CASE REPORT  
Niger J Paed 2014; 41 (2): 138 –140  
Frank-Briggs AI  
Oluwatade OJ  
Drug induced aseptic meningitis: A  
diagnostic challenge  
DOI:http://dx.doi.org/10.4314/njp.v41i2,13  
Accepted: 29th September 2013  
Abstract Drug-induced aseptic  
meningitis (DIAM) is a rare but  
important and often challenging  
diagnosis for the physician. Intake  
of antimicrobials, steroids, anal-  
gesics amongst others has been  
implicated. Signs and symptoms  
generally develop within 24-48  
hours of drug ingestion. The pa-  
tient often exhibits the classic  
symptoms of meningitis.  
tone and deep tendon reflexes  
were normal with no cranial nerve  
deficits. Other systems examina-  
tions were unremarkable.  
(
)
Frank-Briggs AI  
Departments of Paediatrics & Child  
Health, University of Port-Harcourt  
Teaching Hospital, Port Harcourt,  
Rivers State, Nigeria.  
Email: afrankbriggs@yahoo.com  
Tel: +2348033092885  
Case II: 15 year old male with no  
significant past medical history  
presented with a day’s history of  
altered mental status, headache  
with no fever. He had been on self-  
medication with over the counter  
Ibuprofen tablets for intractable  
headache three days prior to pres-  
entation. Examination showed  
equivocal neck stiffness clouded  
by profound altered mental status.  
They were both initially managed  
for meningitis. Cerebrospinal fluid  
work-up for both cases ruled out  
infectious etiologies. Possible drug  
induced meningitis was then con-  
sidered.  
Conclusion: Drug-induced aseptic  
meningitis is rare but should be  
considered in the differential diag-  
nosis of patients presenting with  
acute or recurrent symptoms and  
signs of meningitis, especially  
after infectious causes have been  
ruled out.  
Oluwatade OJ  
Department of Infectious Disease/  
Internal Medicine, Central Mississippi  
Medical Center, Jackson, MS,USA.  
Aim: Two cases of drug induced  
meningitis are presented with  
review of literature.  
Case reports:  
Case I: A 13 year old male with a  
three days history of persistent  
fever, vomiting, abdominal pain  
and poor appetite. He also had  
generalized throbbing headache  
and neck pain of a day’s duration.  
®
He had been on Bactrim for uri-  
nary tract infection (UTI) three  
days prior to the onset of the pre-  
sent symptoms.  
On examination, he had altered  
mental status (confused), neck  
stiffness and a positive Kerning’s  
and Brudzinski's signs. Muscle  
Introduction  
reaction. The benign nature of drug induced meningitis  
and the progressively shorter time interval between in-  
gestion of the drug and the appearance of symptoms on  
drug re-e5xposure suggest that an allergic mechanism is  
involved .  
This paper describes two case of DIAM: an antibiotic-  
Bactrim and a non-steroidal anti-inflammatory agent-  
Ibuprofen.  
Drug induced meningitis has been reported following  
administration of various agents including antimicrobial,  
cytotoxic and non-steroidal anti-inflammatory drugs;  
intrathec1al steroids and intravenous immune globulins  
(
IVIGs). Antibiotic induced meningitis has been re-  
1
ported mostly with sulphonamides . Symptoms develop  
a few hours to days after the exposure to the antibiotic  
and include headache, nausea, myalgia, chills, fever, and  
2
confusion . Resolution of symptoms may occur within a  
Cases and Method  
few to several days after drug discontinuation. The clini-  
cal and cerebrospinal fluid profile (neutrophilic pleocy-  
tosis) may not allow3 DIAM to be distinguished from  
infectious meningitis .  
Case I  
A thirteen year old male student presented with a three  
day history of persistent fever, vomiting, abdominal pain  
and poor appetite. He had generalized throbbing head-  
ache and neck pain of a day duration. He had been on  
prescribed Bactrim for urinary tract infection (UTI) for  
about three days prior to the onset of the present  
symptoms. On examination, the blood pressure was  
100/70mmHg, thoe pulse rate was 113/ minute, tempera-  
ture of 38.2 C, anicteric, altered mental status  
There are no specific characteristics associated with a  
specific drug- thus posing a diagnostic and management  
myth. Typical cerebrospinal fluid (CSF) findings consist  
of polymorphonuclear pleocytosis, normal glucose, and  
®
4
elevated protein . The mechanisms proposed involve  
either a direct chemical irritation or a hypersensitivity  
1
39  
(
confused, with incoherent speech and impaired orienta-  
Laboratory Results  
tion), with neck stiffness and a positive Kerning’s and  
Brudzinski signs. He also had a normal tone and deep  
tendon reflexes. There were no cranial nerve deficits.  
Chest was clinically clear to auscultation and he had no  
murmurs. Abdominal and other system examinations  
were essentially normal.  
9
White blood cell count (WBC) was 5.6 x 10 /l, Hg/  
9
Hct13.9/dl /41%, Platelets 114×10 /L, Cr 1.6, BUN15m-  
mol/l, Na 137mmol/l. Cerebrospinal fluid (CSF): open-  
ing pressure ~ 200mmH O, gram stain was negative,  
2
sugar 42mg/dl, protein 102mg/dl, WBC 75cells/microL,  
red blood cell 0-1, lymphocytosis 73%, neutrophils  
17%, blood cultures were negative. CSF white cell count  
was 65 with 75% polymorphs.  
CSF: Bacterial detection antigen screen was negative,  
gram stain showed no organism. Polymerase chain reac-  
tion (PCR) showed no detection for cytomegalovirus,  
herpes simplex virus I&II, Arbovirus panel and Myco-  
bacterium tuberculosis and Ebstein barr virus. Miscella-  
neous tests such as galactomannan assay, urine histo-  
plasma antigen, Quantiferon Gold Assay, HIV tests  
were all negative. Computed tomography scan (CT) and  
MRI of the brain showed no acute brain lesions. Ibupro-  
fen was discontinued and his symptoms resolved within  
72 hours of admission with no neurological deficits.  
Laboratory Results  
9
White blood cell count (WBC) was 2 x 10 /l, haemoglo-  
bin / hematocrit ( Hgb/Hct) values were 9.5g/dl /30%,  
9
Platelets 20 ×10 /L, Cr 3.6, blood urea nitrogen (BUN)  
1
8mmol/l,sodium (Na) 137mmol/l. Cerebrospinal fluid  
CSF): opening pressure 200mm H O, gram stain was  
negative, sugar 30mg/dl, protein 115mg/dl, WBC  
25cells/microl and lymphocytosis 80%. CSF: bacterial  
(
2
1
antigen screen was negative, polymerase chain reaction  
showed no detection for Cytomegalovirus, Herpes sim-  
plex virus I&II, arbovirus panel and Mycobacterium  
tuberculosis and Ebstein barr virus. CSF and blood cul-  
tures yielded no growth after 48 hours and five of days  
incubation respectively.  
Other tests done included: Galactomannan Assay, urine  
histoplasma antigen, Quantiferon Gold Assay, HIV test  
which were all negative. Computed tomography scan  
Discussion  
(
brain showed no acute lesions.  
CT) and magnetic resonance imaging scan (MRI) of the  
The two cases presented here were on drugs namely  
Bactrim and Ibuprofen respectively. The interval be-  
tween drug intake and the development of meningitis  
varies widely. Signs and symptoms usually appear  
within 24 to 48 hours after drug ingestion, but symptoms  
may not appear in some cases for up to two years post-  
The child was empirically started on intravenous Ro-  
cephin, Vancomycin and Acyclovir pending further evi-  
dence of non-infectious etiology. The bactrim was dis-  
continued on admission with serial monitoring of  
creatinine which trended down to normal prior to dis-  
charge. His mental status and neurologic findings im-  
proved within 48 hours.  
6
therapy. Our patients had symptoms appearing early.  
This p7,a8ttern has also been noted and reported previ-  
ously.  
Platelet transfusion was given prior to lumbar puncture  
to prevent bleeding as quantitative versus qualitative  
defects could not be ruled out at presentation. The pa-  
tient was discharged from the hospital with a presump-  
tive diagnosis of aseptic meningitis caused by Bactrim  
hypersensitivity. The patient was advised to avoid taking  
bactrim in the future. He has continued to do well on  
follow up.  
Drug-induced aseptic meningitis (DIAM) has been re-  
ported as an uncommon adverse reaction to numerous  
drugs. It is a diagnosis of exclusion, and clinical signs  
5
and CSF findings vary greatly . The incidence of drug  
induced meningitis remains unknown as most cases di-  
agnosed are unreported and many remain unrecognized.  
The body of evidence regarding DIAM is largely in the  
form of anecdotal case reports and must be interpreted  
6
carefully bearing this in mind . The major categories of  
Case II  
causative agents are non-steroidal anti-inflammatory  
drugs, antimicrobials, intravenous immunoglobulin,  
intrathecal agents including steroids, vaccines and a  
number of other less frequently reported agents such as  
vitamins. Drug induced aseptic meningitis can mimic  
an infectious process as well as meningitis secondary to  
systemic di6s,9o,1r0ders for which treatment of these drugs  
were used.  
This was a 15 year old male with no significant past  
medical history who was admitted via the emergency  
room for evaluation of altered mental status. For the last  
three days prior to presentation, he had been taking sev-  
eral pills of Ibuprofen for an intractable headache. This  
was not his first exposure to Ibuprofen. On examina-  
o
tion, temperature was 39 C, blood pressure of 110/65  
altered mental status, he was talking irrationally, disori-  
ented in time and place, equivocal neck stiffness, Ker-  
nig’s sign was positive, hypertonia of the lower limbs.  
The other systems examinations were normal. He was  
empirically started on intravenous Rocephin and Vanco-  
mycin for presumptive bacterial meningitis which were  
discontinued after 72 hours as there was no evidence of  
infective etiology.  
Drug-induced aseptic meningitis may develop in a pa-  
tient who initially was able to tolerate the causative  
drug. The patients in our report have had previous expo-  
sures. Prior exposure to the drug has been noted in 45%  
of patients taking NSAIDs; and 35% and 3% for antibi-  
2
otics and IVIGs respectively . These rates of prior expo-  
sures are not surprising, considering the inappropriate  
and high frequency with which NSAIDs and antibiotics  
are prescribed.  
1
40  
The majority of patients with DIAM, irrespective of the  
offending drug, present with headache, fever, meningis-  
mus and changes in mental status which are also symp-  
patients, early in its course, there may be prevalence of  
neutrophils in the CSF with a subsequent shift to  
lymphocytosis.  
3
toms characteristic of infectious meningitis .Therefore,  
the clinical presentation does not help to differentiate  
DIAM from infectious meningitis. DIAM is also associ-  
ated with other systemic diseases. There appears to be  
an association between DIAM and connective tissue  
disease, particularly systemic lupus erythematosus and  
Ibuprofen; mi4graine has been suggested as a predispos-  
ing condition.  
Enteroviruses may be isolated by culture or PCR tech-  
niques. This test being highly sensitive and specific was  
negative in both patients. Herpes simplex I/II PCR was  
also negative. It was concluded that viral encephalitis/  
meningitis was ruled out since the viral PCR remained  
undetected.  
There are two major proposed mechanisms for DIAM.  
The first involves direct irritation of the meninges by  
intrathecal administration of the drug, and the second  
involves immunological hypersensitivity to the drug  
most likely type III and type IV hypersensitivity reac-  
tions. The mechanism of action of antibiotic- induced  
meningitis is due to hypersensitivity reaction just as it is  
Neuroimaging was normal in both cases as well. This is  
similar2 to other cases that have been reported previ-  
1
ously. However, there are some cases of NSAID –  
induced DIAM described in literature where diffuse  
contrast hemispheric enhancement was evident by mag-  
netic resonance imaging and computed tomographic  
scan probab9l,y12reflecting a blood-brain barrier  
breakdown.  
2
for NSAIDs . Recognition and diagnosis of DIAM is  
important, as it is treatable by withdrawal of the drug  
and recurrence is thus prevented. The outcome of DIAM  
i1s0,1g1 enerally good, usually without long term sequelae  
Conclusion  
The Patients’ clinical presentations provide an opportu-  
nity to discuss the differential diagnosis of meningitis.  
Acute Bacterial meningitis is usually of sudden onset  
and characterized by an appearance of being ill: High  
fever, Headache, Photophobia, abnormal CSF picture  
such as predominance of neutrophils, elevated protein  
and decreased glucose. The predominance of lympho-  
cytes in the CSF and negative cultures makes diagnosis  
of bacterial meningitis unlikely in both cases. Viral  
meningitis (VM) though typically diagnosed in young  
There should be a high index of suspicion in all patients  
presenting with symptoms of meningitis with negative  
CSF culture. Detailed drug history should be obtained  
including a thorough search for over the counter medica-  
tions which very often are either ignored or taken for  
granted both by the physicians and patients.  
Conflict of interest: None  
Funding: None  
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