Case Study 20
Craig Horbinski, M.D., Ph.D.
Question 1
The patient was a full-term, 4-week-old baby who
presented with failure to thrive, lethargy, hypotonia, poor
feeding, rapidly developing apnea and bradycardia, and
hypothermia. CT and MRI scans were performed.
What do you see? What is the likely cause?
CT
CT
T1
T1
Answer
Extensive diffuse cerebral encephalomalacia with
calcifications (best seen on CT) and relative sparing of
some deep grey matter structures and posterior
fossa. Intrauterine TORCH infection is the most likely
cause, but an intrauterine stroke is also a possibility.
Question 2
Additional clinical history reveals that the patient was born to a G4 P2 mother
via cesarean section without complications. The pregnancy was
uncomplicated with no infections and normal fetal movements and only
gestational diabetes (controlled by diet.) Mother was GBS negative, and
there was no history of HSV 1 or 2, and prenatal labs were negative. The
mother reports that the baby seemed normal for the first few days of life but
then at four days of age she noted that he was having repetitive twitching and
jerking of the upper and lower extremities which did not stop with
stimulation. He also was very lethargic and had to be awakened for feeds,
and did not fix or follow well. Blood, urine, and CSF cultures were
negative. Toxoplasmosis, CMV, and rubella titers were negative. An
ophthalmologic exam revealed possible retinitis.
He developed progressive apnea and bradycardia. The severity of the baby's
brain injury and the grim prognosis were discussed with the family,
whereupon they chose to withdraw further care. The patient died one day
later. You are asked to perform the autopsy on the brain.
What do you see?
Answer
Severe symmetric encephalomalacia of the entire
cerebrum, sparing only the posterior portion of the
occipital lobe, the diencephalon (thalamus), cerebellum,
and brainstem. Coronal sections of the left cerebral
hemisphere reveal extreme hydrocephalus ex vacuo, with
complete obliteration of the frontal, parietal, and temporal
lobes as well as obliteration of the basal ganglia and
hippocampus. The thalamus and hypothalamus are
relatively spared.
Question 3
The eyes are sent to you separately for
evaluation. Externally, they were both unremarkable, so
you sectioned them to examine the interior.
What do you see? (FYI, both eyes looked like this.)
Answer
The retina has several well demarcated patches of tan to
dark brown mottling.
Question 4
You get the eye slides before you get the brain slides.
What do you see? What should you do next?
Click here to view slides.
Answer
There are discrete areas of retinal necrosis with
dystrophic calcification, some associated disruption of the
retinal pigment epithelium, and chronic
chorioretinitis. The correct term to use for the retinal
lesions is necrotizing chorioretinitis with dystrophic
calcification. These are the sort of lesions seen in
TORCH infections, so immunostains for TORCH
infectious agents, in particular toxoplasmosis, CMV, and
HSV1/2, are appropriate. (Because it is so rare due to
vaccinations, rubella immunostain is not available in the
immunohistochemistry lab.)
Question 5
While you’re waiting for the immunostains on the retinal
lesions, the brain slides arrive. Sections of the frontal
lobe and thalamus are shown for your review.
What do you see? What’s the best term to use for this in
the final diagnosis?
Click here to view slides.
Answer
Sections of the cerebral hemisphere show no
recognizable cortical or subcortical structures, only a
mass of blood vessels, macrophages, and
calcifications. The thalamus has extensive neuronal loss
along with scattered macrophages and
calcifications. This is best diagnosed as severe cystic
encephalomalacia with extensive calcifications.
Question 6
The immunostains on the retinal lesions have arrived.
Assuming the other immunostains are negative (they
were), what do you think of these stains? What do they
mean?
Click the following links to view slides: HSV1/2, HSV2,
HSV1
Answer
The immunostains show positive cells for HSV1/2 and
HSV2. HSV1 is negative. This is proof of an HSV2
infection.
In the eye, take care to 1) order the stains with red
chromogen so they’ll stand out from the disrupted brown
retinal pigment epithelium; 2) only consider nuclear
staining as positive for herpesvirus, as some of the
macrophages have granular cytoplasmic positivity that
may be due to incompletely quenched endogenous
peroxidase activity.
Question 7
Additional immunostains on the brain were attempted, but
all were negative. Moreover, repeat HSV PCR on 2
separate samples of the patient’s CSF at 2 separate
laboratories was negative.
Does this change your overall diagnosis in this case?
Answer
No. The combination of severe encephalomalacia and
bilateral retinitis is a classic presentation of an intrauterine
TORCH infection. It is not uncommon for the virus to be
difficult to detect immunohistochemically in the brain, as
the process may have “burned out” by the time you see
the specimen. The negative PCR findings may also
reflect this “burned out” status, or may be due to a
technical problem with the assays.
Question 8
What are the TORCH infections? Why are they lumped
together in an acronym? Is there anything weird about
the cause in this case being a herpesvirus?
Answer
TORCH infections are the collection of nonbacterial agents known to cause
perinatal central nervous system disease. These include Toxoplasmosis,
Other (e.g. syphilis, varicella-zoster, parvovirus B19, Epstein-Barr), Rubella,
Cytomegalovirus, and Herpes simplex virus types 1 and 2. These agents are
grouped together because most produce similar clinical and pathologic
findings, including chorioretinitis, cerebral atrophy with periventricular
calcifications, and severe neurologic sequelae. These are usually acquired
via the transplacental route in either the first or second trimester. One
notable exception is herpesviruses, which are mainly acquired via passage
through the birth canal. Identifying the causative agent requires additional
immunohistochemical and molecular diagnostic studies aimed at all the
potential agents, not just a few.
This case of TORCH is unusual because the causative agent was
herpesvirus type 2. As stated above, the majority of herpes simplex virus
TORCH infections are acquired during passage through an infected birth
canal. This baby was born via caesarean section, so the infection must have
been transmitted via the less common transplacental route. Also, the
absence of an HSV history or positive prenatal lab result clearly does not
exclude these agents when evaluating a case pathologically.