0148-396 X/87/2006-0969$02.00/0
NEUROSURGERY
Copyright © 1987 by the Congress of Neurological Surgeons

Vol. 20, No. 6, 1987
Printed in U.S.A.

Phenylpropanolamine: An Over-the-Counter Drug Causing
Central Nervous System Vasculitis and Intracerebral
Hemorrhage

Case Report and Review

Roberta Glick, M.D., John Hoying, M.D., Leonard Cerullo, M.D., and Susan Perlman, M.D.

Department of Neurosurgery, Cook County Hospital—University of Illinois Hospital (RG), and Departments of Neurosurgery (LC) and
Rheumatology (JH, SP), Northwestern University Medical School, Chicago, Illinois

Phenylpropanolamine (PPA) is the major ingredient in more than 70 over-the-counter preparations including diet pills,
nasal decongestants, and the legal “look-alike” stimulants. Structurally and functionally similar to amphetamine and
ephedrine, PPA has recently been associated with several neurological manifestations including psychosis, stroke, severe
headache, seizures, and intracerebral hematoma. We report a case of intracerebral hematoma and subarachnoid
hemorrhage in a young woman with angiographic and biopsy-proven vasculitis of the central nervous system (CNS)
induced by PPA in her diet pills. From review of the literature, we distinguish drug-induced vasculitis as a separate
entity from primary CNS vasculitis, both clinically and pathologically. This report should alert physicians, in general,
to this potentially fatal side effect of PPA, a commonly used over-the-counter drug. Also, neurosurgeons in particular
should consider the possibility of drug-induced vasculitis when faced with cases of intracerebral or subarachnoid
hemorrhage without apparent cause. (Neurosurgery 20:969-974, 1987

Key words: Central nervous system vasculitis, Drug-induced vasculitis, Intracerebral hematoma, Phenylpropanolamine,

Subarachnoid hemorrhage

INTRODUCTION

Phenylpropanolamine (PPA) is the major ingredient in
more than 70 over-the-counter preparations including diet
pills, nasal decongestants, and the legal “look-alike” stimu-
lants (1, 2, 12, 44, 45, 53). Structurally and functionally
similar to amphetamine and ephedrine (12, 44, 64), PPA
recently has been associated with several neurological mani-
festations including psychosis (32, 48, 60, 66), stroke (1, 30,
34, 38), severe headache (51), seizures (1, 44), and intracere-
bral hematoma (1, 34, 46). We report a case of intracerebral
hematoma and subarachnoid hemorrhage in a young woman
with angiographic and biopsy-proven vasculitis of the central
nervous system (CNS) induced by PPA in her diet pills. The
proximity of the ingestion of PPA to the acute onset of
symptoms, the clinical presentation and course, the histopath-
ological findings, and the structural and functional similarity
of PPA to ephedrine and amphetamine (both of which can
cause CNS vasculitis or hematoma), lead to this conclusion.

CASE PRESENTATION

The patient is a 35-year-old, right-handed mother of five
children who was 3 weeks postpartum when she developed
the sudden onset of headache in the posterior-occipital area,
associated with nausea, vomiting, photophobia, and extreme
fatigue. She was seen at a local hospital emergency room and
discharged with pain medication. Her symptoms persisted,
and 4 days later she was admitted to another hospital. A
computed tomographic (CT) scan then demonstrated a right
frontal intracerebral hematoma and subarachnoid blood. She
was transferred to Northwestern University Medical School
Hospital the next day.

On admission, major complaints were severe headache and
mild photophobia. She said that she had not used ampheta-

969

mine, heroin, or other drugs except librium, 5 mg orally, 3
times a day, prescribed for postpartum depression, which she
had discontinued 2 days before the ictus. Later, she reported
using an over-the-counter diet pill, Dexatrim, Extra Strength
(Thompson Medical Co., New York, New York) which con-
tains PPA. She took Dexatrim for 2 years, but stopped taking
the diet pills when she discovered she was pregnant. She then
took her first Dexatrim tablet in many months 1/4 hours
before the onset of her symptoms.

She was employed as a business executive. Her medical
history was negative except for a cesarean section in 1980 and
the use of birth control pills 10 years before admission. Her
family history was remarkable for stroke (maternal grand-
father) and myocardial infarction (mother, age 52).

Physical examination showed that the vital signs and gen-
eral physical condition were normal. Neurological examina-
tion demonstrated minimal nuchal rigidity, mild diffuse hy-
perreflexia, and no focal abnormalities. The admitting com-
plete blood count, SMA 20, coagulation profile, chest x-ray
film, urinalysis, and electrocardiogram (EKG) were normal.
The Westergren sedimentation rate was 14 mm/hour.

The patient was admitted to the neurosurgical intensive
care unit, where she was placed at total bedrest and received
dioctyl sodium sulfosuccinate, phenytoin, pain medication
(acetominophen), maintenance fluids, dexamethasone (4 mg
orally every 6 hours), and cimetadine (300 mg orally every 6
hours).

The following morning, a CT scan again showed a right
frontal hematoma with surrounding edema. Transfemoral
bilateral carotid and left vertebral angiography demonstrated
diffuse segmental narrowing and dilation of intracranial ar-
terial branches involving both the anterior and the posterior
circulation, including small, medium, and large vessels (Fig.
1), consistent with vasculitis. In addition, there was a shift of
the right anterior cerebral artery to the left, secondary to mass

970 GLICK et al

effect. No aneurysm or arteriovenous malformation was seen.
Collagen vascular, infectious, and metastatic disease work-
ups by medical consultants all were negative. The working
diagnosis entertained was primary CNS vasculitis. Dexameth-
asone was stopped. and intravenous methylprednisolone (300
mg every 6 hours) was begun.

On the 7th hospital day, repeated neurological examination
showed the development of a slightly blurred right disc margin
and an equivocal upgoing toe on the left; her severe headache
persisted. Consequently, craniotomy was performed for evac-
uation of the intracerebral hematoma, leptomeningeal biopsy,
brain biopsy, and biopsy of the hematoma cavity. Histopath-
ological examination demonstrated necrotizing vasculitis of
small arteries and veins, with infiltration of polymorphonu-
clear leukocytes, particularly prominent in the intima, and
subsequent thickening and reduction of the lumen, areas of
vessel occlusion, and fragmentation of the elastic lamina (Fig.

Neurosurgery, Vol. 20, No. 6

2). Areas of subarachnoid hemorrhage organizing with fibro-
blastic proliferation and recent small infarcts involving the
gray matter were also noted. No evidence of tumor or infec-
tion was found.

Neurologically, the patient did well postoperatively. Post-
operative digital subtraction angiography showed irregularity
of the proximal right carotid artery, but the distal vasculitic
changes were not visualized. Cytoxan (125 mg orally, 3 times
a day), was begun, and she was discharged 10 days postoper-
atively. Two months after admission, she continued to note
intermittant headaches. A CT scan with contrast infusion and
magnetic resonance (MR) scan were obtained. The CT scan
did not demonstrate any active disease process. The MR scan
showed increased signal in the deep right frontal lobe inter-
preted as residual intracerebral hematoma, gliosis, or ische-
mia. Four months postictus, her headaches had resolved, and
cerebral angiography showed almost complete resolution of

Fic. 2. Photomicrograph of the biopsy specimen. .4, section showing a larger artery with intimal proliferation‘and infiltration of polymorpho-
nuclear leukocytes. B. section showing a large and surrounding small arteries with more infiltration of polymorphonuclear leukocytes and
disruption of the vessel. C, section showing complete destruction of the architecture with necrosis and fragmentation.

June 1987

PHENYLPROPANOLAMINE CAUSING VASCULITIS AND ICH 971

FiG. 3. Cerebral angiogram showing resolution of previously noted lesions. A. lateral carotid; B, AP vertebral.

all previously noted lesions (Fig. 3). Over the ensuing 7
months, medications were tapered and stopped.

DISCUSSION

Phenylpropanolamine, the major ingredient in more than
70 over-the-counter preparations of diet pills, decongestants,
and stimulants (1, 2, 12, 44, 45, 53), has recently been
associated with intracerebral hemorrhage (1, 34, 46). Our
patient is the first angiographic and biopsy-proven case of
CNS vasculitis and intracerebral hemorrhage associated with
the use of PPA. There are several reasons to believe that this
is a case of drug-induced rather than primary CNS vasculitis:
(a) The proximity in time of the ingestion of PPA to the acute
onset of symptoms is similar to other cases of drug-induced
vasculitis (7, 8, 11, 13, 23, 33, 39, 40, 50, 65, 68, 69). (b) the
clinical presentation and remitting course are similar to those
seen with drug-induced vasculitides in contrast to primary
CNS vasculitis, which is usually a progressive and fatal disease
(3-6, 9, 10, 14-16, 20, 22, 24, 25, 28, 29, 31, 35, 41-43, 47,
49, 52, 55-57, 62, 63, 70). (c) The occurrence of intracerebral
hemorrhage is frequently associated with drug-induced vas-
culitis, but is rare with primary CNS vasculitis (4, 5, 9, 24,
49). (d) PPA is structurally and functionally similar to am-
phetamine and ephedrine (12, 44, 64) (Fig. 4), both of which
have been shown to cause CNS vasculitis with intracerebral
hemorrhage (7, 11, 23, 33, 39, 40, 50, 67-69). (e) The histo-
pathological findings in our patient are similar to those in
patients with other drug-induced vasculitides (8, 21, 33, 65)
and differ from those of primary CNS vasculitis (3-6, 9, 10,
14, 20, 24, 25, 28-29, 35, 43, 47, 49, 52, 63, 70).

Primary CNS vasculitis, a rare disease that is by definition
confined to CNS, had been considered invariably fatal until
recently (10, 43). Approximately 30 cases of primary CNS
vasculitis have been reported in the world literature (3-6, 9,
10, 14-16, 20, 22, 24-25, 28-29, 31, 35, 41-43, 47, 49, 52,
55-57, 62-63, 70), but the diagnosis has been made by
premortem biopsy in only 3 cases (6, 10, 20). The initial
symptoms in the reported cases are shown in Table |. Seizures
occurred as the presenting event in 8 patients, and systemic

PHENYLPROPANOLAMINE

Scrum
| | |

OH CH, H

AMPHETAMINE

CH, H
EPHEORINE
| |
OH CH, x)

Fic. 4. Structural similarities among phenylpropanolamine, am-
phetamine, and ephedrine.

symptoms notably were absent. In 90% of the patients, there
is progressive neurological deterioration; death occurred in all
but the 4 most recently reported cases (10). The difficulty
encountered in establishing the diagnosis of primary CNS
vasculitis is that no single laboratory test can firmly establish
or exclude it. Changes in spinal fluid show the pattern of
increased pressure, increased protein, normal glucose, and
lymphocytic pleocytosis. However, angiography was positive
in only 8 of the 12 cases in which it was performed (Table 2),
and 4 patients with negative angiograms were found to have
vasculitis at autopsy (Table 2) (5, 24, 28, 29). The character-
istic angiographic findings of vasculitis include segmental
areas of stenosis and dilation described as “beading” or “sau-

972 GLICK et al

TABLE |
Primary CNS Vasculitis: Clinical Presentation in 30 Cases
Symptoms Pars Description
CNS 22 Headache, mental status changes,
nausea and vomiting, confu-
sion, decreased intellectual
function
Cranial nerve 16 Diplopia, blurred vision, nystag-
mus, dysarthria, pupillary ab-
normalities
Focal 17 Hemiparesis and/or aphasia
Seizures 8 Focal or generalized

TABLE 2
Selected Variables in Primary vs. Drug-induced Vasculitis

Primary Drug-Induced

No. patients os a 30 25
No. hemorrhages (total) ......... 5 1
Xanthrochromic CSF (LP)* ..... 4
Intraventricular hemorrhage : 1
Subarachnoid hemorrhage . . F 4
Intracerebral hematoma ...... 7
No. positive angiograms/total no. 8/12 24/25
performed bcc cece
No. positive histological specimens/ 25/30 8/8
total no. performed
Biopsy .. bug ERS ge ee a3 Bil 3
AUtOpsy ss eisieeeesmevie oe 23 5

“ CSF, cerebrospinal fluid; LP, lumbar puncture.

sage” patterns and nonspecific small vessel occlusion (10).
Also, aneurysms may be present (10, 20). Thus, the mainstay
of diagnosis remains tissue biopsy. In all but 3 cases in the
literature, the diagnosis of primary CNS vasculitis was made
postmortem (6, 10, 20). Histological examination shows the
characteristic gramulomatous inflammation, with vessel ne-
crosis and almost uniform involvement of the leptomeninges
(10, 14). This last finding has led to the recommendation that
“leptomeningeal biopsy be the test of choice in establishing
the diagnosis of primary CNS vasculitis” (10). In the 7 ante-
mortum biopsy cases reported in the literature (4, 6, 10, 20,
24, 25, 28), leptomeningeal biopsy was diagnostic in all 3
patients in which it was performed (6, 10, 20).

An association of primary CNS vasculitis with intracerebral
hemorrhage is suggested but not substantiated in the litera-
ture. Xanthrochromic cerebrospinal fluid was found in 4 of
the 22 patients studied (4, 9, 24, 49), and intraventricular
hemorrhage occurred as the terminal event in another patient
who suffered a protracted course (Table 2) (5). Several of the
autopsy reports mention subarachnoid hemorrhage, pete-
chiae, and infarcts, but none mentions intracerebral hema-
toma specifically.

In contrast, drug-induced vasculitis is commonly associated
with both intracerebral hematoma and subarachnoid hemor-
rhage (Table 2) (7, 11, 23, 33, 39, 40, 50, 58, 65, 67-69).
Cerebral hemorrhage has been well described in patients using
amphetamines (7, 11, 13, 17, 19, 23, 37, 50, 54, 61, 65, 69),
as has the pathological syndrome of necrotizing angitis (8,
21). Experimentally, angiographically, and histologically con-
firmed vasculitis has been induced in animals immediately
after the intravenous injection of amphetamines (59). A re-
view of the world literature reveals 24 well-documented cases
of drug-induced vasculitis of the CNS secondary to amphet-

Neurosurgery, Vol. 20, No. 6

amine (7, 8, 11, 23, 33, 39, 40, 50, 65, 68, 69) and | due to
ephedrine use (67). Eleven patients had intracerebral hemor-
rhages: 7 hematomas (23, 33, 39, 65, 68, 69) and 4 subarach-
noid hemorrhages (7, 11, 40, 50). Almost all patients with
intracerebral hemorrhage experienced the abrupt onset of
severe headache minutes after the oral or intravenous admin-
istration of the drug. The admission blood pressure was most
often normal. Twenty-four of the 25 patients had angio-
graphic evidence of vasculitis. Histological examination was
positive in all patients in whom it was performed, including
3 premortem biopsies (11, 33, 65) and 5 autopsies (8, 50). In
the 1 patient with ephedrine-induced vasculitis, skin biopsy
was positive for immune complex deposition of immunoglob-
ulin M and C3 component of complement (67); angiography
was initially negative, but 7 days later showed the typical
features of vasculitis. Clearly, the presentation and clinical
course of our patient most strongly resemble those seen in
cases of drug-induced vasculitis and not those of primary CNS
vasculitis.

It may be possible to differentiate drug-induced vasculitis
from primary CNS vasculitis (Table 3). The findings in drug-
induced vasculitis are indistinguishable from those of immune
complex-mediated vasculitic disease, i.e., polyarteritis nodosa
(PAN). Involvement of small and medium vessels (usually
arteries) is predominant; there is a predisposition for bifurca-
tion points; the lesions are segmental and at different stages
of development; early lesions show intimal proliferation, in-
filtration of polymorphonuclear leukocytes, and luminal nar-
rowing; later lesions often show marked fibrinoid necrosis
and fragmentation of elastic lamina (10, 14). Characteristi-
cally, no giant cells or granulomas are present, the cells are
mainly polymorphonuclear leukocytes, and the reaction is
most pronounced within the intima of the vessel. In contrast,
the lesions of primary CNS vasculitis are more restricted to
small vessels; there is no preference for bifurcation points;
infiltrating cells are usually lymphocytes and monocytes; the
inflammatory reaction is more pronounced in the media and
adventitia; and necrosis is less marked than in PAN or drug-
induced disease (10, 14). In primary CNS vasculitis, both
giant cells and granuloma formation are noted, suggestive of
a cell-mediated immune vasculitis (10, 14).

The pathological findings in our patient are most consistent
with the diagnosis of drug-induced immune complex-me-
diated vasculitis and not primary CNS vasculitis. Infiltration
was predominantly with polymorphonuclear leukocytes and
was most marked in the intima. Necrotizing vasculitis of
small vessels was present, and no giant cell or granuloma was
observed.

Differences demonstrated by histopathological examination
suggest that different immune mechanisms underlie the pro-
duction of drug-induced vasculitis and primary CNS vasculi-
tis. The mechanism of immune complex vasculitis best ex-
plains the pathological changes seen in drug-induced vasculitis
and also would account for the rapid onset of symptoms and
the production of pathological changes after exposure to
amphetamine-like substances. Because of the presence of giant
cells and granuloma formation, the pathological picture of
primary CNS vasculitis seems more consistent with a cell-
mediated immune vasculitic process.

The pharmacological properties of PPA also may have
contributed to the clinical course of this patient. Structurally
and functionally similar to amphetamine and ephedrine (Fig.
4), both of which are known to cause vasculitis and intracer-
ebral hemorrhage (12, 44, 64, 67), PPA has recently been
implicated as a cause of intracerebral hematoma in three
patients (1, 34), although no studies were performed in those
patients to establish the diagnosis of vasculitis. PPA in com-

June 1987 PHENYLPROPANOLAMINE CAUSING VASCULITIS AND ICH 973
TABLE 3
Histopathology of Primary and Drug-induced Vasculitis

Feature Drug-induced Primary
Vessels Small, medium arteries Arteries and veins
Lesions Multiple stages Multiple stages
Cellular infiltrate Predominantly polymorphonuclear Predominantly lymphocytes,

leukocytes monocytes
Giant cells None Characteristic
Granulomas None Characteristic
Microaneurysm Occasional Occasional
Necrosis Marked Moderate
Vessel wall in- Intimal Adventitial
volvement

bination with caffeine will produce intracerebral hemorrhage
in hypertensive or stroke-prone rats (46) and, in a clinical
experiment, a single dose of PPA-containing diet pills caused
disastolic hypertension (27). PPA-induced hypertension (18,
26, 27, 36), then, may play a role in the production of
intracerebral hemorrhage in these patients, especially if vessels
are concurrently injured by vasculitis.

Diagnosis and classification of the vasculitis are based on a
combination of clinical, angiographic, and pathological fea-
tures. Based on the clinical and experimental data, we propose
the following outline as an appropriate sequential diagnostic
approach to a patient suspected of having CNS vasculitis: (a)
detailed history-taking and physical examination, noting all
prescribed and over-the-counter medications and drug use,
allergies, pregnancy history (eclampsia), hypertension, stroke,
and use of caffeine and cigarettes; (b) noninvasive neurologi-
cal testing: CT scan, lumbar puncture, radionuclide brain
scan; (c) collagen vascular, infection, and metastatic work-up;
(d) invasive testing—angiography; (e) leptomeningeal and
cortical biopsy.

Surgical biopsy should be performed when the diagnosis
remains in question or when the clinical condition—such as
an intracerebral hematoma—necessitates operation. Because
there seem to be discernible histological differences between
drug-induced and primary CNS vasculitis, leptomeningeal
biopsy may be the definitive means of differentiating these
two entities.

The preferred treatment of primary CNS vasculitis is still
being established. In the treatment of drug-induced vasculitis,
removal and discontinuance of the offending agent is essen-
tial. The combination of cyclophosphamide and prednisone
has been recommended because of its efficacy in the treatment
of other life-threatening vasculitides, e.g., PAN and Wegener’s
granulomatosis (10, 14, 43). Initial success has been obtained
in halting the progression of primary CNS vasculitis, a disease
previously thought to be progressive and invariably fatal. The
good response in our patient with drug-induced CNS vascu-
litis suggests that chemotherapy and antiinflammatory agents
also may be appropriate for the critically ill patient with severe
and diffuse vascular changes due to vasculitis, although pre-
vious studies have not addressed this issue.

In summary, this report should alert physicians to this
potentially fatal side effect of PPA, i.e., CNS vasculitis with
intracerebral hemorrhage, and its diagnostic and therapeutic
implications. Also, neurosurgeons should consider the possi-
bility of drug-induced vasculitis when faced with cases of
intracerebral or subarachnoid hemorrhage without apparent
cause.

Received for publication, November 10, 1986: accepted, December
21, 1986.

Reprint requests: Dr. Roberta Glick, Department of Neurosurgery,
Cook County Hospital, 1835 West Harrison, Chicago, Illinois 60612.

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