ORIGINAL CONTRIBUTION

Neurologic Adverse Events Associated With Smallpox Vaccination in the United States, 2002-2004 James J. Sejvar, MD Robert J. Labutta, MD Louisa E. Chapman, MD, MPH John D. Grabenstein, PhD, RPh John Iskander, MD, MPH J. Michael Lane, MD, MPH

T

HE UNITED STATES REINstated vaccination against smallpox among military personnel in 2002 and among selected civilian groups in January 2003. Routine smallpox vaccination had been suspended among US civilians in 1973 and among military personnel in the late 1980s. Rare adverse events causally associated with smallpox vaccination include cutaneous,1-4 ocular,1-5 and neurologic1-4,6,7 syndromes. Acute neurologic disease occurs after many vaccinations, including smallpox vaccination.6,7 Central nervous system (CNS) and peripheral nervous system complications of smallpox vaccination are rare but severe vaccine-associated adverse events. The most common CNS complication after smallpox vaccination is encephalitis (postvaccinial encephalomyelitis [PVE]).6 Other neurologic events have been associated temporally with smallpox vaccination. A recent assessment substantiates the frequency of postvaccinial headache. 8 Other neurologic syndromes infrequently historically reported in temporal association with smallpox vaccination include Guillain-

See also p 2734. 2744

Context Neurologic illness is an infrequent but severe adverse event associated with smallpox vaccination. The reinstatement of smallpox vaccination in the United States in response to possible bioterrorism renewed concerns about vaccine-related adverse neurologic events. Objective To determine rates and describe the clinical features of neurologic events associated with smallpox vaccination. Design and Setting We assessed reports of adverse events obtained through active case reporting and review of data reported to the Vaccine Adverse Event Reporting System among 665 000 persons vaccinated against smallpox by the Departments of Defense (n=590 400) and Health and Human Services (n=64 600) during the 20022004 US Smallpox Vaccination Program. Main Outcome Measure Adverse neurologic events temporally associated with smallpox vaccination. Results Between December 16, 2002, and March 11, 2004, 214 neurologic adverse events temporally associated with smallpox vaccination were reported; 111 reports involved Department of Health and Human Services and 103 involved Department of Defense vaccinees. Fifty-four percent of these events occurred within 1 week of vaccination, and 53% were among primary vaccinees. The most common neurologic adverse event was headache (95 cases), followed by nonserious limb paresthesias (n=17) or pain (n=13) and dizziness or vertigo (n=13). Serious neurologic adverse events included 13 cases of suspected meningitis, 3 cases of suspected encephalitis or myelitis, 11 cases of Bell palsy, 8 seizures (including 1 death), and 3 cases of GuillainBarre´ syndrome. Among these 39 events, 27 (69%) occurred in primary vaccinees and all but 2 occurred within 12 days of vaccination. Conclusions During the 2002-2004 smallpox vaccination campaign, reported neurologic events were generally mild and self-limited, and no neurologic syndrome was identified at a rate above baseline estimates. Serious neurologic adverse events, such as postvaccinal encephalitis, Bell palsy, and Guillain-Barre´ syndrome, occurred in accordance with expected ranges. www.jama.com

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Barre´ syndrome (GBS),9 acute cranial neuropathies, 10 poliomyelitis-like syndrome,11 Bell palsy,12 and transverse myelitis.10,13

Between December 16, 2002, and March 11, 2004, we assessed reports of PVE and other neurologic adverse events among US Department of Health and Hu-

Author Affiliations: Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases (Dr Sejvar) and Epidemiology and Surveillance Division, National Immunization Program (Drs Chapman and Iskander), Centers for Disease Control and Prevention, Atlanta, Ga; Department of Neurology, Walter Reed Army Medical Center, Washington, DC (Dr Labutta); and Military Vaccine Agency, United States Army Medical Command,

Falls Church, Va (Dr Grabenstein). Dr Lane is the former director of the Smallpox Eradication Program, Centers for Disease Control and Prevention. Corresponding Author: James J. Sejvar, MD, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifton Rd, Mailstop A-39, Atlanta, GA 30333 ([email protected]).

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Box. Case Definition: Encephalitis/Encephalomyelitis, for Use in the Smallpox Adverse Events Monitoring and Response Activity Case Definition for Acute Encephalitis A. A confirmed case of encephalitis is defined by demonstration of acute cerebral inflammation (± meninges) or demyelination by histopathology B. A probable case of encephalitis is defined by the acute onset of: 1. Encephalopathy (eg, depressed or altered level of consciousness, lethargy, or personality change lasting ⱖ24 hours) AND 2. Additional clinical evidence suggestive of cerebral inflammation, including 2 or more of the following: a. Fever (temperature ⱖ38°C) or hypothermia (temperature ⱕ35°C) b. Meningismus (ie, nuchal rigidity, photophobia/phonophobia) c. CSF pleocytosis (⬎5 white blood cells/mm3) d. Presence of focal neurologic deficit e. Electroencephalography findings consistent with encephalitis f. Neuroimaging findings on magnetic resonance imaging (MRI) consistent with acute inflammation (± meninges) or demyelination of the nervous system g. Seizures, either new onset or exacerbation of previously controlled seizures AND 3. No alternative (investigated) etiologies are found for presenting sign and symptoms C. A suspected case of encephalitis is defined as the presence of the acute onset of 1. Encephalopathy, as outlined for a probable case AND 2. One of the criteria listed for probable encephalitis as clinical evidence suggestive of cerebral inflammation. AND 3. No alternative (investigated) etiologies are found for presenting signs and symptoms Case Definition for Acute Myelitis A. A confirmed case of myelitis is defined by demonstration of acute spinal cord inflammation (± meninges) or demyelination by histopathology. B. A probable case of myelitis is defined by the acute onset of: 1. Myelopathy (development of sensory, motor, or autonomic dysfunction attributable to the spinal cord, including upperand lower-motor neuron weakness, sensory level, bowel or bladder dysfunction) AND 2. Additional evidence suggestive of spinal cord inflammation, including 2 or more of the following: a. Fever (temperature ⱖ38ºC) or hypothermia (temperature ⱕ35°C) b. CSF pleocytosis (⬎5 white blood cells/mm3) c. Presence of focal neurologic deficit d. Electromyographic studies suggestive of central (spinal cord) dysfunction e. Neuroimaging findings on MRI demonstrating acute inflammation (± meninges) or demyelination of the spinal cord AND 3. No alternative (investigated) etiologies are found for presenting sign and symptoms C. A suspected case of myelitis is defined as presence of the acute onset of: 1. Myelopathy as outlined for a probable case AND 2. One of the criteria listed for probable myelitis, as evidence suggestive of spinal cord inflammation AND 3. No alternative (investigated) etiologies are found for presenting sign and symptoms Cases fulfilling the criteria for both encephalitis and myelitis in any category would be classified as encephalomyelitis.

man Services (DHHS) and Department of Defense (DoD) smallpox vaccinees to characterize them clinically and assess their frequency. All vaccinations were done with the New York City Board of Health strain of vaccinia (Dryvax, Wyeth Pharmaceuticals, Pearl River, NY).

METHODS The Smallpox Vaccine Adverse Events Monitoring and Response Activities (SVAEMRA) identified adverse events after smallpox vaccination through clinical consultation and reporting to the Vaccine

©2005 American Medical Association. All rights reserved.

Adverse Event Reporting System (VAERS). A team of Centers for Disease Control and Prevention (CDC) SVAEMRA clinicians with expertise in smallpox vaccine–related safety responded to calls from health professionals identifying a

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suspected adverse event in DHHS vaccinees. The SVAEMRA clinicians completed case report forms, collecting information on vaccination, demographics, clinical events, and diagnostic studies, and followed up with the reporting clinician until a diagnosis was reached. A similar monitoring and consultation system was instituted by the DoD; this information was reported to VAERS and shared between the DoD and CDC.14-16 Events reported between December 16, 2002, and March 11, 2004, that were primarily neurologic, including those that met the case definition for encephalomyelitis adverse events (BOX), were reviewed in detail by the lead author ( J.J.S.), a board-certified neurologist and epidemiologist. Case report forms, medical records, and interviews with reporting physicians were used to ascertain vaccinee status, characterize the adverse event, and assess its association with smallpox vaccination. We reviewed all cases and conclusions with the Smallpox Vaccine Safety Working Group (SVS WG), a joint expert working group of the CDC’s Advisory Committee on Immunization Practices and the DoD’s Armed Forces Epidemiological Board. VAERS is a passive vaccine safety surveillance system operated jointly by the CDC and the US Food and Drug Administration17 that receives reports of adverse events after administration of USlicensed vaccines. VAERS reports collect information on the nature of suspected vaccine-associated adverse events, on demographics and clinical signs and symptoms, and on vaccinee status. All VAERS reports of neurologic events temporally associated with smallpox vaccination received between December 16, 2002, and March 11, 2004, were reviewed. A systematic database search identified entries containing 1 or more of 199 Coding Symbol for Thesaurus of Adverse Reaction Terms (COSTART) codes that suggested CNS or PNS dysfunction. The lead author (J.J.S.) reviewed VAERS reports of all identified entries to assess the clinical syndromes and the association with vaccination. Cases with minimal or no 2746

clinical detail were excluded. Demographic data on DHHS vaccinees were obtained from the Pre-Event Vaccination System and on DoD vaccinees from the Defense Eligibility Enrollment Reporting System. We classified cases into categories according to the predominant complaint, sign, or symptom. When possible, we compared observed rates (number of reports per number of vaccinations) of neurologic syndromes among vaccinees to expected incidence rates in the general population. Observations in this report are based on VAERS-associated surveillance and response activities, which are exempt from institutional review board review. RESULTS The SVAEMRA clinical team or DoD was consulted on 30 serious events (eg, resulting in hospitalization, disability, or death) temporally associated with smallpox vaccination events and features suggesting neurologic involvement. These 30 cases were actively investigated by the lead author. Twelve were neurologic, were also captured through VAERS report review, and are summarized in TABLE 1. Between December 16, 2002, and March 11, 2004, approximately 665 000 civilians and military personnel received smallpox vaccine, including approximately 435 000 primary (ie, first-time) vaccinees (66%). During this period, 2060 VAERS reports involving smallpox vaccine were received; 670 contained COSTART codes related to neurologic illness, 320 involved DHHS vaccinees (primarily civilian health care workers), and 350 involved DoD vaccinees (primarily military personnel deployed to overseas field situations). A preliminary screen excluded 456 reports unrelated to neurologic illness; the remaining 214 reports underwent detailed review; 2 misclassified cases were subsequently excluded. The 214 neurologic VAERS reports included 111 DHHS and 103 DoD vaccinees: 105 (49%) were women, 106 (50%) were men, and sex was not identified for 3; overall, 17% of vaccinees were wom-

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en.16 One hundred seventy-two (80%) reports were for persons younger than 50 years; the 18- to 29-year group had the largest proportion of adverse events (66; 31%). One hundred thirteen (53%) were reported primary vaccinees. Of reported neurologic adverse events, 54% occurred within 1 week of vaccination and 86% occurred within 30 days. A number of clinical syndromes, including dizziness or vertigo, limb weakness, syncope, and paresthesias, were poorly defined and unassociated with shortterm morbidity and will not be discussed herein. Headache, the predominant symptom among 44% of reports (TABLE 2), was most common and often accompanied by fever, chills, and fatigue. Most headache cases had no other evidence of neurologic dysfunction and had favorable outcome. Headaches requiring hospitalization and categorized as serious have been described.18 A total of 39 serious neurologic adverse events associated with smallpox vaccination were reported to VAERS; 27 (69%) were among primary vaccinees and all but 2 occurred within 12 days of vaccination (TABLE 3). We classified 13 cases as suspected meningitis, defined by the presence of headache and lumbar puncture performance, indicative of warranting cerebrospinal fluid (CSF) examination. Of these 13, 1 had a documented pleocytosis, and 1 was reported as having CSF “consistent with meningitis,” without further data. The remaining 11 reported normal or negative CSF or other study results (eg, head computed tomography, brain magnetic resonance imaging [MRI]). No reports of meningitis occurred more than 14 days after vaccination. Eight (62%) were primary vaccinees. We initially classified 4 cases as suspected encephalitis or myelitis, including the 2 cases on which SVAEMRA consulted and 2 identified through VAERS review alone. One report of transverse myelitis described normal CSF and onset 61 to 120 days following vaccination and was excluded. Of the remaining 3 cases, one man had

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probable encephalitis defined by altered mental status, pleocytosis, and multifocal demyelinating lesions on brain MRI 10 days after primary vaccination. Another man with suspected encephalitis developed fever, altered

mental status, and pleocytosis 8 days after primary smallpox vaccination and several weeks after multiple other vaccinations; he recovered completely within 8 days. Cerebrospinal fluid polymerase chain reaction testing of

both patients for vaccinia nucleic acid by the CDC’s Poxvirus Laboratory was negative. A third patient with suspected encephalitis 7 days after primary vaccination had mental “slowing” that resolved completely in 1 day;

Table 1. Case Synopses of “Serious” Suspected Neurologic Adverse Events After Smallpox Vaccination* Patient No./Sex/ Age Range, y

Vaccinee Status

Symptom Onset After Vaccination

1/F/20-30

Primary

0d

2/F/30-40

Primary

3/F/50-60

Revaccinee

4/F/30-40

Primary

5/F/40-50

Clinical Syndrome/ Category

Method of Review† Physician interview, medical record review

Central facial paralysis

10 d

Physician interview

Headache, vertigo

20 d

Medical record review

Transient global amnesia

7d

Physician interview, medical record review

Paresthesias

Revaccinee

5d

Physician interview, medical record review

Headache

6/M/50-60

Revaccinee

2 mo

Medical record review

Stroke

7/F/40-50

Revaccinee

6d

Medical record review

Headache

8/M/20-30

Primary

1d

Physician interview, medical record review

Guillain-Barre´ syndrome

9/M/40-50

Primary

90 d

Medical record review

Bell palsy

10/F/50-60

Revaccinee

99 d

Physician interview, medical record review

Multiple sclerosis‡

11/M/30-40

Primary

10 d

Physician interview, medical record/neuroimaging review

PVE/ADEM

12/M/20-30

Primary

8d

Physician interview, medical record review

PVE

Synopsis Central facial paresis, question of mild left hemiplegia; extensive neurologic evaluation failed to identify an etiology Otherwise uncomplicated headache and vertigo temporally associated with vaccination; no sequelae Features consistent with transient global amnesia, including repetition of questions, confusion, complete recovery, negative imaging and CSF studies; condition has no known association with vaccination Development of painful dysesthesias requiring hospitalization and pain control but no other evidence of objective neurologic dysfunction; outcome unknown Patient with history of poorly controlled migraines experienced headache typical of migraines 5 d after vaccination; required brief hospitalization Occurrence of stroke 2 mo after vaccination; predisposing risk factors include hypertension and tobacco use; long interval to onset, no indication of vaccination-related event Headache and photophobia reported; CSF and head computed tomography normal Service member receiving multiple other simultaneous vaccinations 14 d before and smallpox vaccine 1 day before onset of ascending flaccid paralysis Peripheral facial nerve palsy occurring 90 d after vaccination; complete recovery Complex neurologic diagnosis with multiple neurologic complaints; extensive neurologic evaluation performed, the result of which was nondiagnostic; long interval suggests association is unlikely Vaccinee with onset of mental status changes, seizures 10 d after vaccination; lesions consistent with demyelinating disease on MRI; neurologic sequelae still present 1 y after event Service member developing unresponsiveness, pleocytosis 8 d after smallpox vaccination; other vaccinations given several weeks earlier; complete recovery

Abbreviations: ADEM, acute disseminated encephalomyelitis; CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; PVE, postvaccinial encephalitis. *Prospectively reported to the Vaccine Adverse Event Reporting System (VAERS) after being identified through consultation with the Smallpox Vaccine Adverse Events Response and Monitoring Activities and the Department of Defense. †Review done in addition to VAERS. ‡Diagnosis in the VAERS report.

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CSF white blood cell count was 6 cells/mm 3 (normal ⬍5 cells/mm 3 ). The observed rate for encephalomyelitis with these 3 cases was 5 per million vaccinations (7/million primary vaccinations). No reports of encephalitis occurred more than 14 days after vaccination. Bell palsy (facial weakness) was reported in 11 vaccinees. The median interval between vaccination and reported onset was 7 days (range, 3-8

Table 2. Clinical Syndrome and Incidence Among Reports of Neurologic Adverse Events Associated With Smallpox Vaccination, VAERS—United States, 2002-2004 (N = 214)

Syndrome Headache (with or without other symptoms) Limb paresthesias Dizziness/vertigo Limb pain Meningitis (with LP) Bell palsy/facial weakness Limb weakness Seizures Mental status change Syncope/presyncope Encephalitis (with LP)*† Tinnitus Visual changes Guillain-Barre´ syndrome Dysphagia Movement disorder† Demyelinating disease† Brachial neuritis Stroke

Cases, No. (%)

Incidence per 100 000 Vaccinations

95 (44)

14.3

17 (8) 13 (6) 13 (6) 13 (6) 11 (5)

2.5 1.9 1.9 1.9 1.7

11 (5) 8 (4) 7 (3) 5 (2) 4 (2)

1.7 1.2 1.1 0.8 0.6

4 (2) 4 (2) 3 (1)

0.6 0.6 0.5

2 (⬍1) 1 (⬍1) 1 (⬍1)

0.3 0.2 0.2

1 (⬍1) 1 (⬍1)

0.2 0.2

Abbreviations: LP, lumbar puncture; VAERS, Vaccine Adverse Events Reporting System. *Includes 1 case of transverse myelitis. †Diagnosis in the VAERS report.

days). Six (55%) were primary vaccinees. We estimate the rate of reported Bell palsy to be 1.7 per 100 000 vaccinations (0.9/100 000 primary vaccinations). Eight patients had reported seizures 9 days after vaccination. Seven (88%) were primary vaccinees. Three (38%) had a history of seizures. Among the remaining 5, 1 patient’s seizure was attributed to hypoglycemia. Two had apparent new-onset seizures: neuroimaging, electroencephalography (EEG), and CSF analysis results were normal, and no recurrences were experienced 2 months after onset for one patient and 4 months for the other. The 2 remaining cases included one with apparent new-onset seizures with no EEG or MRI findings reported and another for whom seizures occurred in a clinical context of severe respiratory distress, cardiac abnormalities, and ultimately death. This case was reported in detail by a Sentinel Review process of the SVS WG and other DHHS entities19; the suspected underlying etiology was a new-onset autoimmune syndrome. GBS was reported twice in primary vaccinees and once in a revaccinee. The referring physicians attributed 2 cases to other concomitantly administered vaccinations; the interval between these vaccinations and onset was not reported. One individual for whom neurologic examination, CSF, or EMG findings were not available had GBS onset 1 day after vaccination, an interval biologically unlikely to reflect vaccine causality. Presuming all 3 temporal associations are valid and these cases were

Table 3. Reports of Neurologic Adverse Events Associated With Smallpox Vaccination Reported to VAERS—United States, 2002-2004 (n = 39)

Syndrome

No.

Meningitis Encephalitis/myelitis Guillain-Barre´ syndrome*

13 3 3

Primary Vaccinees, No. (%) 8 (62) 3 (100) 2 (66)

Bell palsy Seizures

11 9

6 (55) 8 (88)

2 1

9 6

0 2

Total

39

27 (69)

5

30

2

Interval ⬍2 d 1 0 1

Interval 2-30 d 12 3

Interval ⬎30 d 0 0

Abbreviation: VAERS, Vaccine Adverse Events Reporting System. *Interval data unavailable for 2 cases.

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not misclassified, the maximum observed rate of GBS was 0.5 cases per 100 000 vaccinations. COMMENT Vaccines have reduced neurologic morbidity and mortality from many infections.20-22 However, vaccines, including smallpox vaccine, carry a risk of adverse reactions, including rare severe neurologic syndromes.23-25 Historically, PVE was the most frequent severe neurologic adverse event associated with smallpox vaccination. Estimated PVE rates vary significantly among studies, presumably because of differences in case definitions, variability in completeness of ascertainment and clinical evaluation, and differences among vaccine strains. An assessment of PVE in the United Kingdom between 1951 and 1960 found a reporting rate of 14 cases per million vaccinations.25 Assessments in Germany in the 1940s and 1950s determined rates ranging from 121 to 449 per million vaccinations.26-28 Studies done in the United States in the 1960s suggest a relative infrequency (9-51 cases/million vaccinations) but apparent severity of PVE, with 53% of 68 smallpox vaccine–associated deaths between 1959 and 1966 attributed to PVE.1,2,4 The case-fatality rate for PVE was approximately 25%.4 The rate and severity varied with the vaccinia strain, with certain reactogenic, neurotropic strains associated with higher rates.29-31 Historically, PVE has been nearly 10fold more common after primary vaccinations than revaccinations.32 Clinicohistopathologic assessments in the 1920s and 1960s identified 2 clinicopathologic manifestations: microglial encephalitis and postvaccinial encephalopathy.6,33-35 Microglial encephalitis was more frequent in persons older than 2 years, occurred 10 to 20 days after vaccination, and was characterized by fever, vomiting, headache, and malaise, followed by decreased consciousness, seizures, and coma. Neuropathologically, these persons had widespread demyelination of subcortical white matter. Postvaccinial encephalopathy

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occurred mainly in children younger than 2 years at 6 to 12 days after vaccination and presented as fulminant seizures, hemiplegia, and elevated intracranial pressure. These patients had diffuse cerebral edema, lymphocytic meningeal infiltration, and perivascular hemorrhages. Vaccinial viremia and virus isolation from brain or CSF was sometimes detected.36,37 Although clinicopathologic correlates of PVE during the era of modern neuroimaging and neuroimmunology have not been possible, the demyelinating form of PVE probably corresponds to acute disseminated encephalomyelitis (ADEM) or postvaccination encephalomyelitis, whereas the cytotoxic form may represent an acute neuroinvasive vaccinial encephalomyelitis. We identified 3 persons with probable or suspected encephalitis after smallpox vaccination, with cerebral inflammation evidenced by altered mental status and pleocytosis. One patient had a longer interval between vaccination and illness onset and MRI findings suggestive of ADEM, and the other 2 had features more consistent with acute viral encephalitis, including a shorter interval between vaccination and onset and rapid recovery. Our estimated reporting rate of probable or suspected PVE cases of 5 cases per million vaccinees is consistent with previous assessments conducted in the United States. Wide availability of neuroimaging and CSF examination allow distinction between mild neurologic symptoms and true cerebral inflammation, reducing misclassification of encephalitis. None of the persons in this study with suspected encephalitis died, perhaps because of improved supportive neurocritical care. Aseptic meningitis was reported in 13 patients. However, only 2 demonstrated pleocytosis, suggesting that aseptic meningitis may have been overdiagnosed in earlier studies. Bell palsy and GBS have been reported after infections and immunizations. Most population-based assessments have not found higher-thanexpected rates of these phenomena after vaccination, but a statistically signifi-

cant association has been made for Bell palsy after intranasal influenza vaccine and hepatitis B vaccination38,39 and for GBS after rabies vaccination and some formulations of influenza vaccine.40,41 However, specific antecedent events are not usually evident. The expected rate of Bell palsy among the general population ranges between 15 and 40 cases per100 000 per year.42,43 The 11 cases of Bell palsy yields a rate of 1.7 per 100 000 vaccinations, about or lower than the expected incidence. Published estimates of GBS among the general population range from 0.4 to 4.0 cases per 100 000 per year.44 The 3 cases of suspected GBS (estimated reporting rate of 0.5/100 000 vaccinations) is much lower than that observed within the general population. Further, 1 case of GBS was reported 1 day after vaccination, which suggests it was misclassified because a biological link with vaccination would be implausible. Our estimations of the occurrences of GBS, Bell palsy, and PVE per number of vaccinations are ratios of reported events compared with the number of vaccinations. They are not expressed relative to units of time and are not directly comparable to the published populationbased incidence rates. Although not statistically valid, comparison of these ratios with known background rates may be a useful indicator of adverse-events trends associated with vaccinations.45,46 Overall, 69% of the serious neurologic adverse events, including all 3 cases of encephalitis, occurred among primary vaccinees, which is consistent with historical data describing more adverse events among primary vaccinees than among revaccinees. Our assessment has limitations. Like all passive surveillance systems, VAERS reports are subject to underreporting, ascertainment bias and differential reporting, and variability in report quality and completeness.46 We did not attempt to obtain additional information from medical record reviews beyond the 12 cases prospectively identified through clinical consultation. Some military personnel receive multiple vaccinations, making it difficult to associate any one

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with the presumed adverse event. Data on intercurrent infections in cases of suspected meningitis and encephalitis were not available. Our findings identified many milder neurologic adverse events temporally but not necessarily causally associated with smallpox vaccination. They suggest that such events are generally selflimited, nonserious, and not associated with severe morbidity or mortality when screening defers persons with high-risk conditions. Smallpox vaccine is given to healthy people, which creates a low tolerance for associated risk. Risks associated with vaccines are best identified through population-based assessments.47,48 New, possibly less reactogenic smallpox vaccines are currently under development. Continued monitoring for neurologic events is needed to assess the safety of smallpox vaccines and to better characterize the spectrum of neurologic illness associated with them. Author Contributions: Dr Sejvar had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Sejvar, Chapman, Grabenstein, Iskander. Acquisition of data: Sejvar, Labutta, Chapman, Grabenstein, Iskander, Lane. Analysis and interpretation of data: Sejvar, Labutta, Chapman, Grabenstein, Lane. Drafting of the manuscript: Sejvar, Chapman, Grabenstein, Lane. Critical revision of the manuscript for important intellectual content: Sejvar, Labutta, Chapman, Grabenstein, Iskander, Lane. Statistical analysis: Sejvar. Obtained funding: Sejvar. Administrative, technical, or material support: Sejvar, Chapman, Grabenstein, Iskander. Study supervision: Sejvar, Chapman, Grabenstein, Lane. Financial Disclosures: None reported. Funding/Support: This study was supported by the Centers for Disease Control and Prevention (CDC) and the US Department of Defense. Role of the Sponsor: The Departments of Health and Human Services (CDC) and Defense reviewed and approved the manuscript. Disclaimer: The content of this article reflects the views of the authors and does not necessarily reflect the official position of the CDC, the Department of the Army, Department of Defense, Department of Health and Human Services, or the US government. Acknowledgment: We thank the Advisory Committee on Immunization Practices–Armed Forces Epidemiological Board joint Smallpox Vaccine Safety Working Group, as well as the many other parties whose work enabled the observations reported here, including entities of the US Department of Defense and the US Department of Health and Human Services; colleagues in the pharmaceutical industry (Wyeth and Acambis); civilian and military health care profession-

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SMALLPOX VACCINATION AND NEUROLOGIC EVENTS als; state, territorial, county, city, and local health department professionals; and the civilian response team and monitoring activity volunteers. We thank Claudia Chesley, BA, for review and editing of the manuscript.

REFERENCES: 1. Lane JM, Ruben FL, Neff JM, Millar JD. Complications of smallpox vaccination, 1968: national surveillance in the United States. N Engl J Med. 1969;281: 1201-1208. 2. Lane JM, Ruben FL, Neff JM, Millar JD. Complications of smallpox vaccination, 1968: results of 10 statewide surveys. J Infect Dis. 1970;122:303-309. 3. Copeman PW, Wallace HJ. Eczema vaccinatum [letter]. BMJ. 1964;2:906. 4. Lane JM, Ruben FL, Abrutyn E, Millar JD. Deaths attributable to smallpox vaccination, 1959 to 1966 and 1968. JAMA. 1970;212:441-444. 5. Ruben FL, Lane JM. Ocular vaccinia. Arch Ophthalmol. 1970;84:45. 6. de Vries E. Postvaccinial Perivenous Encephalitis. Amsterdam, the Netherlands: Elsevier; 1959. 7. Spillane JD, Wells CD. The neurology of Jennerian vaccination: a clinical account of the neurologic complications which occurred during the smallpox epidemic in South Wales in 1962. Brain. 1964;87: 1-44. 8. Frey SE, Couch RB, Tacket CO, et al. Clinical responses to undiluted and diluted smallpox vaccine. N Engl J Med. 2002;346:1265-1274. 9. Kisch AL. Guillain-Barre´ syndrome following smallpox vaccination. N Engl J Med. 1958;258:83-84. 10. Miller HG. Prognosis of neurologic illness following vaccination against smallpox. Arch Neurol Psychiatry. 1953;69:695-706. 11. Neff JM, Levine RH, Lane JM, et al. Complications of vaccination, United States 1963, II: results obtained by four statewide surveys. Pediatrics. 1967;39: 916-921. 12. Polack MF. Complications of smallpox vaccination in the Netherlands, 1959-1970. In: International Symposium on Smallpox Vaccine, Symposia Series in Immunolobiological Standardization. Basel, Switzerland: S. Karger; 1973:235-242. 13. Orovcanec K, Mudric V, Vuckovic S, Vukovic B. Neuropsychiatric complications caused by smallpox vaccination. Med Pregl. 1974;27:25-28. 14. Notice to readers: Smallpox Vaccine Adverse Events Monitoring and Response System for the first stage of the smallpox vaccination program. MMWR Morb Mortal Wkly Rep. 2003;52:88-89, 99. 15. Grabenstein JD, Winkenwerder W Jr. US military smallpox vaccination program experience. JAMA. 2003;289:3278-3282. 16. Casey CG, Iskander J, Roper MH, et al. Adverse events associated with smallpox vaccination: results

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from the US Department of Health and Human Services Smallpox Vaccine Safety Monitoring and Response System, January-October 2003. JAMA. 2005; 294:2734-2743. 17. Singleton JA, Lloyd JL, Mootrey GL, Salive ME, Chen RT. An overview of the Vaccine Adverse Event Reporting System (VAERS) as a surveillance system. Vaccine. 1999;17:2908-2917. 18. Sejvar J, Boneva R, Lane JM, Iskander J. Severe headaches following smallpox vaccination. Headache. 2005;45:87-88. 19. Chapman LE, Iskander JK, Chen RT; for the CDC with the Smallpox Vaccine Safety Working Group. The United States Smallpox Vaccine Safety Sentinel Review Process, 2003-2004. Atlanta, Ga: CDC; August 4, 2005. 20. American Academy of Pediatrics Committee on Infectious Diseases. Measles: reassessment of the current immunization policy. Pediatrics. 1989;84:11101113. 21. Kim-Farley RJ, Schonberger LB, Nkowane BM, et al. Poliomyelitis in the USA: virtual elimination of disease caused by wild virus. Lancet. 1984;2: 1315-1317. 22. De Wals P, Deceuninck G, Boulianne N, De Serres G. Effectiveness of a mass immunization campaign using serogroup C meningococcal conjugate vaccine. JAMA. 2004;292:2491-2494. 23. Plesner A, Arlien-Soborg P, Herning M. Neurological complications to vaccination against Japanese encephalitis. Eur J Neurol. 1998;5:479-485. 24. Fenichel GM. Neurologic risk of immunization: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 1999;52:1546-1552. 25. Miller H, Stanton JB, Gibbons JL. Acute disseminated encephalomyelitis and related syndromes. BMJ. 1957;23:668-672. 26. Herrlich A. Probleme der Pocken und Pockenschurtzimpfung. Munch Med Wochenschr. 1954;96:529-533. 27. Seelemann K. Zerebrale Komplikationene nach Pock-enschutzimpfungen mit besonderer Berucksichtigung der Alterdisposition in Hamburg 1936 bis 1958. Dtsch Med Wochenschr. 1960;85:1081-1089. 28. Stuart G. Memorandum on postvaccinial encephalitis. Bull World Health Organ. 1948;1:36-53. 29. Berger K, Heinrich W. Decrease in postvaccinal deaths in Austria after introducing a less pathogenic virus strain. In: International Symposium on Smallpox Vaccine, Symposia Series in Immunobiological Standardization. Basel, Switzerland: S. Karger; 1973: 199-203. 30. Marrenikova SS, Chimishkyan KL, Maltseva NN, et al. Characteristics of virus strains for production of smallpox vaccines. In: Gusic B, ed. Proceedings of the Symposium on Smallpox: September 2-3, 1969. Zagreb, Croatia: Yugoslav Academy of Arts and Sciences; 1969:65-79.

JAMA, December 7, 2005—Vol 294, No. 21 (Reprinted with Corrections)

31. Khliabich G, Sumarokov A, Shkol’nik R, Karinskaia G. Relationship between the incidence of neurologic complications following smallpox vaccination and the generation and infectious activity of vaccine from strain L-IVP. Zh Mikrobiol Epidemiol Immunobiol. 1977;10:77-80. 32. Neff JM, Lane JM, Pert JH, Moore R, Millar JD, Henderson DA. Complications of smallpox vaccination, I: national Survey in the United States, 1963. N Engl J Med. 1967;276:125-132. 33. Turnbull HM, McIntosh J. Encephalomyelitis following vaccination. Br J Exp Pathol. 1926:181-222. 34. Thompson R. The aetiology of posvaccinial encephalomyelitis. Arch Pathol. 1931;12:601-632. 35. Thalassings N, Contoyannis P. CNS involvement after smallpox revaccination. Lancet. 1973;1:1130. 36. Kurata T, Aoyama Y, Kitamura T. Demonstration of vaccinia virus antigen in brains of postvaccinial encephalitis cases. Jpn J Med Sci Biol. 1977;30:137-147. 37. Gurvich E, Movsesyants L, Stepenekova L. Isolation of vaccinia virus from children with postvaccinial encephalitis at late intervals after vaccination. Acta Virol. 1975;19:92. 38. Naruse H, Miwata H, Ozaki T, et al. Varicella infection complicated with meningitis after immunization. Acta Paediatr Jpn. 1993;35:345-347. 39. Shaw FE, Graham DJ, Guess HA, et al. Postmarketing surveillance for neurologic adverse events reported after hepatitis B vaccination. Am J Epidemiol. 1988;127:337-352. 40. Haber P, DeStefano F, Angulo F, et al. GuillainBarre´ syndrome following influenza vaccination. JAMA. 2004;292:2478-2481. 41. Boe E, Nyland H. Guillain-Barre´ syndrome after vaccination with human diploid cell rabies vaccine. Scand J Infect Dis. 1980;12:231-232. 42. Rowlands S, Hooper R, Hughes R, Burney P. The epidemiology and treatment of Bell’s palsy in the UK. Eur J Neurol. 2002;9:63-67. 43. Brandenburg NA, Annegers JF. Incidence and risk factors for Bell’s palsy in Laredo, Texas: 1974-1982. Neuroepidemiology. 1993;12:313-325. 44. Hughes R, Rees J. Clinical and epidemiologic features of Guillain-Barre´ syndrome. J Infect Dis. 1997; 176(suppl 2):S92-S98. 45. Varricchio F, Iskander J, Destefano F, et al. Understanding vaccine safety information from the Vaccine Adverse Event Reporting System. Pediatr Infect Dis J. 2004;23:287-294. 46. Intussusception among recipients of rotavirus vaccine: United States, 1998-1999. MMWR Morb Mortal Wkly Rep. 1999;48:577-582. 47. Stratton KR, Howe CJ, Johnston RB, eds. Adverse Events Associated With Childhood Vaccines: Evidence Bearing on Causality. Washington, DC: National Academy Press; 1994. 48. Fenichel GM. Adverse events following immunization: assessing probability of causation. Pediatr Neurol. 1989;5:287-290.

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LETTERS

That approach leaves several critical issues unresolved. First, federal policy actively discourages high-quality research by making access to marijuana by researchers exceedingly difficult. Even when access to marijuana is finally granted, there is substantial variability in the purity and content of the product. Second, researchers need to test the assumption noted by Das that THC is the active ingredient responsible for the perceived beneficial effects. Although that assumption is reasonable, there remains the possibility that marijuana, not THC in isolation, achieves the desirable effects. Third, researchers should test the most efficient delivery system. There may be some added value in smoking that needs to be evaluated. If research concludes that THC is the beneficial ingredient and that delivery by tablet is safest and most effective, then there is justification for approval of that method only. A synthetic THC oral medication (dronabinol) is already available for prescription with US Food and Drug Administration-approved indications for anorexia associated with weight loss in patients with AIDS and for nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments. Regulation of the use of marijuana for medical purposes is feasible and socially desirable, but it will require a different way of thinking about the problem. It requires viewing marijuana as a potential medication subject to carefully controlled research, rather than as a drug of strict prohibition. Lawrence O. Gostin, JD, LLD (Hon) [email protected] Georgetown Law Center Washington, DC Financial Disclosures: None reported.

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JAMA, December 28, 2005—Vol 294, No. 24 (Reprinted)

CORRECTIONS Author Contribution Omissions: In the Original Contribution entitled “HighDose Atorvastatin vs Usual-Dose Simvastatin for Secondary Prevention After Myocardial Infarction: The IDEAL Study: A Randomized Controlled Trial” published in the November 16, 2005, issue of JAMA (2005;294:2437-2445), several contributions were omitted for the author Anders G. Olsson, MD, PhD. In addition to his contributions listed in the article, Dr Olsson contributed to the study concept and design, acquisition of data, drafting of the manuscript, and statistical analysis for the IDEAL trial. Duplicated Text: In the Original Contribution entitled “Neurologic Adverse Events Associated With Smallpox Vaccination in the United States, 2002-2004” published in the December 7, 2005, issue of JAMA (2005;294:2744-2750), a section of text was duplicated. The first 4½ lines on the top of page 2747 should be deleted. Thus, the last sentence on the bottom of page 2746 and continuing onto 2747 should read: “Of the remaining 3 cases, one man had probable encephalitis defined by altered mental status, pleocytosis, and multifocal demyelinating lesions on brain MRI 10 days after primary vaccination.” Incorrect Wording and Data: In the Original Contribution entitled “Combined Tetanus, Diphtheria, and 5-Component Pertussis Vaccine for Use in Adolescents and Adults” published in the June 22/29, 2005, issue of JAMA (2005;293:30033011), incorrect wording appeared at the end of the Results section. On page 3009, lines 15-16 of the fourth paragraph, “ . . . the complaint resolved within 1 day” should read “the patient was hospitalized for 1 day and the complaint subsequently resolved without sequelae.” In addition, in Table 4, for the entry “Axillary node swelling,” in column 2 (Tdap Adolescents) 676 should be 67. Incorrect Data: In the Original Contribution entitled “Adverse Events Reported Following Live, Cold-Adapted, Intranasal Influenza Vaccine,” published in the December 7, 2005, issue of JAMA (2005;294:2720-2725), there were incorrect data in the first full paragraph on page 2724. The corrected paragraph is reprinted below: Among 11 reports concerning individuals with a prior history of chronic cardiovascular disease, 1 serious case involved a 42-year-old man with a history of uncontrolled hyperlipidemia who was hospitalized with a myocardial infarction 2 days after vaccination. He underwent cardiac catheterization. Among 10 reports from individuals with preexisting metabolic conditions (including 8 with thyroid disease), 1 (a 30-year-old man hospitalized with pneumonia 7 days after vaccination) was serious. There were no other hospitalizations. Among the remaining 15 individuals, 13 had chronic conditions (3 with chronic neurological conditions, 4 with chronic respiratory diseases, 2 with pernicious anemia, 2 with sarcoidosis, 1 with fibromyalgia, and 1 with lupus) and 2 were pregnant; none resulted in hospitalization. One report, in a 48-year-old woman who had a prior history of Bell palsy, was classified as serious.

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LETTERS

blood pressure regulation and provides the basis for targeting research to the stimulation of endogenous nitric oxide synthesis as a novel blood pressure–lowering principle. Dirk Taubert, MD, PhD [email protected] Department of Pharmacology Norma Jung, MD Department of Internal Medicine Renate Roesen, PhD Department of Pharmacology University Hospital of Cologne Cologne, Germany Financial Disclosures: None reported. 1. Tsikas D, Raida M, Sandmann J, Rossa S, Forssmann WG, Frolich JC. Electrospray ionization mass spectrometry of low-molecular-mass S-nitroso compounds and their thiols. J Chromatogr B Biomed Sci Appl. 2000;742(1):99-108. 2. Stamler JS, Jaraki O, Osborne J, et al. Nitric oxide circulates in mammalian plasma primarily as an S-nitroso adduct of serum albumin. Proc Natl Acad Sci U S A. 1992; 89(16):7674-7677. 3. Jocelyn PC. Biochemistry of the SH Group: The Occurrence, Chemical Properties, Metabolism and Biological Function of Thiols and Disulphides. New York, NY: Academic Press; 1972:1-46. 4. Murphy KJ, Chronopoulos AK, Singh I, et al. Dietary flavanols and procyanidin oligomers from cocoa (Theobroma cacao) inhibit platelet function. Am J Clin Nutr. 2003;77(6):1466-1473. 5. Liu L, Yan Y, Zeng M, et al. Essential roles of S-nitrosothiols in vascular homeostasis and endotoxic shock. Cell. 2004;116(4):617-628. 6. Rassaf T, Kleinbongard P, Preik M, et al. Plasma nitrosothiols contribute to the systemic vasodilator effects of intravenously applied NO: experimental and clinical study on the fate of NO in human blood. Circ Res. 2002;91(6):470-477. 7. Neishi Y, Mochizuki S, Miyasaka T, et al. Evaluation of bioavailability of nitric oxide in coronary circulation by direct measurement of plasma nitric oxide concentration. Proc Natl Acad Sci U S A. 2005;102(32):11456-11461.

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JAMA, October 24/31, 2007—Vol 298, No. 16 (Reprinted)

CORRECTIONS Incorrect Data: In the Original Contribution entitled “Tolterodine and Tamsulosin for Treatment of Men With Lower Urinary Tract Symptoms and Overactive Bladder: A Randomized Controlled Trial” published in the November 15, 2006, issue of JAMA (2006;296[19]:2319-2328), a P value was incorrectly reported. On page 2323 in the “Efficacy End Points” subsection, the section of the first sentence that read “or 146 (71%) of 207 receiving tamsulosin (P=.03 vs placebo)” should have read “(P=.064 vs placebo).” Incorrect Title: In the Perspectives on Care at the Close of Life: Coda entitled “Lateral Sclerosis: ‘Prepare for the Worst and Hope for the Best’ ” published in the September 12, 2007, issue of JAMA (2007;298[10]:1208-1208), the title should have read “Amyotrophic Lateral Sclerosis: ‘Prepare for the Worst and Hope for the Best.’ ” Incorrect Data: In the Original Contribution entitled “Neurologic Adverse Events Associated With Smallpox Vaccination in the United States, 2002-2004” published in the December 7, 2005, issue of JAMA (2005;294[21]:2744-2750) the abstract misstated the subgroups of civilian and military vaccinees. The 665 000 persons vaccinated against smallpox were compiled from the experience of the Departments of Defense (n=625 400) and Health and Human Services (n=39 400). The erroneously reported subtotal values (Department of Defense n=590 400 and Department of Health and Human Services n=64 600) appeared only in the abstract, were not used in the analyses, and did not influence the information reported in the body of the article. On page 2748, at the top of the second column, the reporting rate of Bell palsy among primary vaccinees was also misstated. The correct rate is 1.4/100 000, not 0.9/100 000. The overall rate described was correctly stated (1.7/100 000 vaccinations). The number of seizures reported in Table 3 was also misstated, although they are correctly stated elsewhere in the article. Overall 8 seizures were reported, of which 7 (85%) were among primary vaccinees. Five of these occurred in the interval of 2-30 days, and thus 29 adverse events occurred in that interval in Table 3. The error in reported seizure cases was carried over to the total number of serious neurologic events reported elsewhere in the article. The correct value is 38 (not 39), with 26 (not 27) among primary vaccinees, and a proportion among primary vaccinees of 68% (not 69%). On page 2748, in the first sentence of the first paragraph in column 2, the word “median” is missing. That sentence should read, “Eight patients had reported seizures a median of 9 days after vaccination.” We consider none of these errors to affect the discussion points or the conclusions of this article, nor to affect the validity of the conclusions reached in our study.

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