Moebius Sequence and Prenatal Brainstem Ischemia

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Pr

EXPERIENCE

AND

REASON-Briefly

Recorded

‘

‘In Medicine one must pay attention not to plausible theorizing but to experience and reason together. ...I agree that theorizing is to be approved, provided that it is based on facts, and systematically makes its deductions from what is observed. .. .But conclusions drawn from unaided reason can hardly be serviceable; only those drawn from observed fact.

‘‘

Hippocrates: Precepts. (Short communications of factual material are published here. Comments and criticisms

appear as Letters to the Editor.)

Moebius

Sequence

and

Prenatal

Brainstem

lschemia

Congenital

nonprogressive

(bilateral)

facial

palsy

and

external

ophthalmoplegia

are

essential

clinical

features

for

the

diagnosis

of Moebius

syndrome.”2

One

century

after

its

initial

thorough

description,3

the

precise

delineation

and

pathogenesis

of

the

syndrome

still

remain

obscure.

Heuristic

hy-potheses

concerning

the

latter

have

been

put

for-ward.”3”

Three

major

theories

of etiology

remain

valid:

primary

brainstem

nuclear

hypoplasia,7

sec-ondary

brainstem

nuclear

degeneration,3

and

brain-stem

atrophy

secondary

to muscular

defect.9

None

of these

theories

easily

explains

why,

apart

from

cranial

nerve

dysfunction,

the

Moebius

syndrome

is frequently a part

of oral-limb

deficiency

anomaly

syndromes.’

In this

article,

in vivo

support

is given

to a theory

recently

formulated

in which

a disruption

sequence

in the

vascular

territory

of the

subclavian

artery

might

explain

the

Moebius

sequence,

among

oth-ers.4

CASE

REPORT

D.S.O.

was born June 1987 as the second daughter of healthy unrelated white parents. Following a 38 weeks’ gestation complicated only by a first trimester flu-like illness, she was delivered vaginally in vertex position.

Apgar

scores

were

7 and 9 at 1 and 5 minutes, respec-tively. The neonate weighed 2380 g, measured 47 cm, and her occipitofrontal circumference was 33 cm. Because of

consistently unsuccessful attempts at oral feeding, re-sulting in cyanotic attacks and bradycardia, and because

of unspecified dysmorphic features, the infant was

re-ferred to our neonatal intensive care unit on day 26 of life with the presumptive diagnosis of a chromosomal aneuploidy (Fig 1).

When she was admitted to our hospital, the girl needed

artificial ventilation for frequent attacks of repetitive clonic flexion movements in the arms accompanied by tonic contractions of the intercostal and diaphragmatic muscles. These led to life-threatening respiratory arrest

Received for publication Aug 15, 1988; accepted Oct 11, 1988. Reprint requests to (PG.) Dept of Pediatrics and Neonatal

Medicine, State University of Gent, De Pintelaan 185, B-9000

Gent, Belgium.

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EXPERIENCE

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571

with severe hypoxemia and bradycardia. The attacks were joined by vasomotor signs such as paleness and facial sweating, followed by flushing and a blunted pain

re-sponse. Anticonvulsant therapy, including pyridoxine, was unsuccessful. It was not possible to wean the baby from the respirator through day 42 of life. Even after

extubation, brief episodes of bradycardia persisted at a

rate of as many as 20 attacks in 12 hours, without visible seizures.

Thorough clinical examination became possible after extubation. The skull and anterior fontanel appeared

normal. The face was masklike (Fig 1), mimicking fea-tures when crying hardly differing from those at rest. The forehead was without wrinkles and the temporal

regions were somewhat depressed. The nose was

broad-based. Gentle pinpricking of the cheeks resulted in Bell’s sign and head withdrawal. There were no nasolabial grooves and the upper lip was short and almost without

philtrum.

Small

telangiectatic

capillaries

were covering both cheeks. The upper lip discretely overlapped the lower one on the left. The tongue was small and the

irregular

surface

revealed

obvious

muscle

loss

on the left without fasciculations. Masseter contractions were

pre-sent. The gag reflex was symmetrically weak. The baby’s

voice was low pitched, but vocal cord paralysis was ruled out by endoscopic visualization ofthe larynx. The auricles

appeared normal and auditory contact was evident from birth. She had long eyelashes and epicanthal folds. There was inability to abduct either eye beyond the midline;

vertical and adduction movements could be elicited, how-ever. Touching the cornea invariably resulted in upward eye convergence (Bell’s sign). Glabellar tap elicited no

eye blink. When the baby was asleep, both eyes were

incompletely closed. Pupillary reaction to light was nor-mal and discrete tearing was present.

Somatically, the infant had hypotonia of axis and limbs

without knee tendon reflexes. All joints were slightly

hypermobile. Temperature sensitivity seemed normal. In contrast to frequent thumb-sucking, swallowing was nearly absent at the outset. Even when the baby was 6 months of age, switching her from nasogastric to oral feedings took 5 months and a feeding of normal intake

took 30 to 60 minutes. Head control with severe tituba-tion was achieved when she was approximately 6 months of age; at 12 months of age, she still could not sit

inde-pendently. Visual tracking became possible when the girl was 4 months of age, but conjugate eye movements were

still absent. At 10 months of age, the girl was monitored at home because of erratic bradycardias at rest. Although here face remained expressionless, psychosocial contact

became progressively evident, despite clear delay in

psy-chomotor development. Weight, length, and head circum-ference harmoniously evolved between the 3rd and 10th

percentiles.

Additional investigations excluded diagnoses of

con-genital heart defect or skeletal and urologic

abnormali-Fig 2. CT scan at 3 months ofage. Top, Pontine section: minute calcifications in the floor of the fourth ventricle, large peripontine cisterns. Bottom, Medullary section: central calcification in the medulla oblongata.

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ties. Fundoscopic results appeared normal. According to cerebral ultrasound scan on day 28 of life, there was

discrete

asymmetry

of

the lateral ventricles without pa-. renchymal density alterations. Results of routine brain

CT

scan and several EEG examinations, including a 24-hour recording, were normal. Chromosomally, the infant was a normal female 46,XX karyotype. Known inborn errors of metabolism were excluded by extensive

screen-ing tests. Creatine kinase activity in serum appeared normal

and

CSF f3-endorphin level was 71 pg/mL at 5 months of age by radioimmunoassay (approximately twice the expected value).

Results

of somatosensory evoked potentials appeared normal for amplitudes as well as latencies between tibial or median nerves and cortex. No evidence for any gen-eralized neuromuscular disorder was provided by

electro-myographic studies. According to tracings of facial mus-des, there was no recordable activity in the right

orbi-cularis oculi muscle, whereas the right orbicularis oris muscle appeared to have normal rest activity and volun-tary contraction features. The right facial nerve could

not be stimulated and blink reflexes were bilaterally

absent. In brainstem evoked response audiometry meas-urements done when the infant was 6 months of age, bilateral post III anomalies were shown, in contrast to peripheral waves that appeared normal.

On a repeated

CT scan

focusing

on the posterior

fossa,

with reconstructed sagittal and frontal images, a

deline-Fig 3. Top left, sagittal reconstruction: linear calcifica-tion from pons to medulla. Top right, Accompanying line drawing. Bottom left, Frontal reconstruction: median

ated pontomedullar calcification was observed in the floor

of the fourth ventricle (Figs 2 and 3). Peripontine and basal cisterns were large.

DISCUSSION

With the postmortem finding of focal brainstem

mineral deposits in some patients with Moebius

syndrome,

prenatal

ischemic

necrosis

was

suggested as a possible cause.’2 Before the present time, in vivo visualization of brainstem structural anomalies in this syndrome was limited to the

demonstration

of hypoplasia

of the

brainstem

on

pneurnoencephalography’3

or

CT

scan.’4

Cystic

malformations

underneath

the

cerebellar

tentorium

are probably associated with atypical cases of

con-genital facial palsy.’5”6 Brainstem dysfunction has

been

shown

by means

ofbrainstem

evoked

response

audiometry’4”7

and

somatosensory

evoked

poten-tial’4 in a few cases.

From a clinical point of view, this case offers no

surprises

apart

from

the

finding

that

small

buccal

telangiectatic

vessels

might

be

a feature

of

long-standing facial palsy in the neonate. In much the same way, the abnormal brainstem evoked response

audiometry

and

fl-endorphin

in CSF

do not

tempt

PONS CEREBELLUM

MEDULLA OBLONGATA

CEREBELLUM

BRAINSTEM

/

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EXPERIENCE AND REASON 573 us to draw any conclusions regarding their role in

our

understanding

of the

pathogenetics

of the

syn-drome; they simply suggest that congenital facial

palsy

and

ophthalmoplegia

deserve

elaborate

neu-rophysiologic

testing.

On the

contrary,

the

small

but

definite

increased

tissue densities on the brainstem

CT

scan,

suggest-ing

focal

calcium

deposits,

have

not

been

shown

previously in patients with Moebius syndrome.

They

point

to a prenatal

ischemic

brainstem

lesion.

One

can

but

speculate

concerning

the

probable

vascular

origin

of such

a lesion.4

The

hypothetical

vascular

cause

of

associated

limb

defects

follows

that

same

line

of thought.

If a fetal

vascular

prob-lem

is considered

causal

of the

Moebius

syndrome

in this

infant,

some

of the

patients

with

this

syn-drome

may

be

linked

to

an

expanding

group

of

prenatal

hypothetical

vascular

lesions.

These

in-dude

hemifacial

microsomia,’8

spina

bifida,’9

the

spectrum

of vascular

lesions

in multiple

monocho-rionic

pregnancy,20’2’

and

Poland,

Klippel-Feil,

and

Moebius

anomalies.4

ACKNOWLEDGMENT

We thank

Professor

Vandevelde

(Department

of

Ra-diology)

for CT

imaging

and

interpretation

and

de Vel

(Department of Otorhinolaryngology) for brainstem evoked response audiometry registration and interpreta-tion.

REFERENCES

PAUL GOVAERT,

MD

PIET VANHAESEBROUCK,

MD

CLAUDINE DE PRAETER,

MD

URLIEN FRANKEL,

MD

JULES LEROY,

MD

Department

of Pediatrics

and

Neonatal

Medicine

State University of Gent

Gent,

Belgium

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Wochenschr. 1888;35:91-94

4. Bavinck JNB, Weaver DD. Subclavian artery supply disrup-tion sequence: hypothesis of a vascular etiology for Poland, Klippel-Feil and M#{246}biusanomalies. Am J Med Genet. 1986;23:903-918

5. Evans PR. Nuclear agenesis. M#{246}bius’syndrome: the congen-ital facial diplegia syndrome. Arch Di.s Child. 1955;30:237-243

6. Hanissian AS, Fuste F, Hayes WT, et al. M#{246}biussyndrome in twins. Am J Dis Child. 1970;120:472-475

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9. Pitner SE, Edwards JE, McCormick WF. Observations on the pathology ofthe Moebius syndrome. J NeurolNeurosurg Psychiatry. 1965;28:362-374

10. Reed H, Grant W. M#{246}bius’s syndrome. Br J OphthairnoL 1957;41:731-740

11. Van Allen MW, Blodi FC. Neurologic aspects ofthe M#{246}bius

syndrome. Neurology. 1960;10:249-259

12. Thakkar N, O’Neil W, Duvally J, et al. Moebius syndrome due to brainstem segmental necrosis. Arch Neurol. 1977;34:124-126

13. Hellstr#{246}m B. Congenital facial diplegia. Acta Paediatr. 1949;37:464-473

14. Sudarshan A, Goldie WD. The spectrum of congenital facial

diplegia (Moebius syndrome). Pediatr NeuroL

1985;1:180-184

15. Beerbower J, Chakeres DW, Larsen PD, et al. Radiographic findings in Moebius and Moebius-like syndromes. Am J Neurol RadiOL 1986;7:364-365

16. Nardelli, E, Vio M, Ghersini L, et al. Moebius-like syndrome due to multiple cerebral abnormalities including hypoplasia of the descending tracts. J NeuroL 1982;227:11-19

17. Harris GP, Davidson TM, May M, et at. Evaluation and treatment of congenital facial paralysis. Arch Otolaryrtgol. 1983;109:145-151

18. Robinson LK, Hoyme HE, Edwards DK, et al. Vascular pathogenesis of unilateral craniofacial defects. J Pediatr. 1987; 111:236-239

19. Stevenson RE, Kelly JC, Aylsworth AS, Phelan MC. Vas-cular basis for neural tube defects: a hypothesis. Pediatrics. 1987;80:102-106

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21. Journ#{233}esnationales de N#{233}onatologie 1988: Nouveaux pro-bl#{232}mesposes par les grossesses multiples (Table Ronde) Paris 1988. Paris, France: Soci#{233}t#{233}Nationale de N#{233}onatolo-gie;1988

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1989;84;570

Pediatrics

FRÄNKEL and JULES LEROY

PAUL GOVAERT, PIET VANHAESEBROUCK, CLAUDINE DE PRAETER, URLIEN

Moebius Sequence and Prenatal Brainstem Ischemia

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