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The Annals of Pharmacotherapy 2001 December, Volume 35 1
Peripheral Neuropathy Associated with Fluoroquinolones

Jay S Cohen

EARCH REPORTS

www.theannals.com

Infectious Diseases

Author information provided at the end of the text.

OBJECTIVE: To survey cases of fluoroquinolone-associated adverse events that included peripheral nervous system (PNS)

symptoms posted on Internet Web sites.

METHODS: Cases were obtained with the assistance of members of Web sites formed by people sustaining fluoroquinolone-related events. Information obtained met the standards of MedWatch, and each reported case was assessed using the Naranjo probability scale.

RESULTS: In contrast to previous reports suggesting that fluoroquinolone-associated PNS events are mild and short-term, 36 of the 45 cases reported severe events that typically involved multiple organ systems. Although many newer cases are still evolving, symptoms had lasted more than three months in 71% of cases and more than one year in 58%. Onset of adverse events was usually rapid, with 15 (33%) events beginning within 24 hours of initiating treatment, 26 (58%) within 72 hours, and 38 (84%) within one week. Sixty courses of fluoroquinolones were prescribed: levofloxacin (n = 33 cases), ciprofloxacin (n = 11), ofloxacin (n = 6), lomefloxacin (n = 1), trovafloxacin (n = 1); in eight cases the same antibiotic was prescribed twice.

CONCLUSIONS: These cases suggest a possible association between fluoroquinolone antibiotics and severe, long-term adverse effects involving the PNS as well as other organ systems. The severity of these cases may reflect a different population than typically reported to drug companies or MedWatch, which often originate from healthcare providers. In contrast, Internet Web sites may provide a forum for patients experiencing adverse effects that have not resolved promptly. Further study is warranted. Meanwhile, the occurrence of PNS symptoms during fluoroquinolone therapy should prompt immediate discontinuation of the agent used.





The fluoroquinolone antibiotics are an important, frequently

prescribed group of medications. Fluoro-quinolone

adverse events involving the central nervous

system (e.g., dizziness, headache, seizures, psychosis) are

well known.1-11 However, less recognized are fluoro-quinolone-

associated peripheral neuropathies, and only a

few reports 12-16 and one article 17 have been published in the

medical literature regarding such events, which are usually

described as mild and of short duration.

In contrast, in recent years hundreds of reports involving

fluoroquinolone-associated events involving the central

nervous system (CNS), musculoskeletal system, and peripheral

nervous system (PNS) have been posted on Inter-

net Web sites by patients or concerned family members.

Many of these events are described as severe and long-lasting,

causing substantial pain, impairment of functioning,

and, in some cases, long-term disability. In order to

provide a central forum for these people, in February 1999

the Quinolone Antibiotics Adverse Reaction Forum was

established at www.geocities.com/quinolones/ to provide a

central forum for individuals to self-report adverse events

experienced in association with fluoroquinolones. The

Web site also offers links to the National Institutes of

Health and other relevant medically oriented Web sites,

and encourages people to use its link to the Food and Drug

Administration’s (FDA’s) MedWatch program for filing

official reports. As of October, 2001, the site received more

than 73 000 visitors and 5000 posts. With the assistance of

members of this Web site, a survey of cases involving PNS

symptomatology was conducted in order to examine the

number and characteristics of these adverse events in this

population.

Events since September 11, 2001, have heightened the

importance of physicians’ and the public’s awarewness of

serious adverse effects associated with fluoroquinolones.

Because of the current anthrax threat and the hoarding of

ciprofloxacin by thousands of people, the benefits of this

antibiotic and other fluoroquinolones must be weighed

carefully and treatment must be undertaken judiciously.

The media, generally, have presented only a few fluoro-quinolone

adverse effects, which are usually described as

mild. One leading news magazine stated that a 30-day

course of ciprofloxacin "wouldn’t cause a healthy adult

much direct harm" unless also taken with theophylline.18

There are anecdotal reports of people already taking cipro-floxacin

prophylactically. The 45 cases presented in this article,

as well as previous published articles about the neurotoxicity

and effects of fluoroquinolones on musculosketetal

structures, should give patients and physicians pause before

using fluoroquinolones without specific indication. More-over,

people need to know what to do if potentially serious

fluoroquinolone adverse effects occur.

Methods

RECRUITMENT OF CASES

Forty-seven patient cases were obtained by posting a message re-questing

submission of cases involving PNS events for the purpose of a

medical survey. One case was sent directly to the author, and five cases

were forwarded from another fluoroquinolone-related adverse event

Web site (the Tropicalpenguin Health Forum: http://www.tropicalpenguin.

com/health/forum/messages/241.html).

INCLUSION OF CASES

All cases involving symptoms suggestive of peripheral neuropathies

and fulfilling inclusion criteria described below were included. Accept-able

symptoms included sensory abnormalities (tingling, numbness,

prickling, pins/needles sensation, burning pain, "electrical" or shooting

pain, skin-crawling sensation, hyperesthesia, hypoesthesia, allodynia,

numbness), and motor abnormalities (weakness, twitching, fasciculations,

tremors, spasms, contractions).



DATA REQUIRED

Cases were required to provide information that equaled or exceeded

the standards of the FDA’s MedWatch program. Information requested

included name (or another identification for patients preferring anonymity),

age, gender, weight; date antibiotic was taken, reason for antibiotic

use, specific antibiotic used, dosage, duration; time of use until onset of

symptoms; symptoms of the adverse events and the degree of discomfort

and/or impact, if any, on normal functioning; duration of events; prior

medical problems and/or medications; subsequent treatment, if any, for

adverse events; whether a MedWatch report was submitted to the FDA.

IDENTIFICATION OF ADVERSE DRUG EVENT

Adverse events were defined according to the FDA’s current definition:

"an undesirable effect, reasonably associated with the use of the

drug, that may occur as part of the pharmacologic action of the drug or

may be unpredictable in its occurrence."19 Likelihood of the event being

associated with fluoroquinolone treatment was rated by the author ac-

cording to the Naranjo et al.20 probability scale. Patients were asked

about other possible causes of their events.

SEVERITY OF ADVERSE EFFECT

The author categorized the adverse drug events (ADEs) as follows: a

mild ADE was associated with mild to moderate pain or discomfort lasting

less than two weeks; a moderate ADE was associated with substantial

discomfort and/or significant limitations in normal functioning lasting

less than two months; a severe ADE was associated with severe discomfort

and/or limitations in functioning that lasted more than two

months.

CONFIRMATION OF INFORMATION

Information from each patient was entered and organized into a computer

database. Each patient was E-mailed a copy of his patient information

and asked to confirm its accuracy, as well as to provide missing in-formation

or explain unclear details. Patients were also requested to pro-vide

identifying information such as address and telephone number,

electively.

EXCLUSION OF CASES

Cases that were not confirmed were excluded by the author. Cases

that appeared equivocal or in which patients had other conditions or

were taking other medications that might explain the adverse events

were also excluded.

Results

Forty-five cases fulfilling all criteria were received. The

specifics of 15 representative cases are listed in Table 1.

Based on established scales for assessing the probability

of an event’s relatedness to a prescribed treatment,20 31

cases fulfilled the criteria of possible adverse drug events:

(1) the events represented recognized events with these

drugs; (2) the events occurred in a credible temporal sequence

with the treatment; (3) the events could not be reasonably

explained by information provided about the patients’

conditions or other factors. Six cases were rated as

probable because, in addition to meeting the above criteria,

withdrawal of the drug led to lessening of the events. Eight

cases were rated as definite, because the patients experienced

some symptom resolution after finishing an initial

course of a fluoroquinolone, then experienced worsening

of symptoms with repeated exposure to the same or another

fluoroquinolone.

PATIENTS’ CHARACTERISTICS

Of the 45 cases, 23 (51%) were women and 22 (49%)

were men. The average age was 42 years (range 11–68). Of

39 patients providing details about their prior health status,

24 (62%) had no prior medical problems, 11 had one other

medical disorder (28%), and four (10%) had two medical

disorders. These disorders were generally mild and included

chronic allergies/sinusitis (n = 5), controlled asthma (4),

controlled hypertension (3), thyroid disorders (3), mild depression

(2), osteoporosis (1), and mild immunoglobulin

deficiency (1). The specific disorders that necessitated fluoroquinolone

treatment are listed in Table 2.

ANTIBIOTIC USE

Levofloxacin was taken by 33 patients; ciprofloxacin,

11; ofloxacin, 6; lomefloxacin, 1; and trovafloxacin, 1.

Overall, the 45 patients received 60 courses of fluoroquinolone

antibiotics. Five patients received two different

fluoroquinolones and one received three; in each of these

cases, adverse events had occurred with the initial prescription.

Eight patients received two courses of the same

antibiotic; six of these patients described adverse events

with their initial fluoroquinolone prescriptions.

The onset of adverse events was usually rapid, with 15

of the 45 patients’ (33%) events beginning within 24 hours

of initiating fluoroquinolone treatment, 26 (58%) beginning

within 72 hours, 38 (84%) occurring within seven

days, and 43 (96%) within 14 days. Events began while receiving

fluoroquinolones in all 45 cases.

TYPES AND DURATION OF SYMPTOMS

Of the 45 cases, 21 (47%) reported both sensory and motor

abnormalities of the PNS. Twenty (44%) reported only

sensory abnormalities, and four (9%) reported only motor

abnormalities.

Forty-two patients (93%) experienced symptoms involving

systems outside the PNS; many experienced symptoms

in multiple organ systems. CNS symptoms were reported

in 78% of cases; musculoskeletal symptoms, 73%; special

senses, 42%; cardiovascular, 36%; skin, 29%; and gastrointestinal,

18%. The nature of these events are listed in Table 3.

The duration of symptoms exceeded one month in 41 of

45 cases (91%), three months in 32 cases (71%), one year

in 26 cases (58%), and 12 (27%) have exceeded two years’

duration. One case has continued more than four years and

another more than six years. These numbers are not final

because some cases were relatively new and are still evolv-ing.

SEVERITY OF SYMPTOMS

Based on the severity scale defined in the Methods sec-tion,

two cases were mild (4%), seven moderate (16%),

and 36 severe (80%). The severity of symptoms caused 11

patients to seek assistance at emergency departments, and

one patient went twice. Many patients offered unsolicited

descriptions of impaired functioning or a severity of pain

or other symptoms that appeared traumatic.

RECOGNITION OF ADVERSE EVENTS

Eighteen patients stated that their physicians either failed

to recognize or dismissed the significance of their neu-4

ropathies or more commonly recognized fluoroquinolone-associated

events such as joint pain, tendon pain, or CNS

symptoms. Mild adverse events often were not recognized.

Four patients reported being told to continue taking the antibiotics

despite complaining of adverse events.

TREATMENT

Eighteen patients reported receiving no medical treatment

for these events. Twenty-seven respondents received

medication therapy. Fourteen patients received nonspecific

treatment such as antidepressant, antiinflammatory, hypnotic,

or pain medication, usually with limited benefit. Ten

patients received steroids; of these, five reported partial

improvement of musculoskeletal symptoms, while two reported

worsening of neurologic symptoms. Five patients

received benzodiazepines, of whom three reported partial

improvement. One patient received gabapentin, and experienced

partial improvement. Many patients undertook

their own treatment measures such as improving their diets

and/or beginning or increasing their exercise, if symptoms

allowed.

SUBMISSION TO MEDWATCH

Patients were asked whether they had filed reports to the

FDA MedWatch program: 21 had filed a report, and two

of these had filed two reports; 10 filed no report; one patient

asked her physician to file a report but was not sure

whether he did; 13 patients did not answer this question.

Discussion

USE OF CASES COLLECTED VIA INTERNET

The Internet has facilitated a volume and rapidity of

communication that not even science-fiction writers imagined.

Already, many physicians have had to review information

of variable quality brought to them by concerned

patients. In this article, the use of the Internet to conduct a

survey naturally raises questions of reliability. However, all

science begins with observation, and the Internet presents

unique opportunities as a source of concentrated, elective,

patient-based information not previously available.

Some precedent exists in the use of the Internet as a

source of medically useful information. A common Web

site and communication channel for patients with erythromelalgia,

a rare and painful vascular disorder, spawned

The Erythromelalgia Association (TEA); (available at

www.erythromelalgia.com). This in turn facilitated the collection

of data from the largest group of erythromelalgia

patients ever assembled and the publication of a much-needed

review article 21 describing the diagnosis, pathophysiology,

and treatment of this often-recalcitrant disorder.

Similarly, in the present study, a common concern about

possible fluoroquinolone-related adverse events has led to

the informal association of thousands of individuals reporting

cases and/or sharing information in a manner that was

impossible before the Internet. Thus, these and other Web

sites may represent different populations than those reflected

by traditional reporting mechanisms (FDA, drug manufacturers).

With Internet cases, information is derived directly

from patients, whereas reports to the FDA and manufacturers

usually originate from healthcare providers.

Internet cases are, therefore, likely to present a different

perspective and different biases. It should be noted, however,

that patient-based reporting is accepted, indeed encouraged,

by the FDA, so these reports are a legitimate

source of information. Indeed, the ability to contact patients

to clarify and confirm information provided a degree

of completeness of information often lacking in reports

submitted to the FDA.

NEUROTOXICITY AND FLUOROQUINOLONE ANTIBIOTICS

CNS effects are the second most common type of ad-verse

event reported with fluoroquinolones,9,22,23 occurring

at an incidence of 1–7%.2-4,9,24-26 It is established that fluoroquinolones

can be neurotoxic,2-4,7,27,28 and that these

drugs can produce dose-related CNS excitation through inhibition

of . -aminobutyric acid (GABA) receptors,2,3,24,28,29

and perhaps N-methyl-D-aspartate or adenosine receptors.

9,29 Fluoroquinolones lower seizure thresholds 7,23,29 and

impede neuromuscular transmission,30 and they have been

associated with seizures and psychoses.2,4,7-9,23,31 Interestingly,

fluoroquinolone-associated seizures usually develop

within a few days of commencing treatment,9,25 which is

similar to the pattern reported here in which adverse events

began within three to four days in 58% of cases and within

seven days in 84%.

In contrast to CNS events, fluoroquinolone-associated

PNS events are not widely recognized. Although adverse

events such as paresthesias or neuropathies occurred at an

incidence of <0.5–1%, according to manufacturers 31 ; the

manufacturers of levofloxacin (personal communication,

Laura Mack RN, Ortho-McNeil Pharmaceuticals, April

24, 2001) and ciprofloxacin (personal communication,

Steve Paine RPh, Bayer Corp., April 24, 2001) have received

no postmarketing reports involving the PNS. The

only previous report in the medical literature involving

more than a few cases of fluoroquinolone-related neuropathies

was published in 1996 by the Swedish Adverse

Drug Reactions Advisory Committee.17 This report listed

37 cases of peripheral sensory disturbances submitted to

the Swedish authorities over a period of seven years

(1987–1993). Most of these events were mild and brief.

The present article describes a more serious problem,

perhaps reflecting the reporting population. The 45 cases

reflected here were provided voluntarily by patients motivated,

in most incidences, by severe or persisting problems,

and motivated enough to seek information via the Internet,

to locate and communicate through the Web site,

and to submit information to the author. These factors may

explain the preponderance of severe cases in this survey

and on Web sites for fluoroquinolone-related reactions that

differ markedly from previous published information.6,12,15-17

Thus, by attracting patients seeking information because of

severe or persistent events, Internet groups may provide a

different perspective on possible long-term events associated

with fluoroquinolones as well as with other drugs.

The preponderance of cases involving levofloxacin cannot

be explained by currently available information. The

secondary Web site from which five cases were received

consists mainly of cases involving levofloxacin, but the

main Web site that provided 39 cases includes all fluoroquinolones.

The preponderance of levofloxacin-associated

cases also cannot be explained by prescribing trends: in

2000, 14 004 000 prescriptions were filled for ciprofloxacin;

9 958 000 were filled for levofloxacin.32 Thus, this trend

may reflect a reporting bias or perhaps a previously unrecognized

tendency toward greater neurotoxicity with levofloxacin.

TREATMENT CONSIDERATIONS

The large number of patients stating that their adverse

reactions were missed or dismissed by their physicians

raises the question of whether some physicians are unaware

that fluoroquinolones have been associated with serious

nervous system effects. Alternately, the physicians

may have been unconvinced that the events were related to

treatment. In some cases, the severity and multiplicity of

these symptoms may have produced a confusing picture

that suggested unrelated conditions, especially since fluoroquinolone-

associated neuropathies are typically de-scribed

in the medical literature as mild and reversed by

discontinuation of the drugs.6,28,33 At the same time, the Internet

population may be biased toward patients dissatisfied

with their treatment and/or outcomes. It may be that

there are as many or even more patients encountering similar

problems, but who obtained better outcomes or were

satisfied with their physicians’ responses.

Clarification of these issues is beyond the scope of this

survey. For now, it appears that immediate discontinuation

is required for patients presenting with fluoroquinolone-related

peripheral neuropathies (or CNS or musculoskeletal

symptoms),34 and further antibiotic therapy should be pro-vided

from a different antibiotic group. Physicians should

be aware that fluoroquinolone-associated events can occur

after a single dose.35 However, in this survey, the majority

of severe cases occurred in patients who continued or

restarted fluoroquinolones after adverse events had occurred.

Thus, prompt recognition and withdrawal appears

imperative, especially because there is no recognized treatment

for these events and, according to this survey, supportive

treatment is often not highly effective.

Because fluoroquinolones compete for GABA receptors,

the use of benzodiazepines may be warranted. In this

survey, one patient reported mild improvement with clonazepam,

a benzodiazepine with a strong affinity for GABA receptors.

Because of interactions involving the nervous system, patients

should be cautioned about using caffeine-containing

foods 4,32,36-38 or nonsteroidal antiinflammatory drugs 4,15,23,24,31

with fluoroquinolones.

LIMITATIONS AND FUTURE STUDY CONSIDERATIONS

Many of the limitations of this study have already been

stated. As with the FDA’s MedWatch program, this survey

obtained voluntary reports from people not directly seen or

evaluated by the author, and the submitted information reflected

the perspectives of the patients reporting it. These

perspectives included interpretations of causality, which

may have differed from the perspectives of some patients’

physicians. Moreover, the reports in this survey emanated

from a subpopulation of patients motivated to seek information

via the Internet and motivated to volunteer for the

survey.

Because of its limitations, this article is not intended or

capable of establishing a cause–effect association between

the described events and fluoroquinolone therapy, and no

statistical tests were performed. Instead, the purpose of the

article is to report the existence of large concentrations of

patients with strikingly similar descriptions of possible fluoroquinolone-

associated adverse events of significant

severity and chronicity, and to suggest that further, more

formal scrutiny is warranted. It is also the intention of this

article to alert healthcare providers of the possible association

of fluoroquinolone therapy with these events in a population

of generally young, previously healthy and active

people.

Summary

Fluoroquinolones are important members of medicine’s

arsenal of antibiotics. Serious ADEs involving the CNS

and musculoskeletal systems have been reported but are

considered infrequent. Mild ADEs involving the PNS have

also been reported. This article, which presents a survey of

a different population (with mainly serious, long-term

symptoms) from a different source (the Internet), offers a

new and different perspective on fluoroquinolone-related

events involving the PNS. Further, better controlled investigation

is warranted. The FDA should also review and re-port

on its cases relating to fluoroquinolone antibiotics. If

the occurrence of fluoroquinolone-associated ADEs of this

severity and duration is confirmed, physicians need to be

informed and warnings might be considered for these

drugs’ product information. In the meantime, healthcare

providers may need to be vigilant regarding ADEs associated

with fluoroquinolones, and even mild events involving

the nervous or musculoskeletal systems should prompt

immediate discontinuation.

Jay S Cohen MD, Associate Clinical Professor, Departments of

Family and Preventive Medicine, and Psychiatry, University of Cal-ifornia,

San Diego, La Jolla, CA

Table 1. Fifteen Cases of Fluoroquinolone-Associated Events a

Pt. Age/ ADE

Gender Drug Use Onset (d) Symptom Course Treatment

32/F Cip UTI 1 tingling, anxiety antibiotic stopped, effects quickly abated none

11/F Lev bone infection 5 tingling, "electrical" pain in pain limited walking, symptoms dis- none

arms and legs appeared 2 d after antibiotic stopped

39/M Lev prostate infection 20 diffuse tingling, skin-crawling moderate discomfort, nearly complete none

sensation, numbness resolution over 14 mo

26/M Lev bronchitis 1 numbness, tingling, twitching, constant discomfort 1 mo, gradual im-allodynia,

anxiety provement over 6 mo, anxiety remains

40/M Lev UTI 4 tingling, burning pain, severe pains, function limited, gradually none

twitching, knee swelling, improved over 40 d, some symptoms

joint/muscle pain, odd smells persist

41/F Lev b sinusitis 2 diffuse numbness, alloydynia, severe initially, greatly limited func- steroids helpful

severe, muscle/joint pain tioning, subsided over 2 wk

32/M Lev prostate infection 1 numbness, tingling, shooting disabling for several mo, unable to NSAIDs minimally

pain, severe tendon pain exercise for 6 mo, resolved after 2 y helpful

34/M Lev b prostate infection 5 numbness, muscle twitching, severe for 4 mo, some symptoms diazepam partially

weakness, impaired coordination, persisting after 12 mo helpful

increased sensitivity to temp-eratures,

fatigue, multiple

joint/muscle pain, palpitations,

blurred vision, fear

31/F Lev sinusitis 3 diffuse tingling, burning pain, functioning limited initially, slow im- none

numbness, "pins/needles," provement, with some symptoms

twitching, multiple severe still lasting after 6 mo

tendinitis, temperature

intolerance

53/M Lev b prostate infection 2 numbness, tingling, cramps, severe initially; some sensory symptoms none

wrist pain, tremors, fatigue, continue, joint pain limits walking after

joint/tendon pain 14 mo; nerve biopsy showed nonspecific

damage

49/F Ofl pelvic infection 1 diffuse numbness, "pins/needles," functioning limited, work affected, some none

burning pain, memory loss, symptoms still present after 3 y

impaired vision, joint pain,

palpitations, diarrhea, stomach

cramps, altered sense of smell,

insomnia, tinnitus, severe panic

attacks

51/F Lev pelvic infection 2 "electrical" sensations, numbness, Achilles tear required cast/crutches for NSAIDs not

allodynia, multiple severe ten- 3 mo; memory problems and multiple helpful; steroids

dinitis, partial tear of Achilles tendinitis persisted after 1 y helped tendinitis

tendon, memory problems,

confusion, impaired concen-tration

56/F Ofl, UTI 3 acute nocturnal onset of severe initially went to ED; disabled, most lorazepam help-Cip

burning pain, numbness, symptoms have persisted 4 y ful for some

twitching; "electrical" sensations, symptoms

carpal tunnel syndrome,

nightmares, confusion,

tachycardia, 30-lb weight loss,

muscle/joint pain, impaired

hearing, altered sense of smell

44/F Cip bronchitis 4 numbness, allodynia, hyper- went to ED; multiple drugs unhelpful; steroids

esthesia, tremors, "electrical" remains disabled after 29 mo; tests worsened

sensations, diffuse burning confirmed nonspecific nerve damage symptoms

sensation, tremors, twitching,

disorientation, visual impairment,

nausea, temperature intolerance,

rash, palpitations

38/M Lom prostate 14 severe twitching, numbness, disabled, most symptoms persisting multiple drugs

"electrical sensations," tingling, after 6 y not helpful

pain, hyperesthesia, muscle/joint

pain, fatigue, multiple CNS

symptoms

Cip = ciprofloxacin; CNS = central nervous system; ED = emergency department; Lev = levofloxacin; Lom = lomefloxacin; NSAIDs = nonsteroidal an-tiinflammatory

drugs; Ofl = ofloxacin.

a Selected to represent the range of symptoms and severity among the 45 cases in this survey.

b Second course of levofloxacin; mild events unrecognized during first course.

Table 2. Disorders Requiring Fluoroquinolone Therapy a

Patients

Disorder n %

Sinusitis 13 33

Prostatitis, epididymitis 9 23

Urinary tract infection 6 15

Pulmonary (asthma, bronchitis, pneumonia) 6 15

Postabdominal surgery 2 5

Inner ear infection 1 2.5

Toe infection 1 2.5

Bone infection 1 2.5

a Thirty-nine patients.

Table 3. Adverse Events Reported a

Patients

System n % Reported Events

PNS, sensory 41 91 tingling, numbness, prickling, burning pain, pins/needles sensation, "electrical" or shooting

pain, skin crawling sensation, hyperesthesia, hypoesthesia, allodynia, numbness

PNS, motor 25 55 weakness, twitching, fasciculations, tremors, spasms, contractions

CNS 35 78 dizziness, malaise, weakness, impaired coordination, nightmares, insomnia, headaches,

agitation, anxiety, panic attacks, disorientation, impaired concentration or memory,

confusion, depersonalization, hallucinations, psychoses

Musculoskeletal 33 73 muscle pain, weakness, soreness; joint swelling, pain; tendon pain or rupture

Special senses 19 42 diminished or altered visual, olfactory, auditory functioning, tinnitus

Cardiovascular 16 36 tachycardia, shortness of breath, hypertension, palpitations, chest pain

Skin 13 29 rash, urticaria, hair loss, sweating, intolerance to heat and/or cold

Gastrointestinal 8 18 nausea, vomiting, diarrhea, abdominal pain

Other symptoms

weight loss 3 7

anemia 2 4

difficulty urinating 1 2

worsening of asthma 1 2

CNS = central nervous system; PNS = peripheral nervous system.

a All patients (n = 45) reported at least one event involving the PNS. In addition, 42 patients (93%) reported events in other organ systems.

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Research Reports

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