Herpes Simplex: A Possible Cause of Brain-Stem Encephalitis

(1)

Herpes

Simplex:

A Possible

Cause

of Brain-Stem

Encephalitis

Patricia H. Ellison, M.D., and Peggy A. Hanson, M.D.

From the Departments of Neurology and Pediatrics, Albany Medical College of Union University, Albany,

New York

ABSTRACT. Herpes simplex virus was isolated from the tracheal aspirate of a 10-year-old boy presenting with acute onset of multiple cranial nerve palsies and a mild right hemiparesis. There was also an elevated herpes complement-fixation titer with decrease in the following weeks. Although the criteria for diagnosis of central nervous system infection by herpes virus have been debated, we propose that this represents a case of brain-stem encephalitis due to herpes simplex infection. The importance of early diagnosis and evaluation of therapy are emphasized by this case in which the patient recovered completely. Pediatrics, 59:240-243, 1977, HERPES VIRUS, ENCEPHALITIS, CRANIAL NERVE PALSIES.

Herpes

simplex

has

been

well

documnted

as

the

cause

of brain-stem

encephalitis

in only

two

patients

in

the

literature,

one

a 14-year-old

boy

who subsequently

died

and

the

other

a

48-year-old

man

who

recovered.’

Other

viruses

have

been

shown

to

cause

cranial

nerve

palsies,

especially

ocular

palsies.

The

designation

“brain

stem

encephalitis”

was

first

made

by

Bickerstaff

and

Cloake

in

1951.’

In

1959,

Bickerstaff

added

five

more

cases

to

the

series.’

Others

have

reported

similar

cases,

the

majority

presenting

in

adult

patients.58

A series

of eight

cases

in children

was

reported

by

Yalaz

and

Tinaztepe

in 1974.”

A case

which

has

significantly

influenced

the

diagnosis

of

brain-stem encephalitis

was

a child

with

evidence

of medullary

enlargement

and

subsequent

recov-ery reported in 1971.’#{176}

The

classical

course

is one

of

multiple

cranial

nerve

palsies

and

pyramidal

tract

involvement

in

a

gravely

ill

child

who

recovers

without

sequelae.

In few

of the

reported

cases has

the

etiologic

agent

been

demonstrated.

No

case

has

been

reported

of a child

with

herpes

simplex

brain

encephalitis

and

subsequent

recov-erv.

The

index

case

is an

example

of severe

neuro-logic

symptomatology

involving

the

brain

stem

with

subsequent

documentation

of herpes

simplex

infection

and

eventual

recovery.

This

case

is an

example of one of several manifestations of

central nervous system infection of

the

herpes

simplex virus,

alerting

physicians

to

attempt

an

early

diagnosis.

(Received March 29; revision accepted for publication June 4, 1976.)

Supported in part by the Eleanor Roosevelt Developmental Services of the New York State Department of Mental

Hygiene.

ADDRESS FOR REPRINTS: (P.H.E.) Department of

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ARTICLES 241

CASE REPORT

A 10-year-old black boy

presented

to the emergency

room

with crossed eyes, difficulty reaching for objects, drooling, and difficulty with swallowing and coughing.

He had been in his usual state of good health until six days

‘

prior to admission, when he developed general malaise and low-grade fever. Three days prior to admission he was taken to a local clinic because of cervical adenopathy. In the next two days he vomited occasionally. He awakened at 5 AM Ofl

the day of admission complaining of pain in the right leg, favoring the right side in walking, and with difficulty swallowing.

He was lethargic but readily arousable and able to follow simple commands. His temperature was 37.2 C; blood pressure, 135/90; pulse, 88 to 120 beats/mm, and respira-tion, 38 breaths/mm. The left pupil was smaller than the right. The fundi were unremarkable. Copious secretions were noted in the pharynx. Discrete, nontender palpable nodes were present in both anterior and posterior cervical areas. Neurological evaluation revealed absent left corneal reflex and weak left masseter function (V), inability to abduct the left eye (VI), inability to smile or frown on the left (VII), absent gag, poor swallowing and drooling (IX, X, XI), and

poor tongue

movement

on the

left (XII). Both horizontal and

vertical nystagmus were noted with an occasional rotatory component. Reflexes were symmetrical and plantar re-sponses flexor. A mild decrease in strength was present in the

right arm and leg. On finger-to-nose testing there was mild

incoordination bilaterally, greater on the left. Mild truncal ataxia was

present

on

sitting. Sensation, vibration, and position senses were intact. Gait was not tested.

A tracheostomy was performed on the day of admission because of an increasing respiratory rate, decreasing tidal volume, and difficulty in handling secretions. Dexametha-sone treatment was begun (4 mg intravenously every six hours).

Initial studies gave the following results: lumbar puncture: nonnal opening pressure, with 20 WBC, 18 lymphocytes, 1 polymorphonuclear leukocyte, and 1 monocyte/cu mm; with glucose, 108/100 ml; protein, 74/100 ml; CBC: hemo-globin, 13.8 gm/100

ml;

hematocrit, 41.4%; WBC, 6,600/cu mm with 64% polymorphonuclear leukocytes, 7% basophils, 18% lymphocytes, and 1 1% monocytes. Serum electrolytes, blood urea nitrogen, and glucose were normal. Serum ammonia was 38 mg/ 100 ml. An EEC recorded some bilateral slowing in the delta frequency, predominantly in the parietal-occipital areas. Echoencephalography revealed a 2-mm left-to-right shift. A skull X-ray film was normal with the exception of a small calcified density in the right posterior lateral quadrant. Brain image and flow revealed a subtle increase in the posterior projection on immediate image suggestive of an inflammatory process. In the delayed images, no definite abnormal concentration was noted.

Additional studies in the course of the illness revealed: cerebral angiography, no abnormalities; repeat EEC (after the seizures), persistent delta activity in the posterior

quadrants; repeat lumbar puncture on hospital day 8, 120 crenated RBC, no WBC, protein, 24 gm/100 ml; and glucose, 65 gm/100 ml (serum glucose 95 gm/100 ml).

On the day after admission a profound right hemiparesis was noted. Respiratory rate had increased to 50 to 60 breaths/mm. Two days after admission the cranial nerve palsies were similar to those at admission and the right hemiparesis had begun

to

improve. On the third day the fifth cranial nerve showed improvement and the respiratory rate had decreased to 36 breaths/mm. On the fourth day a series of generalized convulsions lasting two to three minutes were

observed. These were controlled with intravenously admin-istered phenobarbital and diazepam. The cranial nerve palsies, right hemiparesis, and cerebellar findings continued to improve in the course of hospitalization. Steroid therapy was tapered and discontinued. The child was discharged after 17 days with residual left sixth and seventh cranial nerve palsies.

On the follow-up examination two weeks after discharge the child was alert, active, and responsive. The residual left sixth and seventh nerves facial palsies remained. The child laughed inappropriately and spontaneously throughout the examination. The mother reported that he also laughed frequently at home with no obvious stimulus. One month after discharge the school nurse called reporting that the child was vigorously attacking other children in such a

manner that the teachers feared for the safety of the children and were threatening immediate suspension from school. The child was placed on thioridazine (10 mg three times

daily) and crisis referral was made to the local mental health

unit. With the use of the thioridazine the child continued in

school without further incidents. On examination six weeks after discharge, he no longer complained of diplopia. He had good movement on the left side of the face. His behavior had continued to improve.

The laboratory data from the State Department of Health

returned after the child had been discharged from the

hospital. Serum from the fourth hospital day had a herpes simplex complement-fixation titer of 1:256. Serum from the eighth day had an identical titer of 1:256. Herpes simplex virus was isolated from the tracheal aspirate of the eighth day of hospitalization. Typing of the virus was not performed. The herpes simplex titer at three weeks was 1:64 and 1:32 at five weeks. Other serologic studies included complement fixation or hemagglutination inhibition assays for antibody to mumps, measles, lymphocytic choriomenin-gitis, California encephalitis-Lacrosse and New York State strains, Eastern equine encephalitis, Western equine enceph-alitis, St. Louis encephalitis, and Powassan viruses.

Tow-plasma, Blastoinyces, and Histoplasma titers were also

insig-nificant. Cerebrospinal fluid analysis for cryptocoecal antigen was nonreactive. Virus isolation was also attempted with samples of feces and cerebrospinal fluid in primary Cynomologus monkey kidney cells, diploid strain of human embryonic lung cells, newborn mice by intracerebral route, newborn mice by intraperitoneal route, and 12- to 15-gm mice by intracerebral route. No virus was isolated in these preparations.

In summary, a diagnosis of brain-stem encephalitis probably caused by herpes simplex virus was made on the basis of the significant serum titers and viral isolation.

DISCUSSION

The

differential

diagnosis

of brain-stem

signs

in

children

has

been

reviewed

by

Yalaz

and

Tinaz-tepe.9

The

most

frequent

diagnostic

dilemma

is to

distinguish between brain-stem encephalitis and

brain-stem

glioma.

In summarizing

his criteria

for

brain-stem

glioma,

Matson

selected

multiple

cranial

nerve

palsies,

truncal

ataxia,

pyramidal

tract

signs,

absence

of increased

intracranial

pres-sure,

low

CSF

protein,

and

contrast

studies

with

unequivocal

posterior

displacement

of

the

mid-line

aqueduct

of the

fourth

ventricle.h1 Bickerstaff

emphasized

the

gradual

onset,

severe

lethargy,

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.

ophthalmoplegia

with

other

cranial

nerve

defi-cits,

and

minimal

long

tract

signs

in the

diagnosis

of brain-stem

encephalitis.

Review

of the

Bick-erstaff

cases

suggests

that

the

course

of some

of

the

cases

was

more

in keeping

with

the

C. Miller

Fisher’s

syndrome

of

ataxia,

areflexia,

and

ophthalmoplegia.12

Bickerstaff

suggested

that

lack

of cardiac

or

respiratory

involvement

could

serve

to distinguish

brain-stem

encephalitis

from

encephalomyeloradiculitis.

The

present

case

points

out

the

possibility

of

fairly

severe,

if

temporary, long tract and respiratory

involve-ment

in brain-stem

encephalitis.

The

case

reported

by

Schain

and

Wilson

has

made

the

pediatric

neurologist

reluctant

to

accept

fourth

ventricle

displacement

or

ponto-meckillary enlargement as reliable criteria for the

diagnosis

of brain-stem

glioma.”

They

reported

a

child

with

clinical

improvement

and

disappear-ance

of

medullary

enlargement

when

radiation

therapy

for

tumor

was

delayed

for

several

weeks.

In

the

present

case,

the

acute

course,

elevated

CSF’

protein,

normal

angiography,

and

rapid

improvement

confirmed

the

initial

diagnosis

of

brain-stem

encephalitis.

The

etiology

of

brain-stem

encephalitis

has

been

confirmed

in few

cases

in the

literature.

The

two

herpes

simplex

cases

were

reported

by Dayan

et

al.’

In

their

first

case,

a

14-year-old

with

lethargy and delirium, diplopia, slurred speech,

drooling,

choking,

and

failure

to recognize

family

members,

intravenous

idoxuridine

therapy

was

initiated

on

the

basis

of the

clinical

presentation

and

a focally

abnormal

EEG.

The

herpes

simplex

etiology was confirmed at autopsy. In the second

case

15%

f

the

mononuclear

cells

from

the

CSF

contained

herpes

simplex

antigens

and

20%

contained

IgG

or 1gM.

The

virus

was

also

isolated

from

the

CSF

although

this

information

was

not

available

early

in the

disease.

The

clinical

lesions

were

confined

largely

to the

brain

stem.

No

biop-sy was performed

and

the

patient

improved.

It

is possible

that

other

reported

cases

may

have

been

caused

by

the

herpes

simplex

virus.

Criteria

for

making

a diagnosis

of central

nervous

system

infection

secondary

to

herpes

simplex

have

been

subject

to

debate.

The

lumbar

punc-ture

and

CSF

analysis

have

been

noted

by Bellanti

et a!. to be

inadequate

to diagnose

encephalitis.”

In two

of their

patients,

no cells

were

found

in the

CSF.

The

protein

ranged

from

22 to 66 gm/100

ml

and

the

glucose

from

66 to

87 gm/

100 ml.

Several

authors

have

documented

the

difficulty

of

isolating

herpes

simplex

from

the

CSF.”’3

For

a time,

serologic

studies

were

used,

relying

on

titer

increases

in neutralizing

or

complement-fixing

antibodies.

With

increasing

use

of

brain

biopsy

and

isolation

of

the

virus

from

biopsy

material

or

immunofluorescence

with

herpes

antigen,

brain

biopsy

became

accepted

as

the

only

definitive

way

to

establish

the

diagnosis.’6

Criteria

for

biopsy

included

clinical

evidence

of

encephalitis,

abnormal

EEG,

CSF

sterile

for

bacteria,

fungi,

and

other

viruses,

and

abnormal

carotid

angiography.’T

More

recently

computer-ized

axial

tomography

has

been

used

instead

of

the

carotid

angiography.

Sarubbi

et

al.

#{149}

have

emphasized the requirement of radiologic

evi-dence

of focal

abnormality

before

biopsy

in order

to maximize

biopsy

yield.’8

Electron

microscopy

of biopsy

material

with

demonstration

of

herpes-like

particles

has

also

been

used.’9

In such

cases

as

the

one

presented

here

neither

EEG

nor

radio-graphic

studies,

including

cerebral

angiography,

localized

a lesion

such

that

biopsy

could

even

be

considered.

Other

techniques

proposed

for

rapid

diagnosis

have

included

immunofluorescent

examinations

of the

CSF,21’

passive

hemagglutinating

antibody

determination in

CSF,2’

and

separate

analysis

of

serum

complement-requiring

and

non-comple-ment-requiring

neutralizing

1

None

of

these

has

achieved

widespread

acceptance

as

a

reliable

technique.

The

urgency

of making

the

diagnosis

depends

largely

on

the

proposed

use

of

antiviral

agents.

Initial

reports

of therapeutic

success

with

idoxu-ridin&3’7”222’

have

been

followed

by

subse-quent

studies

noting

poor

clinical

response

and

serious

complications

of leukopenia

and

thrombo-cytopenia.24

Cytosine

arabinoside

was

also

initially

reported

to

be

effective252

with

later

reporting

of serious

side

effects.21’

In both

drugs

it

has

been

difficult

to select

a dose

high

enough

to

be

effective,

yet

low

enough

to minimize

immu-nologic

and

hematologic

toxicity.

A study

of adenine

arabinoside

is presently

in

process

after

initial

reports

of success

in treating

herpes

simplex

infections.”

The

drug

was

noted

to

have

little

hepatic,

renal,

or

hernatologic

toxicity.3’

A

combination

of

adenine

adenoside

and

herpes

simplex

antibody

preparation

is also

under investigation.

Illis

and

Merry

have

reviewed

the

use

of ACTH

and

corticosteroid

therapy,

noting

the

difficulty

in

selecting

appropriate

criteria

for

the

diagno-sis.22 Some have been reluctant to use steroids on

the

basis

that

steroids

would

enhance

viral

repli-cation

and

suppress

the

synthesis

and

action

of

interferon.12 Some have suggested giving

the

steroids after the stage of viremia when antibodies

were

already

formed.

The

steroids

may

be

effec-tive

in

reducing

the

edema

secondary

to

the

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ARTICLES

243 indicated

a decrease

in

mortality

from

70%

to

44%

with

use

of

steroids

but

no

evidence

of

decrease

in morbidity.

Steroids

were

used

in

our

case.

It

may

have

been

significant

that

antibody

titers

were

elevated

at the

time

steroid

therapy

was

initiated,

perhaps

making

this

an

appropriate

case

for

steroid

therapy.

The

child

responded

well

clini-cally,

but

this

may

have

been

a reflection

of the

natural

course

of the

disease.

Thus,

the

issue

of

drug

therapy

for

central

nervous

system

infection

secondary

to

herpes

simplex

has

not

been

resolved.

The

physician

awaits

the

results

of

double-blind,

controlled

studies in

order

to

choose

appropriate

therapy

with

due

awareness

of the

limitations

of presently

available

techniques

in

making

a

prompt

and

definitive

diagnosis.

Summary

A

10-year-old

black

boy

presented

with

niultiple cranial nerve palsies and

mild

right

hemiparesis.

Significantly

high

serum

titers

to

herpes

simplex

were

reported

with

a drop

in the

subsequent

weeks.

The

virus

was

also

isolated

from

the

tracheal

aspirate.

Two

other

cases

of

brain-sten

encephalitis

resulting

from

herpes

simplex virus have been reported in the literature.

Methods of brain biopsy useful in generalized

encephalitis are not useful

in

brain-stem

enceph-alitis.

While

specific

antiviral

therapies

remain

controversial, double-blind, controlled studies

may

settle

this

issue

so that

rapid

diagnosis

and

prompt institution

of therapy

become

imperative.

The

physician

is alerted

to

the

presentation

of

brain-stem encephalitis as a manifestation of

central nervous system infection by the herpes

simplex virus.

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herpesvirus hominis. Br Med

J

4:405, 1972. 2. Ford FR: Diseases of the Nervous System in Infancy,

Childhood and Adolescence, ed 6. Springfield,

Illi-nois, Charles C Thomas, 1973,

pp

419, 674, 694. 3. Bickerstaff ER, Cloake PCP: Mesencephalitis and

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8. Walker 511: Acute idiopathic bulbar encephalomyelitis. Am

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10.

Schain RJ, Wilson G: Brainstem encephalitis with radiographic evidence of medullary enlargement. Neurology 21:537,. 1971.

11.

Matson DD: Neurosurgery of Infancy and Childhood, ed 2. Springfield, Illinois, Charles C Thomas, 1969, pp 469-477.

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1977;59;240

Pediatrics

Patricia H. Ellison and Peggy A. Hanson