Herpes Zoster Ophthalrmcus and Delayed
Contralateral Hemiparesis Caused by
Cerebral Angutis: Diagnosis and
Management Approaches
Dana C. Hilt, MD, David Buchholz, MD, Allan Krumholz, MD, Howard Weiss, MD,
and Jerry S. Wolinsky, MDX

Four patients with herpes zoster ophthalmicus and delayed contralateral hemiparesis are described, and their findings

are compared with those in patients previously reported in the English language literature. The current patients
evidenced multifocal ipsilateral cerebral angiitis by angiography and multifocal infarcts in the distribution of the
ipsilateral middle cerebral artery by computed tomographic scanning. Cerebrospinal fluid showed mononuclear
pleocytosis, positive oligoclonal bands, and an elevated immunoglobulin G index. Two patients were treated with
corticosteroids and acyclovir, and 1 with corticosteroids alone, all without apparent response. Necrotizing angiitis
ipsilateral to the herpes zoster ophthalmicus was demonstrated postmortem in 1 patient with multifocal cerebral
infarction and progressive leukoencephalopathy. Neither herpes varicella zoster immunocytochemical reactivity nor
viral inclusions were seen. The leukoencephalopathy associated with herpes varicella zoster either may be caused by
cerebral angiitis or, as previously reported, may be a temporally remote manifestation of persistent herpes varicella
zoster infection. The cerebral angiitis associated with herpes varicella zoster is histologically similar to granulomatous
angiitis, and both may be related to herpes varicella zoster infection of the cerebral vasculature.
Hilt DC, Buchholz D, Krumholz A, Weiss H, Wolinsky JS: Herpes zoster ophthalmicus and delayed
contralateral hemiparesis caused by cerebral angiitis: diagnosis and management approaches.
Ann Neurol 14:543-553, 1983

Nervous system syndromes associated with herpes
varicella zoster virus (HVZ) infections include varicella
myositis [43}, zoster radiculopathy C23, 38, GO), zoster
myelitis [23, 25, 36, 381, cranial neuropathy including
Ramsay-Hunt syndrome 113, 29,471, zoster rneningoencephalitis [ 3 , 6, 38, 39,44, 52, 591, and a temporally
remote leukoencephalitis 1261. A distinctive central
nervous system syndrome associated with H V Z is that
of herpes zoster ophthalmicus (HZO) followed by ipsilateral cerebral angiitis and consequent contralateral
hemiparesis. Only 25 cases have appeared in the English language literature since the original description
by Baudouin and Lantuejoult51 after Dumary in 1919
11, 2, 11, 15, 19,22, 24,28, 31-33, 35, 3 7 , 4 4 , 4 6 , 4 9 ,
53, 5 5 , 61-63]. Some cases may escape recognition
because of the temporal dissociation of the acute vesicular rash and the subsequent hemiparesis. Pathogenetic
mechanisms are unknown, but the finding of focal cerebral angiitis within the sensory field of the trigeminal

nerve suggests active H V Z infection by direct extension via the trigeminal nerve. An immune-mediated
angiitis triggered by the H V Z infection is a possible
alternate mechanism. This report describes four patients with HZO with contralateral hemiparesis seen
consecutively over one year and compares their clinical
features, diagnostic evaluations, and, in 2 cases,
neuropathological findings with examples previously
reported in the English language literature.

From the Department of Neurology, The Johns Hopkins University,
Baltimore, M D 21205.

Received Jan 28, 1983, and in revised form Mar 28, 1083. Accepted
for publication Apr 1, 1383.

”Present address: University of Texas Health Science Center at
Houston, Department of Neurology, 643 1 Fannin, Rm 7.044, PO
Box 20708, Houston, TX 77025.

Address reprint requests to D r Wolinsky at his present address.

Case Reports
Patient 1
An 82-year-old right-handed woman was in excellent health
until she developed left HZO, without corneal involvement,
which healed completely. Twenty days after onset of the rash,
she was noted to be “depressed.”At 30 days she was lethargic
but showed no other abnormalities on clinical examination.
The cerebrospinal fluid (CSF) contained 136 white blood
cells (WBC)per cubic millimeter, of which 37% were mono-

543

nuclear cells. The CSF glucose level was 58 mgidl and CSF
protein level was 125 mgidl, of which 39% was immunoglobulin (normal, up to 12%). All cultures were negative. An
electroencephalogram (EEGj was diffusely slow, and a computed tomographic (CT) scan showed mild ventriculomegaly
compatible with age. The encephalopathy did not change
greatly over the next three weeks, and the CSF pleocytosis
persisted. O n transfer to The Johns Hopkins Hospital 70
days into the illness, the patient was lethargic and aphasic,
with a right spastic hemiparesis and left gaze preference. Repeat CSF analysis showed 34 mononuclear cells, a glucose
level of 56 mgidl, and a protein level of 53 mgidl. Viral,
bacterial, mycobaiterial, and fungal cultures and CSF VDRL
and cryptococcal antigen tests were negative, and cytology
showed no abnormalities. The CSF myelin basic protein level
was 15 ngiml (normal, up to 6 ngiml). Agarose gel electrophoresis of CSF showed four oligoclonal bands, and the
immunoglobulin G index was elevated to 1.3 (normal, up to
0.6). C T scans showed an enhancing left parietal infarction
and bifrontal periventricular white matter lucencies (Fig 1).
The EEG was diffusely slow with periodic (0.5 to 1.5 Hz)
high-voltage sharp wAves, right greater than left. Cerebral
angiography showed segmental narrowing of the proximal
M I portion sf the left middle cerebral artery and A , portion
of the left anterior cerebral artery, as well as distal irregularities including segmental beading with pseudoaneurysm
formation, all compatible with cerebral angiitis (Fig 2). Evaluation for systemic vasculitis, endocarditis, cardiac emboli, and
malignancy showed no abnormalities. Methyl prednisolone
was begun at a d:dy dose of 80 mg administered intravenously, and the dosage was tapered over six weeks, and acyclovir, 750 mg every 8 hours, was given intravenously for 10
days. Progressive obtundation ensued, however. Following
acyclovir treatment, the CSF contained 10 mononuclear cells
and normal glucose and protein levels; myelin basic protein
level and oligoclonal bands were unchanged. The patient died
120 days after onset of HZO.
At postmortem examination, areas of focal infarction were

Fig 1 . (Patient 1 .) (A) Noncontrast computed tomographic (CT)
scan at day 70, demonstrating a lej3 parietal infarct (arrow).
(B) Contrast CT scan at day 7 0 , shouring enhancement of the
left pacetal infarct (arrow). (Ci Contrust CT scan at day 84.
showing bifrontalp e r i v e n t r l u white
~
matter lucencies (arrowsj.

Fig 2. (Patient 1 .) Left internal carotid angiogram (anteroposterior view), showing narrowing of the MI portion of the left
middle cerebral artey and the A1 portion of the left anterior cerebral artery and distal irregularities iniluding Jegmental beading
(arrows).

544 Annals of Neurology Vol 14 No 5 November 1983

F i g 3. (Patient 1 .) Photomicrograph showing necrotizing histiocytic angiitis. A n involved vessel and infarcted tissue are seen
on the right; a small area of relatively normal white matter is
seen in the lower left. (H5.E; x 160.)

widespread in white and gray matter of both cerebral hemispheres, cerebellum, and brainstem. The histological appearance was compatible with infarcts several months old. Vessels
in these regions showed evidence of necrotizing angiitis with
infiltration of the vessel wall by histiocytes and occasional
giant cells (Fig 3). No inclusion-bearing cells were seen.
Viral antigens were sought in deparaffinized tissues using
the unlabeled peroxidase-antiperoxidase immunocytochemical procedure of Sternberger [58].Prebleed or postimmunization sera were obtained from rabbits that received a series
of inoculations of purified H V Z virions in complete and incomplete Freund’s adjuvant {by]. The virions were prepared
from the clarified supernatant of infected BSC-1 cells disrupted by sonication and then further purified by gradient
centrifugation in sucrose [20]. Immunoglobulin fractions of
these rabbit sera were used as primary immunocytochemical
reagents 1681. Appropriate dilutions of the immunoglobulins
were selected, using as targets comparably processed uninfected and HVZ-infected cells. These were prepared from
mock- or HVZ-infected BSC-1 monolayers fixed in buffered
4% formalin; then the cells were scraped and collected by

filtration on millipore filters and the cell-containing filters
were embedded in paraffin. Both infected and uninfected
paraffin-embedded cell pellets served as concurrent positive
and negative controls for the tissue sections from patient 1.
Viral antigens could not be detected in any tissue sections
examined by this method.

Patient 2
A 60-year-old right-handed man had a one-year history of
myasthenia gravis, which was treated by resection of an invasive thymoma, mediastinal irradiation, pyridostigrnine, and
oral prednisone, 35 mg every other day. He developed right
HZO with corneal involvement, and the prednisone dosage
was briefly increased to 30 rng daily. The rash healed well,
but at day 28 he became confused and ataxic and developed
marked left hemiparesis with hyperreflexia. The CSF contained 96 WBC per cubic millimeter (92% mononuclear
cells), with a glucose level of 52 rngidl and a protein level of
96 mgidl. Viral, bacterial, mycobacterial, and fungal cultures
and CSF VDRL and cryptococcal antigen tests were negative,
and there were no cellular abnormalities. The EEG was diffusely slow, especially over the right frontal area. Multiple
right pericaudate lucencies that enhanced with contrast were
seen on C T scan. Cerebral angiography showed narrowing of
the right intracranial carotid artery, marked irregularity of the
A l segment of the right anterior cerebral artery, and focal
dilatation of a branch of the right middle cerebral artery, all

Hilt et al: HZO and Cerebral Angiitis

545

Fig 4. (Patient L?.) Right internal carotid angiogram (oblique
view), showing narrowing of the right intrarwanial carotid artevy (filled arrow) and irregular narrowing of the A!portion of
the right anterior cerebral arteq (open arrow).

F i g 5. (Patient 3.) Noncontrast computed tomographicscan at
day 40, showing multiple right basal ganglia and deep white
matter infarcts (arrowheads).

compatible with cerebral angiitis (Fig 4).The patient was
treated with acyclovir, 945 mg intravenously for 6 days, and
his oral prednisone dosage was again increased to 30 mg
daily. His neurological status initially stabilized, but on day 35
he became more lethargic and the left hemiparesis worsened.
Acyclovir was stopped because of mild rcnal insufficiency,
and the prednisone was increased to 5 0 mg twice a day.
Repeat CSF analysis showed 8 mononuclear cells, normal
glucose and protein levels, four oligoclonal bands, and immunoglobulin 25% of total protein. The patient’s mental status
and hemiparesis were improving by day 40. Prednisone dosage was tapered, and he was discharged to home with a residual left hemiparesis that subsequently resolved.

at day 35 revealed no changes. Left hemiparesis and hemihypoesthesia were first noted on day 40.A C T scan showcd
multiple right basal ganglia and deep white matter lucencies
(Fig 5 j, which enhanced with contrast, and an old, small, right
parieto-occipital infarct. Cerebral angiography demonstrated
right intracranial carotid artery narrowing and abnormalities
of the distal right anterior and middle cerebral artery
branches, all compatible with cerebral angiitis (Fig 6 ) . The
right carotid bifurcation was normal. Evaluation for systemic
vasculitis, endocarditis, and metastatic malignancy showed no
abnormalities. Oral dexamethasone, 2 0 mg daily, was started,
and over the next two weeks the patient’s disorientation and
left hemiparesis gradually improved.
The patient did well following discharge from the hospital,
and the dexamethasone dosage was rapered. At day 60, however, she suffered an acute intracranial hemorrhage, and she
died several days later. Postmortem findings included riglit
uncal herniation syndrome and right caudate hemorrhage
with extensive tissue destruction. N o aneurysm or othr:r
source of the hemorrhage was found. A limited histological
evaluation documented old and new infarctions. No evidence
of cerebral angiitis or inclusion-bearing cells was noted.

Patzent 3
A 62-year-old right-handed woman with a remote history of
bilateral resected breast carcinoma, migraine headaches, and
mild angina pectoris developed right HZO with corneal involvement. This was treated with oral prednisont, 60 mg a
day. O n day 10 of therapy she was noted to be “depressed.”
Disorientation and hallucinations ensued, and she was treated
with haloperidol. The neurological findings were otherwise
normal. The CSI: contained 100 WBC per cubic millimeter
(97% mononuclear cells), with a glucose level of 60 mgidl
and a protein level of 62 mddl. The CSF IgG was 1 6 9 of
total protein. Bacterial and fungal cultures and CSF VDRL
and cryptococcal antigen tests were negative, and no cellular
abnormalities were found. The EEG at day 28 was diffusely
slow. The encephalopathy deepened, and repeat CSF analysis

546 Annals of Neurology Vol 14 No 5

Patient 4
A 62-year-old right-handed man with severe rheumatoid arthritis and rheumatoid lung disease developed left HZO with
corneal involvement. O n day 1 0 he was febrile and was admitted to the hospital for treatment of possible sepsis. The
initial neurological findings were normal. The serum HVZ

November 1083

Fzg 6. (Patient 3 . ) Right retrograde brachial cerebral angiograni
(lateral view), showing narrowing of the right intracranial
carotid artery (filled arrow) and distal iwegularities (open
arrows).

reciprocal titer was 256. He gradually became afebrile, antibiotics were discontinued, and the HZO was healing. O n day
2 1 he became lethargic, and neurological examination
showed mild disorientation, mild right central facial weakness, pronation and drift of the right arm, and subtle right leg
weakness. The EEG was diffusely slow. Results o f a radionuclide brain scan were normal, but a C T scan showed a new
small left basal ganglia lucency. The CSF contained 56 mononuclear cells, a normal glucose level, and a protein level of 49
mgidl, of which 40% was immunoglobulin. The IgG index
was elevated to 1.8. Bacterial, mycobacterial, and fungal cultures and CSF VDRL and cryptococcal antigen tests were
negative, and cytology showed no abnormalities. The CSF
HVZ reciprocal titer rose from 4 to 16. Over rhe next two
weeks the hemiparesis and confusion gradually improved
without specific treatment. At day 35 the patient again became confused and combative, and the mild right hemiparesis worsened. A repeat C T scan showed no changes. An

atraumaric cervical puncture showed bloody, xanthochromic
CSF with a disproportionate mononuclear pleocytosis and a
protein level of 365 mgidl. The clinical impression was possible cerebral angiitis with subarachnoid hemorrhage. Angiography was refused, and the patient made an uneventful and
complete recovery over the next month without specific
treatment.

Discussion
The Table summarizes pertinent clinical and laboratory
data in the English language literature on 25 previously
reported patients with HZO and contralateral hemiparesis, to which the current cases are added. Including
the current 4 patients, the mean age is 57 years, with a
range from 7 to 96 years. Nineteen of 29 patients were
age 60 or older, a finding consistent with a selective
decline in cellular immune response to H V Z and increasing incidence of dermatomal zoster with aging
[41).Some patients had systemic malignancies or were
otherwise immunocompromised. The latter group had
a well-documented increased susceptibility to HVZ infections, manifested by dermatomal or disseminated
zoster [14, 53, 64, 651. Fourteen of the patients were

Hilt er al: HZO and Cerebral Angiitis

547

Findings iti 25 Patients u:ith Herpes Zoster Ophthalmicus and Contralateral Hemiparesir

-

Reference

Age, Sex

Interval"

C N S Symptoms

CSF (per mm')

Gordon and Tucker [ 2 2 )

26, M

4 wk

Right HP, aphasia

4 wk' WBC 3, pro N ,
6 wk WBC 38 (95% M), pro 7O
4 wk WBC 5 1, RBC 4, pro 34

xanthoc hromia
Hughes 1281

70, F

4 wk

Left H P

Cope and Jones [ 111
Anastasopoulos et a1 121
Laws 1331
Acers [l}

5 wk
5 wk

Pandi and Romanes [461

54, F
29, M
65, F
32, M
61, M
55, F

2 wk

Left H P
h g h t H P , aphasia
Right HP, aphasia
Right H P
Right H P
Left H P

Kolodny et a1 [ 3 11

96, F

4 wk

Left H P

Norris et a1 [ 4 4 ]
Rosenblum and Hadfield 1531

72, F
64, M

6 nio
6 wk

Disorientation, ataxia, righr H P
Delirium, left H P

Walker e t al L631

7, M

6 mo

Right HP, aphasia

2 wk WBC 65 (M > P), pro
elevated
6 wk WBC 7, RBC 7 , pro 315,
xanrhochromia
6 mo WBC 1, RBC 13

Gilbert [19]

73, M

0

Left HP, right amaurosis fugax

3 wk: N

Victor and Green 1621

58, M

5 wk

5 wk: WBC 55 (98% M), RBC 27,
pro 52, IgG 15%

Pratesi et a1 [401

48, M

10 wk

Delirium, left H P and
hemianopsia, right Homer's
syndrome
Delirium, left H P

Gursoy et a1 1241

24, F

1 wk

Right H P

Ruppenthal I551

72, F

2 wk

Left HP

Kuroiwd and Furukawa I121

G7, M

6 wk

Right H P

6 wk WBC 2 1 (86% M), pro 3 2 ,
elevated IgG

MacKcnLie et al 35 1

34, F
70,M
67, F

4.5 rno
7 wk
6 wk

Right H P , aphasia
Left H P
Right H P , aphasia, memory deficit

4 5 nio N

60, M

12 wk

Confusion, right HP, aphasia

8 wk WBC 14 (50% MI, pro h i

Doyle er al [ 1 5 1

69, F

2 wk

Right H P

Vecht [611

66, M

3 wk

McConias and Gurmann [j71

69, F

8 wk

Right H P and hemianopsia,
aphasia
Stupor, right HP, aphasia

8 wk WBC 59, RBC 72, pro 100

4 mo
3 wk
4 wk

6 wk WBC 4 8 , pro 50
5 wk WBC 4 , pro 4 4
3wk N
4 wk WBC 3 , pro N
2 wk WBC 90 (M > P), RBC 7,
pro 200
1 wk WBC 80 (62% M), pro 200
2-4 wk WBC 110 ( 9 8 % M), pro

445

4 wk: no cells, pro 116
12 wk: no cells, pro 79
1 wk: WBC 1200 ( P > M j pro 100,
glu 3 0
3 wk- N

10 wk N

12 wk WBC 38, RBC 2091, pro 78

4 wk WBC 87 ('92'< Mj, RBC 6,
pro 48, elevated IgG
8 wk WBC 14, pro 5 5

~~

'Approximate time from onset of herpes 2osrer ophthalmicus to onset of contralateral hemiparesis.
"Estimate based on available information.
'Approximate time since onset of herpes zosrer ophrhalmicus.
CNS = ceiirral nervoiis system; CSY = cerebrospinal fluid; CT =- computed tomographic; EEG = elecrroencephalogram; H P = hemiparesis; WRC = white blm~cl
cell count; RBC = rcc: blood cell count; pro = protein; N = normal; M = mononuclear cells; P = polymorphonuclear cells; glu = glucose, MCA :middle cerebral
drrery; ACA = anterior cerebral artery; PCA = pustenor cerebral artery; R = radionuclide, ICA = internal carotid artery

548 Annals of Neurology

Vol 14

No 5

November 1983

Angionraphv

Radionuclide or CT Scan

EEG

Courseiourcome”
Moderate disabilitv

Severe disability

...
...

...
...

...

...
...

...

...
Rtght slowing

Moderate disability
Mild disability
Anticoagulants; moderate disability
Mild disability
Severe disability
Good recovery

...

Diffuse. high-voltage
slowing

Death at S wk; diffuse angiitis with
multiple recent infarcts

...

...

Multiple right MCA branch
occlusions

(R) Increased parietal uptake

Diffuse 1-2 Hz
Rtght delta

Prednisone; good recovery
Death at 6 wk; reticulum cell
sarcoma; giant cell angiitis with
multiple right cerebral infarcts

Segmental narrowing of left
proximal ACA and MCA
branches
Segmental narrowing of right
carotid siphon

(R) Increased left frontoparietal

Left delta

Some recoverv

Right temporal delta

10 wk: right PCA narrowing
16 wk: bilateral proximal MCA
narrowing; occlusion of right
ACA and PCA
2 wk. elevation of left MCA

uptake

(CT) N
(R) #1, N; #2, increased right
occipital uptake

...

(R) N

Right slowing

Anticoagulants and steroids; mild
disability
Right temporal artery biopsy:
mononuclear cell infiltrate; some
recovery
Prednisone; severe disability

(R) Increased left temporal uptake

Left anterior sharp
waves

Ligation of aneurysm; mild
disabilitv

(CT) 6 wk: N
7 wk: multiple left MCA territory
infarcts
(CT) Left internal capsule infarct
(CT) N
(CT) N

Left slowing

Death at 2 wk; multifocal
demyelinarion; ependymitis;
mononuclear perivascular
infiltrate
Mild disability

Left delta

Anticoagulants; good recovery
Anticoagulants; good recovery
Prednisone; some recovery

(CT) Meningiomas

Left temporal delta

Prednisone; death

...

...

(CT) Left internal capsule infarct
(R) N
(CT) Bilateral basal ganglia and
right frontal infarcts

Left temporal and
diffuse slowing
...

Steroids; death at 10 wk; angiicis,
massive left ICA thrombosis and
left cerebral infarct; herpes
virions in left MCA
Unknown

5 wk: left intraperrosal carotid
aneurysm
...

segmental narrowing of left
proximal MCA
Stenosis of left M,
Narrowing of right M , and A2
Segmental narrowing of left M,
and A2
Stenosis of left A? and two MCA
segments
...

...

Left temporal delta

N

Left temporal and meningeal
biopsies N; severe disability

Hilt et al: HZO and Cerebral Angiitis

549

women and 15 were men; 17 had left and 12 right
H Z O . The mean delay from onset of HZO to first
manifestation of contralateral hemiparesis was seven
weeks, with a range from no delay to six months.
The typical clinical history is gradual resolution
of cutaneous H Z O followed by the acute onset of
contralateral hemiparesis, hemisensory symptoms,
or aphasia. The temporal dissociation of HZO and
neurological symptoms may obscure the diagnosis of
HZO-associated cerebral angiitis. The neurological
manifestations are usually monophasic, but some patients have recurrent ischemic episodes in the distribution of the ipsilateral middle cerebral artery. Prognosis
is guarded, and there is a mortality of approximately
25%. Eleven of 29 patients had mild residual disability
or made a good recovery, 10 had moderate or severe
disability, 7 died, and the outcome of 1 is unknown.
Early alteration of mental status was noted in all of
the current patients. In 2 patients psychological depression was diagnosed until progressive focal deficits became evident. An acute confusional state or delirium
was also noted in several previously reported patients.
This encephalopathy probably indicates generalized
bihemispheral involvement, an impression supported
by diffuse EEG abnormalities in all the present cases.
Focal delta slowing over the involved hemisphere is the
most common EEG abnormality reported in previous
patients, however. The periodic sharp waves seen in
patient 1 have not been described previously in any
patient with IIZO-associated cerebral angiitis. This
type of abnormality is similar to that seen in herpes
simplex encephalitis, Creutzfeldt-Jakob disease, and
subacute sclerosing panencephalitis 1421.
The CSF was abnormal in 17 of the 24 patients from
whom it was obtained. The most common finding was a
mononuclear pleocytosis of up to 1,200, but usually
less than 100, WBC per cubic millimeter. The finding
of normal CSF in 7 patients may reflect the timing of
samples. As evidenced in patient 1, during the acute
phase there often is a mononuclear pleocytosis that
then slowly resolves. Patients with either dermatomal
zoster or HZO may have a mononuclear CSF pleocytosis. By itself, the CSF pleocytosis does not distinguish
patients with uncomplicated HZO from those who develop a neurological syndrome secondary to cerebral
angiitis.
Bieger and colleagues [ 6 ] showed elevated CSF
H V Z antibody titers in patients with probable H V Z
meningoencephalitis. In both their patients the serum
titer was much higher than the concurrent CSF titer.
Gershon and associates { 181 demonstrated the usefulness of an indirect immunofluorescence assay for
H V Z antibody in CSF of patients with HVZ-associated
neurological syndromes. Serial CSF and serum titers
were obtained only in patient 4 of the current series.
During the acute HZO episode the serum titer was

550 Annals of Neurology

Vol 14

No 5

256 and the CSF titer was 4. As serum titers subsequently decreased, the CSF titer increased to 16. Serial
determinations of paired serum and CSF titers may aid
the diagnosis of H V Z involvement of the nervous system.
All the current patients had elevated CSF immunoglobulins or IgG indices. These findings presumably
reflect increased intrathecal immunoglobulin synthesis.
Oligoclonal bands were present in the 2 patients in
which they were sought. As stated by Hosein arid
Johnson in a recent review [27), oligoclonal bands are
present in a wide variety of central nervous system
infections and inflammatory processes but have not
been reported previously in patients with HVZassociated cerebral angiitis.
Cerebral angiography was performed in 10 previously reported patients. MacKenzie and colleagues
{ 3 5 ] emphasized segmental narrowing of the proximal
middle and anterior cerebral arteries in the M I , A I , and
AZ segments in their patients. Small distal vessels may
also be involved. Less frequently noted abnormalitic~s
include aneurysm of the intracavernous internal carotid
artery [24], intracranial carotid artery stenosis at the
level of the siphon [19], and total occlusion of the
internal carotid artery from the level of the carotid
bifurcation [IS}. Three patients in the present series
had cerebral angiography with adequate visualization of
the carotid bifurcation, and atherosclerotic lesions were
not seen. Changes compatible with cerebral angiitis
were found at varied sites.
C T scans have been reported in 12 patients and
showed abnormalities in 8. Lesions generally appeared
in the deep gray matter or internal capsule and were
consistent with infarcts in the distribution of the appropriate middle cerebral artery and its branches. One previously reported patient had bilateral basal ganglia infarcts [37). All 4 current patients had infarcts of the
basal ganglia, internal capsule, or pericaudate region:;
ipsilateral to the HZO. Patient 1 had progressive periventricular white matter lucencies documented by C?’
scan. Three of the patients had initial CT scan finding:;
that did not satisfactorily explain their clinical presentations, and abnormalities were documented in the appropriate vascular distriburion only o n follow-up scans
This delayed development of CT scan abnormalities is
typical of small, deep infarcts { 501. The location of thc
infarcts, together with the angiographic findings, suggests deep penetrating branch occlusion secondary to
angiitis. This concept is further supported by available
pathological findings.
CSF myelin basic protein concentration was determined in only patient 1 and was markedly abnormal,
indicating active myelin destruction [g, 101. This
finding was supported further by the presence of progressive periventricular white matter lucencies on CT
scans (see Fig 1C). Leukoencephalopathy has not been

November 1983

reported previously in close association with HZO, although a syndrome of progressive leukoencephalitis
temporally remote from H V Z infection was recently
described by Horten and co-workers [261. They reported 2 immunosuppressed patients with systemic
malignancies who had truncal dermatomal zoster nine
and ten months, respectively, prior to the onset of a
progressive white matter process immunocytochemically directly related to HVZ. Angiitis was not seen in
these patients. In both patients C T scans showed progressive white matter degeneration. Ruppenthal 1551
reported a patient with HZO and delayed contralateral
hemiparesis who showed multifocal demyelination
postmortem with mononuclear perivascular inflammation and ependymitis without viral inclusions. It therefore appears that two pathogenetic mechanisms may be
involved in patients with delayed or progressive white
matter degeneration after H V Z infection. One process, temporally remote, as reported by Horten and
colleagues C261, involves ongoing central nervous system viral infection in an immunocompromised host
and must be distinguished from progressive multifocal
leukoencephalopathy. The other mechanism is exemplified by our patient 1, in whom leukoencephalopathy
appears to be a manifestation of progressive angiitis
involving both gray and white matter.
Although neither viral inclusions nor H V Z immunoreactivity could be demonstrated in patient 1,
there are reports of viral particles within involved vasculature in a patient with HZO and hemiparesis [l5}.
Failure to show H V Z antigens in pathological material
from the current patient may reflect: (1) prior treatment with acyclovir, (2) inactive angiitis at the time of
death, or (3) angiitis triggered by H V Z infection of the
cerebral vasculature but possibly not requiring active
infection once initiated.
At present, herpes simplex virus infection of the
central nervous system is the only treatable viral encephalitis [66, 67). Both adenine arabinoside and,
more recently, acyclovir have been effective in patients
with nonneural H V Z infections 18, 17, 30, 56, 5 7 , 64,
651. Some previously reported patients with HZOassociated hemiparesis have been treated with corticosteroids or warfarin sodium without apparent benefit
115, 19, 33, 35, 44, 491. Because the likely pathogenesis of HZO-associated hemiparesis includes H V Z
infection of cerebral vasculature and consequent cerebral angiitis, 2 of the current patients were treated
with both high-dose corticosteroids and parenteral
acyclovir. One other patient received only corticosteroids. Treatment did not noticeably alter their clinical
courses. Optimal therapy, including the utility of antiviral agents, remains to be defined.
Since its recognition by Cravioto and Feigin 1123,
granulomatous angiitis of the central nervous system
has remained a rare entity characterized by cerebral

angiitis with few if any systemic manifestations [ 7 , 451.
In their review Kolodny and colleagues 13 1) included a
patient with H Z O , contralateral hemiparesis, and white
matter infarcts. Although the pathogenesis of granulomatous angiitis is unexplained, Rosenblum and
Hadfield I531 and Rosenblum and colleagues 1541 suggested that in their 2 patients with systemic malignancy, an association existed between H V Z and the
pathologically proven granulomatous angiitis. Reyes
and co-workers [Sl} reported a patient with granulomatous angiitis and primarily white matter infarcts in
whom viral particles in involved vasculature were demonstrated by electron microscopy. Linnemann and colleagues 1341 reported an additional patient with HZO
and a rapidly progressive multifocal encephalopathy
who showed fulminant vasculitis postmortem with viral
particles in vascular smooth muscle cells demonstrated
by electron microscopy. Most recently, Doyle and associates f l 5 1 reported viral particles within giant cells
in the inflamed middle cerebral artery of a patient with
HZO and contralateral hemiparesis. This mounting
body of evidence suggests viral infection of vascular
structures in both HZO-associated hemiparesis and
some cases of granulomatous angiitis.
The ability of H V Z to infect human brain cells and
trigeminal ganglion cells in tissue culture, the recovery
of virus from affected neurons postmortem, and the
immunofluorescent demonstration of H V Z antigen in
the CSF of patients with H V Z infection and neurological symptoms are all well documented {4, 6, 16, 21,
48, 551. The trigeminal nerve is known to provide sensory innervation to the proximal middle cerebral artery
[40],and it has been proposed that HZO-associated
angiitis is the result of spread of virus along the trigeminal nerve. This may not, however, be the sole mechanism of viral spread. Although the infection may be
initiated in branches of the trigeminal nerve innervating the middle cerebral artery, in some patients there is
widespread bilateral involvement that includes posterior vascular structures not known to be innervated by
trigeminal nerve branches. Additionally, some patients
with HVZ-associated cerebral angiitis have had truncal
rather than trigeminal zoster eruptions. In such patients
either hematogenous or contiguous dissemination via
CSF pathways must be invoked.

Supported in part by Public Health Service Grant NS15721 from
the National Institutes of Health (National Institute of Neurological
and Communicative Disorders and Stroke). J. S. W. is the recipient
of Public Health Service Research Career Development Award
NS00443.
The authors are grateful to Dr Donald H. Gilden for providing the
hyperimmune sera, to Linda Kelly for manuscript preparation, and to
Susan Sim for technicai assistance.

Hilt et al: HZO and Cerebral Angiitis

551

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