Infect Dis Clin N Am 16 (2002) 589605

Central nervous system infections

in injection drug users
Allan R. Tunkel, MD, PhD*,
Sandeep K. Pradhan, MD
Division of Infectious Diseases, MCP Hahnemann University,
3300 Henry Avenue, Philadelphia, PA 19129, USA

Injection drug users are at risk of developing numerous infectious and

noninfectious CNS complications. The injected drugs may be diluted with
various agents, and drug paraphernalia may be treated without attention
to aseptic technique, exposing the user to a wide variety of microorganisms.
Because injection drug users may also be infected with HIV, CNS disease in
these patients may be related to various opportunistic infections not directly
related to the use of injected drugs. The clinical manifestations of CNS
involvement may be masked or altered by the psychotropic eects of the
injected drugs (eg, coma caused by overdose or intoxication), and patients
may also have concomitant head trauma. Thus, the dierential diagnosis of
CNS disease in the injection drug user is challenging and frequently dicult.
When considering the gamut of CNS infections that may occur in injection drug users, it is useful to separate various infectious agents based on
their association with certain conditions. This article focuses primarily on
the CNS complications of infective endocarditis but also reviews the CNS
manifestations of focal neurologic infections (ie, brain abscess and spinal
epidural abscess) and various toxin-mediated diseases which may aect
these patients.

Infective endocarditis
Epidemiology and etiology
The association between infective endocarditis and CNS complications
has been recognized for more than a century [14]. Despite changes in

* E-mail address: allan.tunkel@drexel.edu

0891-5520/02/$ - see front matter 2002, Elsevier Science (USA). All rights reserved.
PII: S 0 8 9 1 - 5 5 2 0 ( 0 2 ) 0 0 0 1 5 - 6

590

A.R. Tunkel, S.K. Pradhan / Infect Dis Clin N Am 16 (2002) 589605

epidemiology (specically the increase in illicit drug use), diagnostic tools

(introduction of echocardiography), and treatment (introduction of antimicrobial agents and cardiac valve replacement), the incidence of neurologic
complications in patients with infective endocarditis has remained essentially
unchanged, ranging from 20% to 40%. In one comprehensive review of
the records of 218 patients with infective endocarditis at the Massachusetts
General Hospital from 1964 to 1973 [5], 84 patients (39%) experienced clinically apparent neurologic complications. The incidence of CNS involvement in patients with infective endocarditis has been reported to be even
higher in series primarily examining neurologic complications and in autopsy studies, because neurologic events often contribute to death [6]. In one
autopsy series of 69 cases, cerebral emboli were found in 46% of all cases
and in up to two thirds of young adults with infective endocarditis [7].
Neurologic complications are most frequently observed in patients with
left-sided infective endocarditis, and valvular location may inuence the
occurrence of neurologic events [5,810]. In one study, [5] 52% of patients
with mitral valve involvement presented with neurologic complications,
compared with only 28% of patients with aortic valve involvement. Another
study, however, found that patients with aortic valve endocarditis, especially
when caused by staphylococci and associated with congestive heart failure,
were at increased risk for cerebral embolization [1]. The incidence of neurologic complications is much lower in patients with right-sided endocarditis
[1113]. Complications, when they do occur, usually present as meningitis,
cerebral abscesses, or encephalopathy, and are related to the presence of
highly virulent organisms (eg, Staphylococcus aureus or Streptococcus pneumoniae) [14]. Systemic embolization can also occur from septic emboli found
in the pulmonary veins, through a patent foramen ovale, or through a pulmonary arteriovenous stula [4,7,15,16].
The frequency of CNS manifestations in injection drug users with infective endocarditis is somewhat dierent from that in nondrug users because
injection drug users are at specic risk of infection of the tricuspid valve. In
injection drug users with left-sided infective endocarditis the incidence of
neurologic complications ranges from 45% to 58%, higher than in nondrug
users [4,17,18]. This higher incidence may result, in part, from the failure of
injection drug users to complete a full course of antimicrobial therapy or
from the diering distribution of infective agents (ie, a higher incidence of
endocarditis caused by S. aureus). In contrast, another study found that
among episodes of S. aureus endocarditis involving the mitral or aortic
valves, injection drug users tend to have fewer strokes (18%) than patients
who do not use drugs (32%) [19]. In injection drug users with isolated
right-sided endocarditis, neurologic involvement is rare, occurring in only
1 of 28 patients with tricuspid valve endocarditis in one study [20] and in
none of 21 patients in another study [21].
The rate, type, and severity of neurologic complications in patients with
infective endocarditis may be aected by the causative agent. Endocarditis

A.R. Tunkel, S.K. Pradhan / Infect Dis Clin N Am 16 (2002) 589605

591

caused by S. aureus is more common in injection drug users than in non

drug users. In published reviews, the frequency of CNS involvement in
patients with endocarditis caused by S. aureus has ranged from 53% to
71%, signicantly higher than the rates of CNS involvement seen in endocarditis caused by other bacteria (eg, enterococci, group D streptococci,
or nongroup D streptococci) [1,5,9,10]. In a review of 178 episodes of
community-acquired native valve endocarditis [8], a neurologic presentation
occurred in 54% of cases of staphylococcal endocarditis but in only 19% of
cases of viridans and enterococcal endocarditis. In another review of neurologic complications in 175 patients with infective endocarditis (113 with
native valves and 62 with prosthetic valves), patients with infection caused
by S. aureus had a signicantly higher incidence of neurologic sequelae and
death. Bacteria such as the Enterobacteriaceae have also been associated
with a high rate of neurologic complications [5].
Other microorganisms may also be associated with specic neurologic complications in patients with infective endocarditis. Although S. pneumoniae
is a rare cause of infective endocarditis (occurring in 1% to 3% of cases),
associated meningitis is frequent (seen in 57% to 91% of cases) [4,22]. Purulent meningitis and brain abscess may also be seen in endocarditis caused by
S. aureus [23]. Microorganisms, such as fungi, have been associated with the
presence of large vegetations with enhanced embolic potential. In one series
of 27 patients with Aspergillus endocarditis, cerebral emboli were recorded
in 11 cases [24].
Pathogenesis
Neurologic complications in patients with infective endocarditis may be
caused by embolization from endocardial vegetations with occlusion of large
or small cerebral arteries; by infection of the brain, meninges, or wall of
cerebral arteries following septic embolization or bacteremia; or by toxic or
immune-mediated injury [4,25,26]. The CNS complications of infective
endocarditis result most commonly from emboli, both septic and bland,
which may aect a single vessel or many vessels. The resultant lesions may
be ischemic or suppurative, resulting in septic or aseptic meningitis, brain
abscess, or encephalopathy [27].
Intracranial mycotic aneurysms may result from septic cerebral embolization that produces inammatory destruction of the intraluminal arterial wall
and subsequent outward penetration of infection. Alternately, infected
embolic material may reach the adventitial layer of an artery through the
vasa vasorum; the resulting destruction of the adventitia and muscularis
results in aneurysmal dilatation [4,25,28]. Most authorities believe that most
mycotic aneurysms are caused by embolus to the vasa vasorum. Factors that
may determine the particular manifestations of these lesions include the site
where the embolus lodges, the microbial load and virulence, and the interval
between the embolism and initiation of antimicrobial therapy.

592

A.R. Tunkel, S.K. Pradhan / Infect Dis Clin N Am 16 (2002) 589605

Clinical presentation
Cerebral embolism is one of the most common CNS presentations in
patients with infective endocarditis, with cerebral infarction aecting 6%
to 31% of patients with endocarditis [46,25,29]. In a retrospective review
of 212 episodes of infective endocarditis in 203 patients, 12% were complicated by stroke [19]; most ischemic strokes (74%) occurred at the time of
presentation, and an additional 13% occurred within the rst 48 hours. In
contrast, in a series from Detroit, which identied 74 cases of infective endocarditis among 180 addicts with bacteremia [12], only 2 of 45 patients with
S. aureus endocarditis had cerebral embolism. The clinical presentation of
cerebral embolism depends on the area of the CNS involved [4,6,25,27].
More than 90% of large emboli lodge in the middle cerebral artery, manifesting as contralateral hemiparesis and a hemisensory decit. Parietal-lobe
signs (eg, sensory loss, neglect, dyspraxia, hemianopia, aphasia) may also be
evident. Emboli to the branches of the anterior or posterior cerebral artery
may involve the lower extremities. Posterior cerebral artery occlusion may
also produce homonymous hemianopia. Lesions of the basal ganglia may
produce signs of Parkinsonism or chorea. In addition, multiple microemboli
may occur resulting in punctate cerebral infarctions and producing a more
diuse clinical syndrome, manifested clinically as an altered level of consciousness, seizures, or uctuating neurologic signs. Microscopic infarcts
may also remain clinically silent and be recognized only at autopsy.
Intracranial mycotic aneurysms are recognized clinically in about 2% of
patients with infective endocarditis and at autopsy in 5% to 10% of cases
[4,6,25]. In one study, 16 of 218 patients with endocarditis were diagnosed
as having cerebral mycotic aneurysms [5]. Six of these 16 patients died from
intracranial hemorrhage within 3 weeks of the onset of symptoms of infective endocarditis. In most of these patients the aneurysm was within the distribution of the middle cerebral artery. Symptoms of an intracranial mycotic
aneurysm usually are not evident unless the aneurysm ruptures or enlarges
before rupture and may manifest as compromised cranial nerve function or
as a premorbid phase with headache or nuchal rigidity. In a series from the
Mayo Clinic [30], all eight patients with intracranial mycotic aneurysm complained of severe, unremitting, localized headache. Aneurysm rupture is life
threatening, producing subarachnoid hemorrhage, intracerebral hemorrhage, or direct intracranial destruction of the brain.
Brain abscesses are rarely associated with endocarditis. The frequency of
macroscopic brain abscesses is only 0.5%, although small brain abscesses
(smaller than 1 cm in diameter) occur in 0.9% to 3.8% of patients with endocarditis [4,25]. One study of complications of endocarditis found evidence of
brain abscess in 4.1% of the 218 patients studied [5]. All the abscesses were
post mortem diagnoses; most were microscopic, multiple, and not associated
with neurologic ndings. The clinical picture of brain abscess is variable and
depends upon the intracranial location of the abscess.

A.R. Tunkel, S.K. Pradhan / Infect Dis Clin N Am 16 (2002) 589605

593

Meningitis is seen in about 7% of patients with infective endocarditis,

although this complication seems to be more common in cases in which
S. aureus or S. pneumoniae is isolated [4,8,25]. The clinical presentation of
meningismus may be caused by invasion of the meninges by the microorganism or by underlying processes such as abscess, leaking mycotic aneurysm,
subarachnoid hemorrhage, cerebral infarction, or vasculitis.
Other neurologic manifestations of infective endocarditis include encephalopathy (manifested as impaired concentration, irritability, drowsiness,
vertigo, or lethargy), seizures (resulting from cerebral infarction or hemorrhage or associated with hypoxia, metabolic imbalances, or drug toxicity),
and headache [4,25]. Mild, intermittent, diuse headache occurs in 25% to
43% of patients with infective endocarditis [30,31]. Severe headache occurs
in only about 3% of cases [30,32] but may indicate disastrous complications
such as an intracranial mycotic aneurysm.
Diagnosis
Neuroimaging
Computed tomographic (CT) scanning is a useful diagnostic modality for
the evaluation and management of patients with infective endocarditis and
neurologic manifestations [5,25]. In one study in which 51 scans were performed in 64 patients with neurologic ndings, 25 scans were abnormal
[10]. Computed tomographic scanning is especially helpful when cerebral
embolization is suspected, both in dierential diagnosis and in distinguishing between hemorrhagic and nonhemorrhagic infarctions. Computed
tomographic scans may also be useful in selecting patients who should have
cerebral angiography to rule out the possibility of intracranial mycotic
aneurysm. In a study of 34 patients with infective endocarditis and neurologic manifestations, the 14 patients with a normal CT scan had no mycotic
aneurysm, whereas aneurysms were found in 11 of the 20 patients with
abnormal CT ndings [33]. Although this study suggests that an intracranial
mycotic aneurysm is unlikely when the CT scan is normal, further studies
are needed to determine the reliability of this observation. Computed tomographic scanning may localize the intracranial mycotic aneurysm directly or
demonstrate adjacent hematoma and delineate the extent of hemorrhage.
Computed tomographic scanning is also useful for demonstrating cerebral
abscesses, although this modality may not detect small abscesses or the presence of cerebritis.
The role of MR imaging and MR angiography continues to evolve [34].
Magnetic resonance imaging is the procedure of choice for the diagnosis of
brain abscess and is also promising for the diagnosis of cerebritis and microinfarcts that cannot be detected by CT scanning [35]. Magnetic resonance
angiography combined with MR imaging seems to have a sensitivity of
86% and a specicity of 100% for intracranial mycotic aneurysms larger
than 3 mm in diameter [36]. In patients with severe and persistent localized

594

A.R. Tunkel, S.K. Pradhan / Infect Dis Clin N Am 16 (2002) 589605

headache, MR angiography should be performed to look for intracranial

mycotic aneurysm, even if CT and MR imaging studies are negative [25].
Cerebral angiography, however, is the only reliable means to establish the
diagnosis and to localize intracranial mycotic aneurysm. In patients with
an abnormal imaging study or neurologic abnormality, angiography is indicated as early as possible to look for evidence of an intracranial mycotic
aneurysm [37,38]. All four vessels (internal carotid and vertebral arteries)
should be examined, because multiple aneurysms are common [33]. Initial
angiograms may not disclose a mycotic aneurysm, however, because aneurysms may not develop until 7 to 10 days after the onset of focal neurologic
symptoms; therefore, an aneurysm may not be discovered until a second
angiographic study or at autopsy [4].
Lumbar puncture
Cerebrospinal uid (CSF) examination has been performed in a number
of patients with infective endocarditis and neurologic symptoms [4,25]. In
one study, CSF examination revealed abnormalities in 48 of 69 patients with
neurologic complications of infective endocarditis who underwent lumbar
puncture [5]. Purulent CSF with neutrophilic pleocytosis and with elevated
protein, with or without reduced glucose, was seen in 28% of cases; an
aseptic CSF with lymphocytic pleocytosis, normal glucose, and normal or
slightly elevated protein was seen in 25% of cases; and a hemorrhagic CSF
was seen in 13% of cases. In 30% of patients, analysis showed normal CSF.
There was no correlation between neurologic event and CSF pattern,
although purulent CSF was more commonly seen in patients with meningeal
signs. Positive CSF cultures were demonstrated in only 11 patients (8 with
S. aureus infection), all of whom had purulent CSF.
Echocardiography
Echocardiography is a useful diagnostic modality in patients with infective endocarditis [39]. Vegetations seen on echocardiography, however, seem
not to be predictive of neurologic complications. Valvular vegetations were
seen in 37% of patients with neurologic manifestations and in 28% of
patients without neurologic manifestations [10,40]. In patients who developed neurologic complications after initiation of antimicrobial therapy,
56% had valvular vegetations seen on initial echocardiography. In a more
recent study [41], vegetations were detected somewhat more often in patients
who experienced episodes of neurologic complications than in those without
neurologic complications (53% versus 45%, respectively).
Management
Antimicrobial therapy
Recommendations for specic antimicrobial therapy directed at various
microorganisms causing infective endocarditis are beyond the scope of this

A.R. Tunkel, S.K. Pradhan / Infect Dis Clin N Am 16 (2002) 589605

595

article. Several reports have examined the timing of stroke events in patients
with infective endocarditis and the relation of these events to initiation
of antimicrobial therapy [42]. Most cerebral emboli occur in the setting of
uncontrolled infection, and the initiation of antimicrobial therapy is temporally associated with a sharp reduction in the number of embolic events.
Stroke, however, is often a presenting feature of infective endocarditis. In
one study of 55 neurologic episodes in 218 patients with infective endocarditis [41], the neurologic manifestation was evident in 76% of episodes
before initiation of antimicrobial therapy and was the rst manifestation
in 47% of episodes.
The natural history of intracranial mycotic aneurysms treated with
antimicrobial therapy is not known. A large proportion of unruptured
peripheral intracranial mycotic aneurysms, proximal intracranial mycotic
aneurysms, and aneurysms of the cavernous sinus may resolve under appropriate antimicrobial therapy [38,43,44], leading some authors to recommend
careful clinical follow up and repeat imaging scans and angiography within
7 to 14 days for unruptured intracranial mycotic aneurysms [44]. In one
study of 27 patients who underwent repeat angiography during antimicrobial therapy [44], the lesion completely disappeared in 8 patients, decreased
in size in 5 patients, did not change in 4 patients, and became larger in 6
patients. A new aneurysm was found in 4 patients. In another study, small
intracranial mycotic aneurysms disappeared or regressed in 17 of 21 patients
receiving antibiotic therapy [43].
Neurosurgery
Given the variable outcome with antimicrobial therapy in patients with
intracranial mycotic aneurysms, optimal management may require a combined medical and surgical approach [30,4547]. Patients should undergo
neurosurgery for ruptured aneurysms of the peripheral cerebral arteries and
when intracranial hematoma or mass-producing aneurysms are present. A
single aneurysm peripheral to the rst bifurcation should be followed with
frequent serial angiograms. Some authors suggest an aggressive surgical
approach, particularly for easily accessible peripheral intracranial mycotic
aneurysms [25,38,45,48]. Standard surgical technique includes ligation of the
aected arterial segment followed by excision of the necrotic aneurysm and
the adjacent vessel wall [30,49]. When the location of the aneurysm is at a
site where a new neurologic decit is likely to be introduced by neurosurgery
(eg, proximal to the rst bifurcation), a surgical approach must be carefully
weighed. Initial antimicrobial therapy may facilitate arteritis resolution with
subsequent development of brosis in the aneurysm wall and parent vessels,
allowing a safer handling of the lesion at surgery [30]. If an aneurysm does
not disappear after antimicrobial therapy, or if it enlarges or bleeds, it
should be promptly resected if feasible. In patients whose general condition
precludes surgery, a minimally invasive endovascular approach is used
to embolize the aneurysm [50]. The situation in patients with multiple

596

A.R. Tunkel, S.K. Pradhan / Infect Dis Clin N Am 16 (2002) 589605

intracranial mycotic aneurysms is more complex, and management must be

individualized. In a review of 15 patients with aneurysms of multiple causes,
11 patients were treated nonsurgically, and none of the patients died [37]. In
another series of 10 endocarditis patients with multiple aneurysms [44], 7
received antimicrobial therapy alone, and only 1 died. If one or more aneurysms enlarges or bleeds, prompt surgical excision should be performed,
with other aneurysms resected based on their accessibility.
Anticoagulation therapy
The use of anticoagulants to prevent cerebral embolism in patients with
infective endocarditis has been the subject of debate. Initial studies suggested that the use of anticoagulants in patients with infective endocarditis
was associated with a high frequency of cerebral hemorrhage, without prevention of major embolic episodes [4]. In an experimental animal model of
septic brain embolism, anticoagulation therapy was associated with an
increased risk of hemorrhage [51]. In a retrospective review of patients with
endocarditis and with neurologic complications, three of seven patients
(43%) treated with anticoagulant therapy developed major intracranial hemorrhage, compared with only 10 of 211 patients (4.7%) who did not receive
anticoagulants [5]. Although some authors have used anticoagulants to prevent recurrent emboli in patients with infective endocarditis [18], the routine
use of anticoagulation therapy is not recommended in patients with nativevalve endocarditis [52]. Patients with infective endocarditis who have other
indications for anticoagulation therapy (eg, mitral valve disease, atrial brillation, or prosthetic cardiac valves) should continue to receive appropriate
anticoagulation therapy, cautiously monitored [53].
Focal central nervous system infections
Although focal CNS infection more commonly occurs in injection drug
users with infective endocarditis and resultant embolization of infected
vegetations (as discussed previously), focal infections within the CNS may
occur in injection drug users in the absence of evidence of infective endocarditis and in those who are infected with HIV. Brain abscess and spinal
epidural abscess are reviewed here.
Brain abscess
Brain abscess is one of the most serious infections of the CNS. Before the
advent of HIV, brain abscess accounted for about 1 in 10,000 hospital
admissions, with 1500 to 2500 patients treated each year in the United States
[54]. Microorganisms can reach the brain by several dierent mechanisms
[5458]. The most common pathogenic mechanism of brain abscess formation is spread from a contiguous focus of infection (ie, from the middle ear,
mastoid cells, or paranasal sinuses). A second mechanism is hematogenous
dissemination to the brain from a distant focus of infection such as chronic

A.R. Tunkel, S.K. Pradhan / Infect Dis Clin N Am 16 (2002) 589605

597

pyogenic lung disease, wound or skin infection, osteomyelitis, pelvic infection, intra-abdominal infection, and in patients with infective endocarditis.
Trauma is a third pathogenic mechanism, resulting from an open cranial
fracture, neurosurgery, or foreign-body injury. Brain abscess is cryptogenic
in about 20% of cases.
The frequency with which various microorganisms are isolated from
brain abscesses depends upon the predisposing condition [54,56,58]. In injection drug users without infective endocarditis who develop a brain abscess,
bacterial causes have included S. aureus and Nocardia spp [59,60]. Fungal
brain abscesses (caused by Aspergillus species, Chaetomium strumarium,
and the agents of mucormycosis) have also been reported [6165]. In addition, injection drug users who are infected with HIV may develop brain
abscesses caused by Toxoplasma gondii, Nocardia spp, Mycobacterium spp
(especially M. tuberculosis), Listeria monocytogenes, and Cryptococcus
neoformans [59,60,6670].
The clinical presentation of brain abscess depends on the intracranial
location of the lesion [54,56,58]. Headache is the most common presenting
symptom, observed in about 70% of patients. Sudden worsening of the
headache, accompanied by new-onset meningismus, may signify rupture
of the abscess into the ventricular space. Less than 50% of patients with
brain abscess present with the classic triad of fever, headache, and focal neurologic decit. Certain pathogens may lead to the development of specic
clinical characteristics after CNS infection. The clinical suspicion of nocardial brain abscess may be increased by the presence of pulmonary, skin, or
muscle lesions. Patients with Aspergillus brain abscess most commonly manifest signs of a stroke syndrome referable to the involved area of brain [64];
these patients often have evidence of aspergillosis involving other organ systems. More than half the patients with nonrhinocerbral brain abscess caused
by the agents of mucormycosis have fever, headache, or focal neurologic
decits; in one review of 22 cases, 50% of the patients were injection drug
users, and the basal ganglia were the most commonly involved CNS site
(in 83% of patients) [65].
Computed tomographic scanning has revolutionized the diagnosis of
brain abscess [54,58]. Before the advent of CT, case fatality rates of brain
abscess ranged from 30% to 60%; after CT, the overall mortality rate has
ranged from 0 to 24%. In patients with brain abscesses, CT scans typically
show a lesion with a hypodense center and a peripheral ring of uniform
enhancement following the intravenous injection of contrast material. Magnetic resonance imaging oers signicant advantages over CT in the early
detection of cerebritis, cerebral edema, and satellite lesions and is now the
diagnostic imaging procedure of choice in the diagnosis of brain abscess.
A major advance in investigating suspected brain abscess is the use of
stereotactic CT-guided aspiration to facilitate microbiologic diagnosis and
to guide antimicrobial therapy [54]. At the time of aspiration, specimens
should be sent for gram staining, routine aerobic and anaerobic cultures,

598

A.R. Tunkel, S.K. Pradhan / Infect Dis Clin N Am 16 (2002) 589605

and smears and cultures for mycobacteria, Nocardia spp, and fungi. Once
abscess material has been obtained for microbiologic and histopathologic
studies, empiric antimicrobial therapy should be initiated based on the
patients underlying condition and the presumed cause of brain abscess.
After an infecting pathogen has been isolated, antimicrobial therapy can
be modied for optimal treatment.
Most patients with brain abscess, however, also require surgical management for optimal results [54,71]. In patients with bacterial brain abscess, all
lesions greater than 2.5 cm in diameter should be excised or stereotactically
aspirated. In patients with brain abscess caused by Aspergillus spp or by
agents of mucormycosis, the importance of surgery cannot be overemphasized. Because of the propensity of these organisms to invade blood
vessels and cause tissue infarction (which impairs the delivery of antifungal
agents to the site of infection), surgery is essential to eliminate the invading
microorganisms.
Spinal epidural abscess
Spinal epidural abscess usually results from hematogenous dissemination
of infection from infected foci elsewhere to the epidural space or by direct
extension in patients with vertebral osteomyelitis [72,73]. Blunt spinal trauma
(a history obtained in up to 30% of patients) may provide a devitalized
site that is susceptible to infection following transient bacteremia [74], as
may be seen in patients who inject drugs [75]. The likely infecting microorganisms are staphylococci, streptococci, and aerobic gram-negative bacilli;
S. aureus and gram-negative bacilli must be considered likely pathogens in
injection drug users. Spinal epidural abscess caused by M. tuberculosis may
also be seen, especially in patients who are coinfected with HIV.
Spinal epidural abscess may present clinically as a rapidly developing syndrome, manifesting within hours following hematogenous dissemination.
Alternately, the presentation may pursue a chronic course (eg, when associated with vertebral osteomyelitis) [72,73,76,77]. Patients initially have focal
vertebral pain; followed by root pain; decits of motor, sensory, or sphincter
function; and nally paralysis [78]. If the cervical spinal cord is involved, respiratory function may also be compromised. Magnetic resonance imaging is
the diagnostic procedure of choice in spinal epidural abscess because it can
visualize the spinal cord and epidural space in both sagittal and transverse
planes and can identify accompanying osteomyelitis, intramedullary spinal
cord lesions, and joint space infection [76].
Pending culture results, presumptive antimicrobial therapy in the injection drug user with a spinal epidural abscess must include an antistaphylococcal agent (either vancomycin or nafcillin) and antimicrobial treatment
directed against aerobic gram-negative bacilli (including Pseudomonas
aeruginosa) [73,76]. Emergent surgical laminectomy with decompression
and drainage may also be required to minimize the likelihood of permanent

A.R. Tunkel, S.K. Pradhan / Infect Dis Clin N Am 16 (2002) 589605

599

neurologic injury. Some patients (ie, those with an unacceptably high surgical
risk or those without neurologic decits) may be treated with antimicrobial
therapy alone [79], although these patients must be followed carefully for
clinical deterioration or radiologic progression [80].
Toxin-mediated diseases
Injection drug users who, because of poor venous access, inject drugs
either intramuscularly or subcutaneously are at risk of developing toxinmediated diseases (eg, tetanus and wound botulism) that have signicant
neurologic manifestations. These toxin-mediated diseases result after inoculation of Clostridium spp at the injection sites; in the proper anaerobic environment, toxin is generated and produces disease [81]. These organisms may
be present in the drug, in diluent, on paraphernalia, or on the colonized skin
before injection.
Tetanus
The worldwide incidence of tetanus is about 1 million cases annually
[82,83], with acute injuries accounting for about 70% of the reported cases
in the United States. Injection drug users are exposed to a signicant risk
of developing tetanus [84]. Of 67 cases of tetanus reported in California
from 1987 to 1997, a total of 27 (40%) occurred in injection drug users
[85]; of these, 24 (89%) cases were in Hispanics. Subcutaneous injection
(skin popping) is highly associated with the development of tetanus,
creating lesions with an environment conducive to toxin production. Narcotic
addicts seem to develop particularly severe tetanus [86], a predisposition
that may be related to the number and severity of skin lesions that provide
a greater opportunity for large amounts of toxin to be produced. Misdiagnosis may also delay appropriate therapy in these patients. Tetanus is
reported to local and state health departments through a passive reporting
system and is, therefore, probably an underreported disease.
Clostridium tetani is a slender, obligate anaerobic bacillus that sporulates
to form a spherical terminal spore that can survive indenitely [82,83]. These
spores germinate after introduction into a wound and multiply under appropriate conditions with a low redox potential. Clostridium tetani produces a
plasmid-borne exotoxin called tetanospasmin. Tetanospasmin reaches the
CNS retrogradely, predominantly through alpha motor neurons, and then
migrates into presynaptic inhibitory neurons. Clinical manifestations are a
consequence of tetanospasmin-mediated inhibition of neurotransmitter release at these presynaptic terminals. In the absence of such central inhibitory
control, the motor system generates intense, sustained muscular spasms [82,83].
The clinical manifestations of tetanus may be local, cephalic, or generalized [82,83]. Trismus (lock-jaw), risus sardonicus, and opisthotonus are
some of the most commonly recognized manifestations of this disease.

600

A.R. Tunkel, S.K. Pradhan / Infect Dis Clin N Am 16 (2002) 589605

Localized tetanus may be characterized by rigidity of muscles, pain, and

enhanced deep tendon reexes. Dysphagia, facial paresis, and Horners syndrome have also been reported [8789]. Respiratory failure, airway obstruction caused by spasms, and autonomic dysfunction can lead to death.
The diagnosis of tetanus remains a clinical one that is easily recognized if
highly suspected in any individual patient [82,83]. Clinical laboratory tests
are used only to exclude other intoxications that may mimic tetanus and
to determine an individual patients immunity. Most clinical laboratories
have limited anaerobic culturing capabilities, and even carefully performed
anaerobic cultures are frequently negative. Furthermore, a positive culture
does not indicate that the isolate is toxigenic. Tetanus may be present without disease in patients with adequate specic immunity.
Patients with generalized tetanus require care that is best provided in a
well-equipped intensive care unit. Neutralization of tetanospasmin that has
not entered the nervous system is important to reduce the severity and duration of the illness. This neutralization is achieved using human tetanus
immune globulin (HTIG). A dose of 500 IU administered intramuscularly
seems to be as eective as larger doses [90]. Although some authors have
suggested intrathecal administration of specic immunoglobulin in patients
with tetanus, a meta-analysis concluded that intrathecal administration of
HTIG is not more ecacious than parenteral administration [91]. Clostridium
tetani is sensitive in vitro to metronidazole, penicillins, cephalosporins,
imipenem, macrolides, and tetracyclines [82,83]. Although the usefulness
of antimicrobial therapy for treatment of what is essentially an intoxication
has been questioned, many authorities have recommended antimicrobial
therapy with penicillin. Penicillin, however, may act synergistically with
tetanospasmin to worsen spasms. One human study that compared metronidazole (500 mg orally every 6 hours) with penicillin (1.5 million units
intramuscularly every 8 hours) demonstrated that patients treated with metronidazole had less progression of disease, shorter hospitalization, and better survival rates [92]. Although this result may reect a true advantage of
metronidazole over penicillin, it more likely corresponds to a negative eect
of penicillin, which is a known antagonist of c-aminobutyric acid (GABA).
Active immunization, as advised by the Advisory Committee on Immunization Practices, and routine booster doses every 10 years with tetanus toxoid
is standard preventive care. Patients with tetanus who are treated with
HTIG should also receive active immunization to prevent recurrent disease,
because the amount of toxin produced in patients with disease may be too
small to be immunogenic. Every opportunity should be used to immunize
injection drug users against tetanus.
Botulism
Wound botulism associated with the use of injected drugs was rst
reported in New York in 1982 and in California in 1988 [93]. In a review

A.R. Tunkel, S.K. Pradhan / Infect Dis Clin N Am 16 (2002) 589605

601

of 47 laboratory-conrmed cases of wound botulism, 9 cases were associated

with injected drug use [94]. Of 49 cases of wound botulism reported in
California from 1988 through 1995, 46 were associated with injected drug
use [95]. A case control study of injection drug users who developed wound
botulism from 1994 through 1996 identied the use of black tar heroin (a
black, gummy form of the drug that is synthesized in Mexico) as the primary
risk factor for acquisition [81]. Most cases have been associated with Clostridium botulinum infection developing at the site of drug injection, which then
causes botulism by producing neurotoxins. Clostridium botulinum produces
one of seven dierent protein neurotoxins. The neurotoxin is absorbed systemically and binds irreversibly to receptors at neuromuscular junctions,
manifesting as the clinical syndrome of wound botulism.
The incubation period of wound botulism is about 4 to 18 days [96].
Because wound botulism results from an infected wound, fever may be
present. Initial neurologic symptoms are blurred vision, diplopia, dysarthria, and dysphagia. Muscle weakness then progresses in a descending
fashion and can lead to respiratory failure. Wound botulism is essentially
similar to food-borne botulism, but gastrointestinal symptoms (ie, nausea,
vomiting, and diarrhea) do not occur [97].
The clinical features of descending paralysis in injection drug users should
arouse suspicion of wound botulism. Identication of the toxin and identication of the organisms by gram stain and culture assist in the diagnosis.
The only reliable method for identication of the toxin is the mouse bioassay [97], which can be performed in state health laboratories and through
the Centers for Disease Control and Prevention. Electromyography may
also be helpful in conrming the diagnosis.
The cornerstone of therapy in this paralyzing illness is meticulous supportive care [97]. After testing for hypersensitivity, trivalent antitoxin of equine
origin may be administered as a single intravenous dose. After antitoxin
administration, wound debridement should be performed to remove the
focus of infection. High-dose intravenous penicillin (10 to 20 million units
per day) is generally given, although its ecacy is not well documented.
Summary
Central nervous system infections in injection drug users are often devastating in terms of excess morbidity and mortality. In injection drug users
with infective endocarditis, embolization from infected valvular vegetations
may cause cerebral infarction, intracranial hemorrhage, and the formation
of brain abscess. Focal intracranial infections (ie, brain abscess and spinal
epidural abscess) may occur in the absence of infective endocarditis, resulting from bacteremia that seeds the brain or epidural space. Antimicrobial
therapy, combined with surgical intervention, may be essential to improve
outcome from these neurologic complications. Toxin-mediated diseases
(especially tetanus and wound botulism) are also seen in injection drug

602

A.R. Tunkel, S.K. Pradhan / Infect Dis Clin N Am 16 (2002) 589605

users. Inoculation of Clostridium spp at injection sites may lead to toxin

generation and disease. Clinicians must maintain a high level of suspicion
for these diagnoses in injection drug users.
References
[1] Garvey GJ, Neu HC. Infective endocarditis an evolving disease. Medicine (Baltimore)
1978;57:10527.
[2] Jones Jr. HR, Siekert RG. Neurological manifestations of infective endocarditis. Review of
clinical and therapeutic challenges. Brain 1989;112:1295315.
[3] Salgado AV. Central nervous system complications of infective endocarditis. Stroke
1991;22:14613.
[4] Tunkel AR, Kaye D. Neurologic complications of infective endocarditis. Neurol Clin
1993;11:41940.
[5] Pruitt AA, Rubin RH, Karchmer AW, et al. Neurologic complications of bacterial
endocarditis. Medicine (Baltimore) 1978;57:32943.
[6] Lerner PI. Neurologic complications of infective endocarditis. Med Clin North Am 1985;
69:38598.
[7] Kane WC, Aronson SM. Cardiac disorders predisposing to embolic stroke. Stroke 1970;
1:16472.
[8] Gransden WR, Eykyn SJ, Leach RM. Neurological presentations of native valve
endocarditis. QJ M 1989;73:113542.
[9] Le Cam B, Guivarch G, Boles JM, et al. Neurologic complications in a group of 86
bacterial endocarditis patients. Eur Heart J 1984;5(Suppl C):97100.
[10] Salgado AV, Furlan AJ, Keys TF, et al. Neurologic complications of endocarditis:
a 12-year experience. Neurology 1989;39:1738.
[11] Hubbel G, Cheitlin MD, Rapaport E. Presentation, management, and follow-up
evaluation of infective endocarditis in drug addicts. Am Heart J 1981;102:8594.
[12] Levine DP, Crane LR, Zervos MJ. Bacteremia in narcotic addicts at the Detroit Medical
Center. II. infectious endocarditis: a prospective comparative study. Rev Infect Dis 1986;
8:37496.
[13] Openshaw H. Neurological complications of endocarditis in persons taking drugs
intravenously. West J Med 1976;124:27681.
[14] Roberts WC, Buchbinder NA. Right-sided infective endocarditis. A clinicopathologic study
of twelve necropsy patients. Am J Med 1972;53:719.
[15] Menda KB, Gorbach SL. Favorable experience with bacterial endocarditis in heroin
addicts. Ann Intern Med 1973;78:2532.
[16] Stagaman DJ, Presti C, Rees C, et al. Septic pulmonary arteriovenous stula: an unusual conduit for systemic embolization in right-sided valvular endocarditis. Chest 1990;
97:1484.
[17] Dreyer NP, Fields BN. Heroin-associated infective endocarditis. A report of 28 cases.
Ann Intern Med 1973;78:699702.
[18] Naggar CZ, Forgacs P. Infective endocarditis: a challenging disease. Med Clin N Am
1986;70:127994.
[19] Hart RG, Foster JW, Luther MF, et al. Stroke in infective endocarditis. Stroke
1990;21:695700.
[20] Ramsey RG, Gunnar RM, Tobin Jr. JR. Endocarditis in the drug addicts. Am J Cardiol
1970;25:60818.
[21] Robbins MJ, Frater RWM, Soeiro RM, et al. Inuence of vegetation size on clinical
outcome of right-sided infective endocarditis. Am J Med 1986;80:16571.
[22] Powderly WG, Stanley SL, Medo G. Pneumococcal endocarditis: report of a series and
review of the literature. Rev Infect Dis 1986;8:78691.

A.R. Tunkel, S.K. Pradhan / Infect Dis Clin N Am 16 (2002) 589605

603

[23] Watanakunakorn C, Tan JS, Phair JP. Some salient features of Staphylococcus aureus
endocarditis. Am J Med 1973;54:47381.
[24] Woods GL, Wood RP, Shaw BW. Aspergillus endocarditis in patients without prior
cardiovascular surgery: report of a case in a liver transplant recipient and review. Rev
Infect Dis 1989;11:26372.
[25] Francioli PB. Complications of infective endocarditis. In: Scheld WM, Whitley RJ, Durack
DT, editors. Infections of the central nervous system. 2nd edition. Philadelphia (PA):
Lippincott-Raven; 1997. p. 52353.
[26] Siekert RG, Jones Jr. HR. Transient cerebral ischemic attacks associated with subacute
bacterial endocarditis. Stroke 1970;1:17893.
[27] Greenlee JE, Mandell GL. Neurologic manifestations of infective endocarditis: a review.
Stroke 1973;4:95863.
[28] Molinari GF, Smith I, Goldstein MN, et al. Pathogenesis of cerebral mycotic aneurysm.
Neurology 1973;23:32532.
[29] Kanter MC, Hart RG. Neurologic complications of infective endocarditis. Neurology
1991;41:101520.
[30] Wilson WR, Lie JT, Houser OW, et al. The management of patients with mycotic
aneurysm. Curr Clin Top Infect Dis 1981;2:15183.
[31] Bush M, Masferrer R, Teitel R, et al. Neurologic complications of infectious endocarditis.
BNI Q 1985;1:138.
[32] Jones Jr. HR, Siekert RG, Geraci JE. Neurologic manifestations of bacterial endocarditis.
Ann Intern Med 1969;71:218.
[33] Stilhart B, Aboulker J, Khouadja F, et al. Should the aneurysm of Oslers disease be
investigated and operated upon prior to hemorrhage?. Neurochirurgie 1986;32:4107.
[34] Huston J, Nichols DA, Luetmer PH, et al. Blinded prospective evaluation of sensitivity of
MR angiography to known intracranial aneurysms: importance of aneurysm size. AJNR
Am J Neuroradiol 1994;15:160714.
[35] Bertorini TE, Laster RE, Thompson BF, et al. Magnetic resonance imaging of the brain in
bacterial endocarditis. Arch Intern Med 1989;149:8157.
[36] Ross JS, Masaryk TJ, Modic MT, et al. Intracranial aneurysms: evaluation by MR
angiography. AJNR Am J Neuroradiol 1990;3:44955.
[37] Frazee JG, Cahan LD, Winter J. Bacterial intracranial aneurysms. J Neurosurg 1980;
53:63341.
[38] Moskowitz MA, Rosenbaum AE, Tyler HR. Angiographically monitored resolution of
cerebral mycotic aneurysms. Neurology 1974;24:11038.
[39] Steckelberg JM, Murphy JG, Ballard D, et al. Emboli in infective endocarditis: the
prognostic value of echocardiography. Ann Intern Med 1991;114:63540.
[40] Sharma S, Desi A, Kumar A, et al. Two dimensional echocardiographic documentation
of disappearance of mobile vegetations following fatal embolization. Indian Heart
1983;35:2479.
[41] Heiro M, Nikoskelainen J, Engblom E, et al. Neurologic manifestations of infective endocarditis. A 17-year experience in a teaching hospital in Finland. Arch Intern Med 2000;160:278187.
[42] Davenport J, Hart RG. Prosthetic valve endocarditis 19761987. Antibiotics, anticoagulation, and stroke. Stroke 1990;21:9939.
[43] Bingham WF. Treatment of mycotic intracranial aneurysms. J Neurosurg 1977;46:42837.
[44] Ojemann RG. Infectious intracranial aneurysms. In: Fein JM, Flamm ES, editors.
Cerebrovascular diseases. New York (NY): Springer-Verlag; 1985. p. 104760.
[45] Bohmfalk GL, Story JL, Wissinger AN, et al. Bacterial intracranial aneurysm. J Neurosurg
1978;48:36982.
[46] Morawetz RB, Karp RB. Evolution and resolution of intracranial bacterial (mycotic)
aneurysms. Neurosurgery 1984;15:439.
[47] Ojemann RG, New PFJ, Fleming TC. Intracranial aneurysms associated with bacterial
meningitis. Neurology 1966;16:12226.

604

A.R. Tunkel, S.K. Pradhan / Infect Dis Clin N Am 16 (2002) 589605

[48] Brust JCM, Dickinson PCT, Hughes JEO, et al. The diagnosis and treatment of cerebral
mycotic aneurysms. Ann Neurol 1990;27:23846.
[49] Roach MR, Drake CG. Ruptured cerebral aneurysms caused by micro-organisms. N Engl
J Med 1965;273:2404.
[50] Turtz AR, Yocom SS. Contemporary approaches to the management of neurosurgical
complications of infective endocarditis. Curr Infect Dis Rep 2001;3:33743.
[51] Foote RA, Reagan TJ, Sandok BA. Eects of anticoagulants in an animal model of septic
cerebral embolization. Stroke 1978;9:5739.
[52] Weinstein L. Life-threatening complications of infective endocarditis and their management. Arch Intern Med 1986;146:9537.
[53] Levine HJ, Pauker SG, Salzman EW. Antithrombotic therapy in valvular heart disease.
Chest 1989;95(Suppl 2):98S106S.
[54] Tunkel AR, Wispelwey B, Scheld WM. Brain abscess. In: Mandell GL, Bennett JE, Dolin
R, editors. Principles and practice of infectious diseases. 5th edition. Philadelphia (PA):
Churchill Livingstone; 2000. p. 101628.
[55] Chun CH, Johnson JD, Hofstetter M, et al. Brain abscess. A study of 45 consecutive cases.
Medicine (Baltimore) 1986;65:41531.
[56] Heilpern KL, Lorber B. Focal intracranial infections. Infect Dis Clin North Am 1996;
10:87998.
[57] Kaplan K. Brain abscess. Med Clin North Am 1985;69:34560.
[58] Mathisen GE, Johnson JP. Brain abscess. Clin Infect Dis 1997;25:763781.
[59] Holtz HA, Lavery DP, Kapila R. Actinomycetales infection in the acquired immunodeciency syndrome. Ann Intern Med 1985;102:2035.
[60] Kim J, Minamoto GY, Grieco MH. Nocardial infection as a complication of AIDS: report
of six cases and review. Rev Infect Dis 1991;13:6249.
[61] Abbott SP, Sigler L, McAleer R, et al. Fatal cerebral mycoses caused by the ascomycete
Chaetomium strumarium. J Clin Microbiol 1995;33:26928.
[62] Caplan LR, Chinnamma T, Banks G. Central nervous system complications of addiction
to Ts and blues. Neurology 1982;32:623.
[63] Hopkins RJ, Rothman M, Fiore A, et al. Cerebral mucormycosis associated with
intravenous drug use: three case reports and review. Clin Infect Dis 1994;19:11337.
[64] Sepkowitz K, Armstrong D. Space-occupying fungal lesions. In: Scheld WM, Whitley R,
Durack DT, editors. Infections of the central nervous system. 2nd edition. Philadelphia
(PA): Lippincott-Raven; 1997. p. 74162.
[65] Stave GM, Heimberger T, Kerkering TM. Zygomycosis of the basal ganglia in intravenous
drug users. Am J Med 1989;86:1157.
[66] Farrar DJ, Flanigan TP, Gordon NM, et al. Tuberculous brain abscess in a patient with
HIV infection: case report and review. Am J Med 1997;102:297301.
[67] Gordon SM, Blumberg HM. Mycobacterium kansasii brain abscess in a patient with AIDS.
Clin Infect Dis 1992;14:78990.
[68] Luft BJ, Remington JS. Toxoplasmic encephalitis in AIDS. Clin Infect Dis 1992;15:21122.
[69] Monno L, Carbonara S, Costa D, et al. Cerebral lesions in two patients with AIDS: the
possible role of Mycobacterium kansasii. Clin Infect Dis 1996;22:11301.
[70] Renold C, Sugar A, Chave JP, et al. Toxoplasma encephalitis in patients with acquired
immunodeciency syndrome. Medicine (Baltimore) 1992;71:22439.
[71] Mamelak AN, Mampalam TJ, Obana WG, et al. Improved management of multiple brain
abscesses: a combined surgical and medical approach. Neurosurgery 1995;36:7686.
[72] Baker AS, Ojemann RG, Swartz MN, et al. Spinal epidural abscess. N Engl J Med 1975;
293:4638.
[73] Danner RL, Hartman BJ. Update of spinal epidural abscess: 35 cases and review of the
literature. Rev Infect Dis 1987;9:26574.
[74] Nussbaum ES, Rigamonti D, Standiford H, et al. Spinal epidural abscess: a report of 40
cases and review. Surg Neurol 1992;38:22531.

A.R. Tunkel, S.K. Pradhan / Infect Dis Clin N Am 16 (2002) 589605

605

[75] Koppel BS, Tuchman AJ, Mangiardi JR, et al. Epidural spinal infection in intravenous
drug abusers. Arch Neurol 1988;45:1331.
[76] Gellin BG, Weingarten K, Camache Jr. FW, et al. Epidural abscess. In: Scheld WM,
Whitley RJ, Durack DT, editors. Infections of the central nervous system. 2nd edition.
Philadelphia (PA): Lippincott-Raven; 1997. p. 50722.
[77] Lasker BR, Harter DH. Cervical epidural abscess. Neurology 1987;37:174753.
[78] Darouiche RO, Hamill RJ, Greenbert SB, et al. Bacterial spinal epidural abscess. Review of
43 cases and literature survey. Medicine (Baltimore) 1992;71:36985.
[79] Wheeler D, Keiser P, Rigamonti D, et al. Medical management of spinal epidural abscess:
case report and review. Clin Infect Dis 1992;15:227.
[80] Baker AS, Ojemann RG, Baker RA. To decompress or not to decompress spinal epidural
abscess. Clin Infect Dis 1992;15:289.
[81] Passaro DJ, Werner SB, McGee J, et al. Wound botulism associated with black tar heroin
among injecting drug users. JAMA 1998;279:85963.
[82] Bleck TP. Tetanus. In: Mandell GL, Bennett JE, Dolin R, editors. Principles and practice of
infectious diseases. 5th edition. Philadelphia (PA): Churchill Livingstone; 2000. p. 253743.
[83] Bleck TP, Brauner JS. Tetanus. In: Scheld WM, Whitley RJ, Durack DT, editors.
Infections of the central nervous system. 2nd edition. Philadelphia (PA): Lippincott-Raven;
1997. p. 62953.
[84] Talan DA, Moran GJ. Tetanus among injecting drug users California. Ann Emerg Med
1998;32:3856.
[85] Centers for Disease Control and Prevention. Tetanus among injecting drug users
California, 1997. MMWR Morb Mortal Wkly Rep 1998;47:14951.
[86] Cherubin CE. Clinical severity of tetanus in narcotic addicts in New York City. Arch
Intern Med 1968;121:1568.
[87] Dastur FD, Shahani MT, Dastoor DH, et al. Cephalic tetanus: demonstration of a dual
lesion. J Neurol Neurosurg Psych 1977;40:7826.
[88] Scholz DJ, Olson JM, Thurber DL, et al. Tetanus: an uncommon cause of dysphagia.
Mayo Clin Proc 1989;64:3358.
[89] Syam B, Owens D. Horners syndrome in severe tetanus. Postgrad Med J 1992;68:27980.
[90] Blake PA, Feldman RA, Buchanan TM, et al. Serologic therapy of tetanus in the United
States. JAMA 1976;236:424.
[91] Abrutyn E, Berlin JA. Intrathecal therapy in tetanus: a meta-analysis. JAMA 1991;
266:22627.
[92] Ahmadsyah I, Salim A. Treatment of tetanus: an open study to compare the ecacy of
procaine penicillin and metronidazole. BMJ 1985;291:64850.
[93] MacDonald KL, Rutherford GW, Friedman SM, et al. Botulism and botulism-like illness
in chronic drug users. Ann Intern Med 1985;102:6168.
[94] Weber JT, Goodpasture HC, Alexander H, et al. Wound botulism in a patient with tooth
abscess: case report and review. Clin Infect Dis 1993;16:6359.
[95] Centers for Disease Control and Prevention. Wound botulism California. MMWR Morb
Mortal Wkly Rep 1995;44:88992.
[96] Merson MH, Dowell Jr. VR. Epidemiologic, clinical and laboratory aspects of wound
botulism. N Engl J Med 1973;289:110510.
[97] Hughes JM, Hatheway CL, Ostro SM. Botulism. In: Scheld WM, Whitley RJ, Durack
DT, editors. Infections of the central nervous system. 2nd edition. Philadelphia (PA):
Lippincott-Raven; 1997. p. 61528.