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Dysautonomia in Guillain-Barr syndrome with dorsal root ganglioneuropathy wallerian degeneration and fatal myocarditis.

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Dysautonomia in Gdain-Barre Syndrome
with Dorsal Root Ganghoneuropathy,
Wderian Degeneration, and Fatal Myocarditis
Andrew K. Hodson, MB, MRCP(UK)," Barrie J. Hurwitz, MB, MRCP(UK), FCP(SA),?
and Renata Albrecht, MD$
An acute Guillain-Barre syndrome presenting as dysautonomia is described in a 12-year-old boy. The patient died of
intractable cardiac arrhythmias and cardiac failure. A severe myocarditis with destruction of dorsal root ganglion cells,
and wallerian degeneration of dorsal roots and peripheral nerves was apparent postmortem. Segmental demyelinatiotl
and inflammatory cellular infiltrations were not present at these sites.
Hodson AK, Hurwitz BJ, Albrecht R: Dysautonomia in Guillain-Barre syndrome with dorsal root
ganglioneuropathy, wallerian degeneration, and fatal myocarditis. Ann Neurol 15:88-95, 1984
The major threats to life in Guillain-Barre syndrome
(GBS) are respiratory failure and autonomic dysfunction. In adults, autonomic dysfunction has been associated with a less favorable prognosis and an increased
mortality I1 11, although there are reports of complete
recovery with pandysautonomia 12 11. In children with
GBS, the incidence and severity of autonomic disturbance have not been well defined 14, 8, 12, 15, IS]. It
has been suggested that early dysautonornia should cast
doubt on a diagnosis of GBS [2}.
We report the clinicai and pathological findings in a
12-year-old boy who had GBS with initial autonomic
dysfunction and who subsequently died of myocarditis.
Case Report
A 12-year-old white boy developed a self-limiting upper respiratory tract infection 2 weeks before the onset of diffuse
pruritus and backache. He was admitted to the hospital with a
5-day history of nausea and vomiting and was found to have a
paralytic ileus, tachycardia ( 120 beats per minute), and hypertension (blood pressure, 130/90 mm H g to 1701110 mm
Hg). Postural or spontaneous hypotension did not occur. After 5 days of persistent hypertension, he was treated with
propranolol, 40 mg four times a day. He developed evidence
of inappropriate antidiuretic hormone secretion (SIADH),
with a serum sodium level of 127 mEgL and a serum osmolality of 267 mOsm; his urinary sodium level was 8 7 mEq/L
with an osmolality of 894 mOsm. Serum dopamine, epinephrine, and norepinephrine levels were elevated to 206 (normal, 0 to YO), 205 (normal, 0 t o 5 5 ) , and 1,026 (normal, 65 to
320) pg/ml, respectively. Normal values were obtained for
From the Departments of "Pediatrics (Pediatric Neurology),
+Medicine (Neurology),and $Pathology,Duke University Medical
Center, Durham, NC 2 7 7 1 0 .
88
complete blood count, aspartate transaminase, alanine trans-.
aminase, creatine kinase, total protein, albumin, globulin,
plasma renin, urinary vanillylmandelic acid, heavy metals, and
porphyrins. Results of barium enema, colonoscopy, and bone
scan were normal. An abdominal computerized tomographic
scan revealed paraaortic lymphadenopathy. The electrocardiogram (ECG) demonstrated sinus tachycardia.
Six days after admission the patient began to complain o f
weakness in his legs. Two days later he was unable to stand
independently. The weakness progressed to involve the face
and arms. He developed urinary retention requirini:
catheterization. Nineteen days after the onset of his illness he
was transferred to Duke University Medical Center. His
blood pressure was 1l0/60 mm Hg. He remained normotensive (without postural change) with a tachycardia (1 20 to 140
beats per minute). There was distention of the abdomen with
decreased bowel sounds and persistent urinary retention rcquiring catheterization. H e had no tachypnea, cough, or
edema. The heart sounds were normal, with no gallops or
pericardial rubs. H e was oriented, with an intact sensorium
and normal language production. Pupils were symmetrical
and normally reactive to light and accommodation. Papilledema was absent, and ocular movements were full. Corneal
reflexes were intact, and facial sensation was normal. He had
a facial diplegia with some slurring of speech. Palatal sensation and movement were mildly decreased. H e was unable to
sit or roll over in bed. Muscle strength in the limbs wits
symmetrically decreased both proximally and distally (MRC
score, 3 to 4). He had marked symmetrical vibratory and
proprioceptive loss with attendant pseudoathetosis. Pain a d
light touch sensation were mildly and symmetrically reduced.
He was areflexic, with absent plantar responses. H e did not
sweat excessively; lacrimal and salivary function appeard
Received Nov 19, 1982, dnd in revised formJune I , 1983. ActepteJ
for publication June 5 , 1083.
Address reprint requests to Dr Hurwitz, Box 3 184, Duke University
Medical Center, Durham, NC 27710.
normal. Treatment with propranolol was discontinued, and
he remained normotensive.
Laboratory studies included a hematocrit of 43%, and
white blood cell and platelet counts of 11,700 and 497,000
per cubic millimeter, respectively. The Westergren sedimentation rate was 54 mm per hour. Cerebrospinal fluid was
clear, with an opening pressure of 18 cm of water, and contained 7 mononuclear cells per cubic millimeter, 166 mg/dl of
protein, and 68 mgidl of sugar. Nerve conduction velocities
as well as sensory and motor distal latencies were normal for
the left median, sural, and tibial nerves. Late responses (Fwaves) were unobtainable from the left median and both
tibial nerves. Electromyography demonstrated a moderately
reduced interference pattern and no spontaneous activity.
ECG revealed a sinus tachycardia; the chest roentgenogram
showed no abnormalities. Pulmonary function studies
showed a 40% decrease in both the expected vital capacity
and the forced expiratory volume in 1 second. Mild hyponatremia was treated with fluid restriction. The patient became
progressively weaker in the 48 hours following admission.
Informed consent was obtained, and the patient was entered into a randomized experimental protocol to undergo
plasmapheresis. He underwent two exchanges without
significant alteration in his vital signs or serum electrolyte
levels. His fluid balance was closely monitored because of the
SIADH and replacement volumes were adjusted to 100 to
200 ml in negative balance. Approximately 8 hours after the
second plasma exchange, he developed episodes of bradycardia and hypotension, which were treated with volume expansion. Acute pulmonary edema ensued, requiring intubation,
external cardiac massage, and ventilatory support. The blood
pressure was maintained with the administration of pressor
agents, colloids, and crystalloids. The patient developed oliguria requiring peritoneal dialysis. Over the following 24
hours his condition stabilized. Then sudden ventricular rachycardia with hypotension occurred, and he progressed to ventricular fibrillation and death.
Pathological Findings
The patient weighed 51 kg and measured 166 cm in
height. The brain, including cerebellum and brainstem, weighed 1,630 gm (normal, 1,400 gm). The gyri
were swollen and blunted, and the intervening sulci
were narrowed. Focal subarachnoid hemorrhages were
noted over the cerebral surface. After sectioning, a
flattened ventricular system was seen, and multiple
punctate, perivascular hemorrhages were present in the
white matter, often adjacent to the gray-white junction.
Perivascular hemorrhages were also present in the gray
and white matter of the spinal cord. Sections of the
right and left frontal, parietal, temporal, and occipital
lobes and of the basal ganglia, thalamus, hypothalamus,
midbrain, and hippocampal formations stained by the
Luxal fast blue method and examined microscopically
revealed only the aforementioned edema and punctate
perivascular hemorrhages. Viral inclusion bodies were
not present, and viral cultures of the brain were negative.
The upper and midportion of the pons, which con-
tained cranial nuclei IV, V, and VIII as well as a portion
of nerve V; the lower and midportions of the medulla,
including cranial nuclei X, XI, and XII; a section of the
cervical spinal cord; five sections of the thoracic cord,
sampled at different levels; and one section of the lumbar cord were studied. Each of the seven sections of the
spinal cord contained the respective intradural portions
of the ventral and dorsal roots. Examination of the
peripheral nervous system included study of dorsal
root ganglia from the cervical region (one), thoracic
region (two), and lumbar region (one). Each of these
ganglia had a short segment of dorsal root attached. In
addition, the celiac ganglion from the sympathetic
chain, a segment of the vagus nerve from around the
midesophagus, and portions of the obturator nerve and
the sciatic nerve from within the pelvis were studied
histologically. The gasserian ganglion was not studied.
The segments of vagus, sciatic, and obturator nerves
were fixed in formaldehyde, cut perpendicular to the
long axis, and embedded in cross section. The paraffin
blocks were later melted down and the segments reoriented longitudinally. Ultimately, between twenty
and forty serial sections of these nerves were available
for histological study. The sections of the pons,
medulla, spinal cord, ganglia, and peripheral nerves
were stained with hematoxylin and eosin, Lwol fast
blue, Masson trichrome, and the Glees and Marshland
silver method for axons.
The most striking histological findings occurred
within the four dorsal root ganglia examined. There
was essentially total destruction of all nerve cell bodies;
a few remaining cells revealed advanced degeneration
and neuronophagia (Fig 1). In the sites of the previous
neurons, there was an exuberant proliferation of plump
capsular cells. No inflammation, necrosis, or viral inclusions were present. The dorsal roots associated with
each of these ganglia, as well as the dorsal roots attached to the seven sections of the spinal cord, manifested moderate to severe degrees of wallerian degeneration (Fig 2). The pregasserian segment of nerve V
contained axonal fragmentation and destruction, often
accompanied by swelling, clumping, and phagocytosis
of the myelin sheaths by macrophages. No demyelinated intact axons were identified. In contrast to the
dorsal roots, the ventral roots at all seven levels of the
spinal cord revealed well-preserved axons and intact
myelin sheaths (Fig 3). The corresponding anterior
horn cells were intact. The nerve cell bodies within the
intermediolateral column were also normal. The rest of
the spinal cord cross sections revealed occasional small
perivascular hemorrhages but otherwise normal architecture. The celiac ganglion was populated by intact
nerve cell bodies, and there was no axonal destruction.
A section of this ganglion, as well as the cervical dorsal
root ganglion, was fixed in 4% glutaraldehyde and examined by electron microscopy. No viral particles were
Hodson et al: Dysautonomia in GBS
89
Fig 1 . Dorsal root ganglion. One residual nerve cell bod^ (arrow)
is undergoing neuronophagia and is surrounded by prominent
capsular cells. Newe cell bodies have been completely destroyed and
replaced by an exuberant proliferation of capsular cells, uv4ic-h
form round cell clusters. (LuxolfaJt blue; x 110.1
Fig 2. Dorsal root. A longitudinal section demonstrates wallerian
degeneration inoolving many of the nerves. Swe/ling, clumping.
and phagocytosis of the myelin sheaths accompany axonal fizgmentation and disintegration. (Luxolfast blue: x 250.i
Fig 3 . (A) Dorsal root. A cross section demonstrates wallerian degeneration. In some regions axons are absent; in other areas they
are degenerating, manifested by variability in diameter. (B) Ventral root. In contrast t o the dorsal root, this specimen reveals preserved architecture with intact axons. (Glees and Marshland
stain; X 170.)
Hodson et al: Dysautonomia in GBS 91
found in either location. The vagus nerve contained
bundles of intact axons evident on Glees and Marshland staining. No lesions were observed in any of the
cranial nerve nuclei. In sections taken from the obturator and sciatic nerves, wallerian degeneration involved some of the fibers (Fig 4). This finding was
confirmed on the teased nerve preparation performed
on a segment of the sciatic nerve (Fig 5).
The heart was diffusely enlarged and weighed 360
gm (normal for age, 250 gm). There was dilatation of
the left and right ventricles. The myocardial tissue was
mottled, with areas of pale discoloration and scant
hemorrhage. Microscopically, there was an overwhelming, diffuse infiltrate of acute and chronic inflammatory
cells. The myocardial fibers were separated by edema
and showed variable degrees of degeneration, loss of
striations, wavy changes, and occasional foci of necrosis. Degenerating, multinucleated myocardial cells
were present (Fig 6). Viral cultures were negative.
Electron microscopy failed to reveal viral particles
within the myocardium.
The other changes noted postmortem were compatible with the history of cardiovascular instability and
compromise. There was extensive edema, congestion,
and focal hemorrhage within the thoracic and abdominal organs (lungs, spleen, liver, adrenal glands, kidneys,
gastrointestinal tract, lymph nodes), and serous effusions were present in the thoracic and peritoneal
cavities.
Bacterial and fungal cultures of the blood, lungs, and
spleen taken at the time of postmortem study did not
identify any pathogens.
92
Annals of Neurology
Vol 15 No 1 January 1984
Fig 4. Sciatic newe. Wulleriun degenerution is present. (Glees
and Murshlund stain: x 170.)
Discussion
The clinical history and physical findings of a symmetrical motor, sensory, and autonomic neuropathy in a 12year-old boy were compatible with GBS. This clinical
diagnosis was supported by an albuminocytological di.ssociation in the cerebrospinal fluid, and absent late responses (F-waves) on electrical studies.
GBS is considered to be an autoimmune, inflammatory polyradiculoneuropathy with a wide spectrum of
pathological changes 13, 91. The earliest finding, as
demonstrated by electron microscopy, is macrophage
invasion, associated with edema and swelling of myelin
1171. This finding is followed by lymphocytic infi1tr;sttion and phagocytosis of myelin. Focal areas of segmental demyelination with perivascular inflammatory
infiltration may he scattered throughout the peripheral
nervous system, but most changes appear at the junction of the ventral and dorsal nerve roots. In severe
cases, inflammatory segmental demyelination may he
accompanied by axonal destruction C3, 91.
The major finding in our patient is the absence of the
usual histological features of GBS. Instead, we o1)served extensive neuronal destruction without inflan-tmation in all dorsal root ganglia examined. The uniiform destruction of neurons suggests a single insult
rather than ongoing or multiple episodes of injury. Tbe
rare residual nerve cells were undergoing neuronophagia. The clusters of prominent plump capsular cells
Fig 5 . Sciatic nerve. Teasedfiber preparation shows variable degrees of wallerian degeneration,inchding axonal swelling and
fragmentation. ( x 400.1
represent a secondary proliferation reactive to
neuronal loss. The advanced degree of these changes
and the absence of inflammatory cells indicate a pathological process of at least 2 to 3 weeks’ duration. Wallerian degeneration was observed in dorsal nerve roots
and fascicles of the sciatic and obturator nerves. The
variable degree of axonal destruction and myelin degradation suggests that these changes followed the neuronal destruction and thus indicates that the wallerian
degeneration is secondary to nerve cell death.
W e are unable to explain the patient’s weakness.
Electrodiagnostic studies 16 days after the onset of illness point to involvement of the proximal motor
nerves. Yet in all sections examined, the anterior horn
cells and ventral nerve roots were normal. We found
no evidence of focal inflammatory demyelination in
these sections. It is possible that the weakness was a
result of focal demyelination in areas not sampled.
The site of autonomic dysfunction in GBS is frequently poorly defined both clinically and pathologically, but it has been attributed to be demyelination of
either sympathetic or parasympathetic nerves, or both
C7, 11, 131. In our patient there was clinical evidence of
both sympathetic (tachycardia, hypertension, SIADH)
and parasympathetic (ileus, urinary retention) overactivity. Histological examination of the intermediolateral columns, vagal nuclei, vagus nerve, and celiac ganglion failed to demonstrate any abnormality to account
for the clinical evidence of autonomic dysfunction. Although the single elevation of dopamine, norepinephrine, and epinephrine levels is of limited significance, it
may be indicative of sympathetic overactivity E7, 141.
The tachycardia and subsequent hypotension may have
been the result of the severe inflammatory myocarditis.
The initial sustained hypertension, however, is uncommon in inflammatory myocarditis [I] and together with
SIADH, paralytic ileus, and urinary retention indicates
an autonomic neuropathy.
The cause of this patient’s disease remains undetermined. The clinical picture of GBS, the antecedent
Hodson et al: Dysautonomia in GBS
93
upper respiratory tract infection, and the severe inflammatory myocarditis all suggest a viral cause. Findings
on electron microscopy and viral cultures, however,
failed to support this hypothesis. Similar instances of
acute dorsal root ganglioneuropathy have been described in association with spinal anesthesia [20) and
chemotherapy [ S } . The endoneurium of dorsal root
ganglia in rats is more permeable to intravenous albumin and Evans blue dye than is the remainder of the
peripheral nerve [ 161. This increased permeability may
make the ganglia more sensitive to some circulating
toxins. Cases of acute sensory neuronopathy presumably caused by dorsal root ganglion disease but without
attendant abnormalities have been reported [6, 191.
Subacute and chronic cases have been described in association with neoplasia and without obvious cause
[lo}. To our knowledge, this is the first pathological
report of acute dorsal root ganglioneuropathy presenting with the clinical picture of acute GBS.
The destruction of nerve cell bodies in the dorsal
root ganglia without associated inflammatory segmental
demyelination in this patient emphasizes that the clinical syndrome of GBS can result from diverse pathological processes. The histological evidence in this case
suggests direct destruction of the dorsal root ganglion
cells.
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94 Annals of Neurology
Vol 15 No 1 January 1984
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Hodson e t al: Dysautonomia in GBS
95
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