndrome: a variant of Fukuyama congenital cerebromuscular dystro­phy. Clin NeuropathoI1982;l:93-8

8. Walker AE. Lissencephaly. Arch Neural Psychia­try 1942;48: 13-29

9. Kumagai T, Hakamada S, Hara K, et al. Develop­ment of human fetal muscles: a comparative histochemical analysis of the psoas and the quadriceps muscles. Neuropediatrics 1984;15: 198-202

Hori et al: Muscular alteraction in agyria 629

10. Fenichel GM. Abnormalities of skeletal muscle maturation in brain damaged children: a histo­chemical study. Dev Med Child Neural 1967;9: 419-26

11. Sarnat HB. Le cerveau influence-t-i1 Ie develop­pement musculaire du foetus humain? Mise en evidence de 21 cas. Can J Neural Sci 1985; 12: 111-20

A Case of Ataxic Diplegia, Mental Retardation, Congenital Nystagmus and Abnormal Auditory

Brain Stem Responses Showing Only Waves I and II

Kumi Aiba, MO, Kenji Y okochi, MO, and T atsuya Ishikawa, MO

A three-year-old boy who had ataxic diplegia, mental retardation, horizontal pendular nystagmus with head nodding and abnormal auditory brain stem responses showing only waves I and II was presented. His clinical features coincided with recent reports in the Japanese literature of cases of a new syndrome that is congenital in origin and seen only in boys.

Aiba K, Yokochi K, Ishikawa T. A case of ataxic diplegia, mental retardation, congenital nystagmus and abnormal auditory brain stem responses showing only waves I and II.

Brain Dev 1986;8: 630-2

In the Japanese literature [1,2], seven boys with psychomotor developmental retardation with spasticity of the lower extremities and an ataxic or athetoid factor, congenital horizontal pendular nystagmus with head nodding and abnormal auditory brain stem responses (ABRs) showing only waves I and II were reported to have a newly recognized syndrome. In this paper, we presented an additional case , and re­viewed the previous case reports [1, 2] .

From the Department of Pediatrics, Seirei-Mikatabara Hospital, Hamamatsu (KA, KY); Department of Pedi­atrics, Nagoya City University Medical School, Nagoya (TI); Department of Pediatrics, Seirei-Hamamatsu Hospital, Hamamatsu (TI) .

Received for publication: March 25,1986. Accepted for publication: June 30, 1986.

Key words: Ataxic diplegia, mental retardation, con­genital nystagmus, auditory brain stem response.

Correspondence address : Dr. Kumi Aiba, Depart­ment of Pediatrics, Seirei-Mikatabara Hospital, 3453 Mikatabara-cho, Hamamatsu 433, Japan.

Case Report

A three-year-old boy visited our hospital because of psychomotor developmental ab­normality . There was no known history of neurodevelopmental disorders among his family members. He was born with an uneventful delivery after an uncomplicated pregnancy. His birth weight was 3,500 gm. At one month, horizontal pendular nystagmus and head nod­ding were noticed. His developmental mile­stones were delayed. He obtained head control at seven months, rolled over at nine months, crept at one year and three months, and could remain sitting with the support of his arms at two years and nine months. He spoke meaning­ful words at three years and one month.

On his first visit to our hospital at three years of age, he was a small boy of 84.5 em height and 10.6 kg weight. He could not sit without support. On sitting with the support of his arms, trunkal ataxia was observed. Rhyth­mic head nodding, that was horizontal and vertical in direction , was seen, whenever he was supine, prone or sitting with support. The head