Case Reports
Child's Brain II: 126-134 (1984)

Neuropathologie Features, Including Pontine
Schwannosis, in a Four-Year Survivor of
Probable Reye’s Syndrome with Secondary
Möbius Syndrome
H.J. Manz a, W. Cochnmh
Departments of “Pathology (Neuropathology) and ^Pediatrics, Georgetown
University. Washington, D.C., USA and Great Oaks Center. Silver Spring. Md..
USA
Key Words. Schwannosis • Reye’s syndrome ■ Möbius syndrome
Abstract. Frequent seizures and loss of motor, language, and intellectual skills necessi­
tated care in an institution for the physically and mentally handicapped for 4 years after diag­
nosis of presumed Rcye’s syndrome in a 10-month-old boy. Möbius syndrome was diagnosed
and bilateral tarsorrhaphy performed for exposure keratitis. Postmortem examination
revealed multiple old boundary zone infarcts in the cerebral cortex, small cavitaled infarcts
in basal ganglia and thalami, diffuse neuronal loss and gliosis, and a focus of old necrosis in
the pons: brain stem herniation during the acute phase of Reye’s syndrome was responsible
for the latter lesion. Irregular congeries of proliferated peripheral nerves, confirmed by ultrastructural study, were ramifying in the gliotic pontine tegmentum. The pathologic substrate
for the neurovégétative state in a long-term survivor of probable Reye’s syndrome appears to
be multifocal cerebral infarction.

Introduction

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For prognostication and treatment, patients with Reye’s syndrome
have been assigned clinical grades on the basis of neurologic and EEG
criteria [3, 18]. Patients in the higher stages of the disease have a high
mortality rate or severe neuropsychiatrie deficits [3, 5. 6, 18,22, 32], The
neuropathology of acutely fatal Reye’s syndrome has been documented as
massive cerebral edema with accompanying intracranial compartment
shifts [5, 25, 32]. In such cases, hemorrhages and acute infarcts affect the
brain stem, as in other situations with elevated intracranial pressure [19].
The dysmetabolic state and bland necrosis of neurons in the cerebral

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127

cortex account for the EEG features; ischemia, mechanical compression,
and necrosis of the vital cardiocirculatory and respiratory centers in the
medulla oblongata result in extreme EEG abnormalities and are the ulti­
mate cause of death. Infarction and hemorrhages in pons and midbrain are
strategically located in the reticular formation with its function in arousal
and wakefulness. In contrast to the central nervous system, regeneration
in the peripheral nervous system is well established. Aberrant proliferation
of Schwann cells and regenerating axons have been described as Schwan­
nosis in the spinal cord, brain stem and basal ganglia [2,9, 11,27]. Schwan­
nosis of the brain stem as a sequel to transtentorial herniation has not
previously been reported. The unique case is presented of a patient with
presumed severe Reye’s syndrome who survived in a neurovegetative state
for 4 years, who had the clinical features of Möbius syndrome, and who
exhibited proliferation of aberrant peripheral nervous tissue in the pons.
Case Report
At the age of 10 months, this white male infant with normal gestation, delivery and
development had an upper respiratory tract infection complicated by otitis media. Seizures,
muscular rigidity, and coma suggested meningitis on admission to the local hospital. Anti­
biotics were administered despite CSF findings which did not support that diagnosis. The
subsequent hospital course and laboratory data led to the diagnosis of Rcye's syndrome: on
review of the hospital chart, results of liver function tests could not be located though the tests
had been ordered. During appropriate therapy, cardiorespiratory arrest occurred, which was
reversed. Severe neurologic damage (loss of previously acquired motor and sensory skills)
necessitated transfer to an intermediate-care institution for mentally retarded. During the
ensuing 4 years of life he manifested opisthotonus and hypertonus, facial diplegia (Möbius
syndrome), no response to auditory, visual, or tactile stimuli (except withdrawal and
grimacing to moderately painful stimuli), and no verbalization. He was frequently thrashing
about wildly. EEG demonstrated diffuse slowing; seizures were ultimately controlled. Bi­
lateral exposure keratitis and corneal ulceration necessitated tarsorrhaphy. The patient
expired unexpectedly and his body was transferred to Georgetown University Hospital for
postmortem examination.

Sections of multiple paraffin blocks of the brain were stained with luxol fast blue-hema­
toxylin cosin. Bodian. phosphotungstic acid hematoxylin, Holzer. Nissl. Masson’s trichrome.
reticulin, and periodic acid-Schiff. After diagnosing the neuropathologic lesion in the pons by
light microscopy, a portion of the area was obtained from the corresponding tissue in the stock
bottle and processed for electron microscopy. Subsequently, the entire brain stem was
processed through paraffin.

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Materials and Methods

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128

Neuropathology

The brain, weighing 1.100 g. had unremarkable external features. On
sectioning the cerebral hemispheres, cortical atrophy was evident in the
depths of the sulci, along the arterial boundary zones. Small foci of old,
cavitary necrosis were recognized in the thalami and putamina. At micros­
copy, multiple microinfarcts were present in the cerebral cortex (fig. 1),
thalamus, subthalamus, and putamina (fig. 2). These foci were character­
ized by neuronal fall-out, residual necrotic detritus, accumulation of
debris-laden macrophages, and gliosis. More diffuse astrocytosis was
evident throughout the cerebral cortex and thalami. The hippocampi
exhibited neuronal loss in Sommer’s sector. Purkinje cell numbers were
significantly reduced with corresponding Bergmann astrocytosis.
The pontine tegmentum contained a zone of gray discoloration and
gelatinous consistency, measuring 0.9 x 0.8 x 0.5 cm (fig. 3). Microscop­
ically, the peripheral rim of this area was composed of closely packed,
congested vessels. The center contained debris, lipophages, and inter­
twining fascicles and conglomerates of Schwann cells and axons (fig. 4).
Connective tissue accompanied these congeries; at the margins, a haphaz­
ard dmixture of collagen, reticulin, and astroglial fibrils were present. By
electron microscopy (fig. 5), some axons in this region were surrounded by
oligodendroglial-derived myelin; others were myelinated by Schwann cells
with their distinctive basement membranes. The cause of death was acute
pulmonary congestion, edema and early bronchopneumonia.

Discussion

Fig. I. Old microinfarcl in the temporal cortex is characterized by neuronal loss, gliosis,
and focal collections of macrophages. (LFB-HE x 63.)
Fig. 2. A similar microinfarct of the putamen reveals a central collection of debris-laden
scavenger cells surrounded by a zone of gliosis. LFB-HE x 100.
Fig. 3. Photograph of midpons depicts remote tegmental necrosis. LFB-HE. x 2.5.
Fig. 4. Peripheral axons and Schwann cells course as irregular and contorted bundles
among debris and residual macrophages in the pontine tegmentum. PTAH. x 100.

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Unqualified proof of Reye’s syndrome does not exist in this case, but
the infant was managed and diagnosed as a victim of Reye’s syndrome.
Marked cerebral edema and intracranial hypertension in the acute phase

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Fig. 5. Electron photomicrograph from pontine tegmentum demonstrates some residual
axons surrounded by central (oligodendroglial-derived) myelin (arrows) as well as several
Schwann cells surrounded by basement membrane and enclosing small myelinated axons.
Interspersed are bundles of collagen and glial processes crowded with filaments. (Uranylacetate/lead citrate, x 6,000.

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of the disease resulted in brain stem herniation and cardiorespiratory
arrest; this caused the boundary zone infarcts, multifocal microinfarcts
and brain stem necrosis. The subsequent psychomotor deficits with
extreme mental retardation and seizure activity seen in this patient have
a structural basis in the multifocal lesions of the cerebral hemispheres,
basal ganglia and brain stem. Purkinje cell loss may be related to the initial
cardiocirculatory arrest and. at least partly, responsible for the poor seizure
control; but epileptic seizures may cause cerebellar degeneration [30],
Opisthotonus and postural abnormalities can be ascribed to the multiple
infarcts in basal ganglia and other components of the extrapyramidal
system (thalami, red nuclei, midbrain tectum and pontine reticular forma­
tion). Neuronal loss and astrocytosisofthe thalami resulted from transsynaptic degeneration secondary to multifocal cerebral cortical and basal
ganglionic necrosis.
The total destruction of the pontine tegmentum, a consequence of
transtentorial herniation with secondary brain stem hemorrhages and
infarction, account for the clinical features of the Möbius syndrome (facial
diplegia, ocular immobility, poor head control and exposure keratitis).
Classically, the Möbius syndrome is due to agenesis or hypoplasia of the
motor nuclei in the brain stem, sometimes with an hereditary pattern,
either autosomal dominant [33] or with chromosomal translocation [37].
However, Towfighi et al. [35] have recently reclassified 15 published cases
into groups of either primary or secondary brainstem lesions, peripheral
nerve involvement, or myopathy. Secondary forms may be due to intra­
partum hemorrhage in the brain stem [4], multifocal necrosis in the pons
[34, 35], peripheral neuropathy [28], dysplasia of the facial musculature
with intact cranial nerve motor nuclei [24], or facioscapulohumeral
dystrophy [13], In our case, facial diplegia resulted from destruction of the
internal genu of each facial nerve. Exposure keratitis and corneal ulcer,
necessitating tarsorrhapy, can be explained by the destruction of the chief
sensory nuclei of the trigeminal complex. Necrosis of the trapezoid body
and its nuclei and lateral lemnisci interrupted the central auditory connec­
tions, accounting for deafness. Tactile stimuli could not be perceived
because of interruption ofthe medial lemnisci, but the response to moder­
ately painful stimuli can be explained by the preservation of the lateral
spinothalamic tracts situated more laterally.
The aberrant ramification of proliferated Schwann cells and periph­
eral axons within the CNS has been termed Scliwannosis [29], myelinated
and nonmyelinated neuromas [9, 10], hyperplasia of sheath elements [27],

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focal axonal proliferation [23] and traumatic neuroma [16]. Predisposing
lesions in the CNS have been destructive [infarction, trauma, herniated
disc, syringomyelia; 15, 17, 36], demyelinalive [multiple sclerosis; 8, II],
neoplastic [Schwannoma, ependymoma; 11, 29], and dysmetabolic
[subacute combined degeneration, diabetes meliitus; 2,9, 10, 23]; no pre­
disposing lesion was apparent in 1 case [7],
Feigin and PopoJf[ 8], Peigin and Ogata [9] and Feigin and Budzilovich [10] contend that neuromas of the CNS take origin from heterotopic
or dysgenetic perivascular nerves and that Schwann cells derive from
maturation of multipotential mesenchyme. However, the failure to
demonstrate Schwannosis in spinal cords of children under 16 years of age,
its increasing prevalence with advancing age, and the multitude of basi­
cally destructive lesions of the CNS with which Schwannosis has been
associated suggest a different pathogenesis [2], Such lesions have been seen
most commonly in the cord, a comparatively small structure of central
nervous tissue in continuity with and proximity to the substantial anterior
and posterior nerve roots. The brain stem with its cranial nerves is the
component of the CNS next most commonly afflicted. In the cord and
brain stem an origin from injured and abberrantly regenerating motor and
sensory nerve roots appears acceptable. Schwannosis of the basal ganglia
demands a different explanation. The autonomic plexus accompanying
the internal carotid arteries and their major branches represents the likely
source. Supplying the basal ganglia, the lenticulostriate arteries are also
surrounded and innervated by vasomotor fibers [21,31]. Thrombosis and
especially thromboembolism may at times evoke an intense local vascu­
litis (1) so that the accompanying autonomic nerves are injured, concur­
rent with infarction of the basal ganglia, and stimulated to aberrant prolif­
eration into the healing infarct.
Acknowledgement
The authors express gratitude for competent assistance to Mr. Dale Gibson. HT (ASCP).
Mrs. Marilyn Davis and Mrs. Elizabeth Ergueta.

I

Adams. J.H.; Graham. D.I.: Twelve cases of fatal cerebral infarction due to arterial
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Psychiat. 30: 479-488 (1967).

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Dr. H. J. Manz. Department of Pathology (Neuropathology).
Georgetown University. 3900 Reservoir Road, N.W.. Washington. DC 20007 (USA)

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