Dokkyo Journal of Medical Sciences
37（3）：173 〜 180，2010

173

Originals

Clinical features and subdural lesions in childhood onset
Haemophilus influenzae meningitis
1

2

1

1

George Imataka , Atsushi Yoshida , Keiko Tsukada , Satomi Koyama ,Naoto Shimura1 , Keitaro Fukushima1 , Osamu Arisaka1
Department of Pediatrics1 and Clinical Laboratory Medicine2 , Dokkyo Medical University School of Medicine

SUMMARY
It becomes difficult to treat the onset of childhood Haemophilus influenza type b（Hib）meningitis due tothe appearance of b -lactamase negative ampicilin resistance（BLNAR）.We investigated the clinical featuresof Hib meningitis with subdural lesions. From January 2000 to December 2006, we experienced 8 patientswith Hib meningitis. All patients were not inoculated with Hib vaccine. Five of them were onset under 1
year old. Rapid latex diagnoses were made in 5 patients, among whom 4 patients showed Hib positive. The
genotypes were determined in 4 patients with BLNAR. Combined with cefotaxime sodium（CTX）and ampicillin（ABPC）were used in 3 patients for the initial antibiotics, panipenem/betamipron（PAPM/BP）in 2,
meropenem hydrate（MEPM）in 1, MEPM ＋ ceftriaxone sodium（CTRX）in 1, and concomitant use of dexamethasone in 7 paitents. MRI showed subdural hygroma in 4 patients and subdural abscess in 4 patients.
Subdural lesions appeared on Day 1 to Day 18 from the onset. Three patients with subdural abscess have
performed subdural taps, and 2of them with difficulties after subdural taps were necessary to do oral administration of chloramphenicol（CP）.
In our report, all of the patients developed subdural lesions. The development of subdural lesions cannot
be avoided with only the conventional antibiotics and dexamethasone therapy. Our cases suggested earlier
subdural taps with oral administration of CP might be to improve both the general condition and control the
subdural lesions with Hib meningitis. Moreover, we should pay attention tothe preventive vaccination of
Hib.
Key Words：Haemophilus Influenzae, subdural hygroma, subdural hematoma, vaccine, magnetic resonance imaging, single photon emission computed tomography

INTRODUCTION

such as epilepsy and auditory damage with hearing
loss are evident in approximately 2 5％ of all pa-

Bacterial meningitis caused by infantile Haemophilus

tients 8 , 9）, even at present, after the advancement ofinfluenza type b（Hib）is a bacterial infectious disease

treatment via antibiotics. Furthermore, in recent years,

with a poor prognosis wherein death occurs in about

with the increase in the use of antibiotics in children,

over 5％ of all patients

1〜7）

and lingering after effects

Hib has rapidly become drug resistant b -lactamase
negative ampicilin resistance（BLNAR）, and Hib infec-

Received June 28, 2010；accepted October 27, 2010
Reprint requests to：George Imataka MD
8 8 0 , Kitakobayashi, Mibu, Shimotsuga,
Tochigi 321-0293 Japan

tions associated with meningitis, septicemia, acute epiglottitis, etc., tend to be increasingly intractable 10,11）.
On such the situation, in 1998, the World Health Organization（ WHO）released a statement to promote

174

George Imataka

regular vaccination with a Hib vaccine in infants, andDJMS

1. Gender, age, time of onset, presence or absence ofregular vaccinations were subsequently introduced inunderlying disease

more than 1 0 0 countries, including developing coun-

The gender and age of onset of the 8 patients weretries throughout the world 12〜16）. By the enforcement of

6 for boys and 2 for girls. The distribution of the age

the regular vaccination of Hib on the internationalof onset was determined as 1 month after birth at thescale by WHO, the frequency of meningitis due to Hib

youngest and 7 years 0 months after birth at the old-

has rapidly decreased, so it is believed that it is a rare

est, and the median was 2 0 months. Of these, 5 pa-

disease on a global scale.

tients were infants who were under 1 year old. The

On the other hand, no Hib vaccine had yet been ap-

months of development were March and June in 7 pa-

proved in Japan 1 1）. Therefore meningitis by Hib stilltients. As for the presence or absence of a backgrounddeveloped in more than 600 patients annually in Japan.

underlying disease, a 7 year and 0 month old girl had

In January 2007, Hib vaccine was finally approved by

cerebral palsy compounded by trouble with a ventricu-

the Ministry of Health, Labour and Welfare and has

loperitoneal shunt. One patient was a newborn baby,

been become available for not only regular but also

but this does not apply as an underlying disease.

voluntary vaccination

17）.

Based on these social circumstances, we summarized

2. Rapid diagnosis by latex agglutination reaction withthe clinical presentations of Hib meningitis including

Hib

BLNAR that we observed at our hospital, and we in-

Rapid diagnoses by latex agglutination reaction us-

sist on the necessity to introduce a regular vaccination

ing a rapid kit（Fig. 1）were made in 5 of 8 patients.

of the Hib vaccine in Japan in this article.

Two of the patients showed no agglutination, so a rap-

PATIENTS AND METHODS
The subjects consisted of 8 patients with acute pu-

id diagnosis could not be determined. The general cultivation of bacteria in the spinal fluids revealed Hib in
all of the patients.

rulent meningitis caused by Hib who were hospitalized
at Dokkyo Medical University Hospital during the

3. analyze the genotypes 1,2）7-year period from January 2000 to December 2006.

We requested the Graduate School of Infection Con-

Acute purulent meningitis was clinically diagnosed

trol Sciences, Kitasato Institute for Life Sciences, to an-based on the increase in the number of spinal fluid

alyze the genotypes only in 4 patients. The results

cells and the results of bacterial cultivation of the spi-showed BLNAR with the variation of the PBP-3 genenal fluids. The following five factors were retrospec-in 4 patients.

tively studied in each subject based on our hospital’s
medical records：1. gender, age of onset, time of onset,

4. Treatment

the presence or absence of underlying diseases；2. dif-

The use of antibiotics was immediately initiated inferences between the results of the rapid diagnoses by

all of the patients. The types of initial antibiotics that

latex agglutination reaction（Applied Bio-Rad Ltd, PA-

were used included ABPC＋CTX in 3 patients and

STOREXⓇ. MENINGITIS, France）and the general

CZOP＋AMK in 1 patient, PAPM/BP in 2 patient,cultivation of bacteria；3. analysis the Hib genotypes,

MEPM in 1 patient and MEPM＋CTRX in 1 patient.

the variation of the penicillin-binding protein（ PBP）

The dosages of the antibiotics that were used consist-

gene 1 , 2）；4 . antibiotics used；and 5 . the presence or

ed of 2 increments of 120 mg/kg/day of MEPM, 3 in-absence of subdural lesions with others.

crements of 200 mg/kg/day of CTX, 2 increments of

RESULTSThe results of summarizing the clinical courses of all
8 subjects are shown in（Table 1）.

200 mg/kg/day of ABPC, 2 increments of 100 mg/kg/
day of PAPM/BP, 1 increment of 1 0 0 mg/kg/day of
CZOP and 8 mg/kg/day of AMK, respectively.
In 7 of 8 patients, dexamethasone was used before
each administration of the antibiotics with a dosage of
4 increments of 0.6 mg/kg/day. The period of adminis-

0y11m/boy（May）

7y0m/girl（June）

0y3m/boy（May）

1y11m/girl（November）

0y6m/boy（May）

0y1m/boy（March）

0y3m/boy（April）

2y6m/boy
（May）

1

2

3

4

5

6

7

8

─

─

─

─

─

─

cerebral
palsy

─

3,750

6,680

34,0005,480

20,701

9,410

ND

7,712

325

359

310

166

356

123

ND

132

BLNAR
（positive）

BLNAR（negative）

BLNAR（positive）

BLNAR（positive）

BLNAS（negative）

ND

ND

ND

4

2

1

2

0.25

0.25

ND

ND

4 days3 daysMEPM→ CTX→ MEPM→ CP

subdural abcess（10）

MEPM＋CTRX

4 daysNU

3 days3 days4 daysNU

PAPM/BP→ MEPM

4 days3 days3 daysNU

ABPC＋CTX→ MEPM→ CTX→ CTRX→ CP
ABPC＋CTX

NU
NU

4 days3 daysventriculo
peritoneal
shunt
evulsion

ND

Surgery

severepsychomotor
development

epilepsy

ND

subdural taps
fromanterior
frontalnormaldevelopment

DIC，
SIADH
HHV-6
infection

SIADH

normaldevelopment

normaldevelopment

normaldevelopment

convulsion, hyperactivity,
epilepsy brain atrophy

SIADH

subdural taps convulsion,
SIADH,
from
DIC
anterior
frontal

ND

ND

normaldevelopment

normaldevelopment

Prognosis─Complication

subdural taps convulsion,
epilepsy,
fromventricle
anterior
dilatation
frontalDexamethasone（0.15 mg/kg×4/day）
Immunoglobrin（150 mg/kg/day）

CZOP＋AMK

ABPC＋CTX

Antibiotics

subdural hygroma
PAPM/BP（4）→ MEPM＋CTX

subduralhygroma＋abcess（15）

subdural hygroma（15）

subdural hygroma（18）

subduralhygroma＋abcess（4）

subdural abcess（1）

subdural hygroma（9）Type of subdural
MinimalUnderlying Cerebrospinal Cerebrospinal Type of Hib
lesions
inhibitory
disease fluid cell count/ fluid protein（Latexmm3（mg/dl） agglutination concentration （diagnosed days
from admission
for ABPC
reaction）（on admission）
on brain MRI）
（mg/ml）

Clinical features with subdural lesions on MRI in 8 cases with childhood onset Haemophilus influenzae type b meningitis

Haemophilus influenzae meningitis associated with subdural lesions

Abbreviations：
ABPC（ampicillin）, CTX（cefotaxime sodium）, CZOP（cefozopran hydrochloride）, AMK（amikamycin）, PAPM/BP（panipenem/betamipron）,MEPM（meropenem hydrate）,
CTRX（ceftriaxone sodium）, CP（chloramphenicol with oral administration）, BLNAR（b -lactamase negative ampicilin resistance）,BLNAS（b -lactamase negative ampicilinsensitive）, Hib（Haemophilus influenza type b）,MRI（magnetic resonance imaging）, NU（not use）
, ND（not done）,SIADH（syndrome of inappropriate secretion of antidiuretic
hormone）, DIC（disseminated intravascular coagulopathy）, HHV（human herpes virus）

Age ofonset/sex（admission
month）

Case
No.

Table 137（3）（2010）
175

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George Imataka

Figure 1

DJMS

Latex agglutination reaction using a rapid kit showed agglutination reaction to
Hi in patient No.5.（1/A：control with Haemophilus influenza type b, 2/B：
Streptococcus pneumoniae, 3/C：Escherichia coli, 4/D：Neisseria meningitides,
5/F：group B streptococci, 6/G：Haemophilus influenza type b）

tration of dexamethasone was 2 patients in 3 days andformed with subdural taps and 2 increments of 1 0 0

5 patients in 4 days.

mg/kg/day of CP were orally administered as part of

The other concomitantly used drugs included man-antibiotics treatment, after which the amelioration of

nitol, and midazolam that was continuously adminis-

the subdural abscess was observed with the passage

tered in subjects in whom convulsive symptoms wereof time.

observed.

In the 4 patients in whom subdural hygroma wasobserved, the continued administration of the already5. Subdural lesions and neurological prognoses

administered antibiotics ameliorated the hygroma.

Several brain CT or MRI examinations were per-As for neurological prognoses, concomitant symp-

formed at appropriate times in all of the patients, andtoms that were observed within the observation period

the complication of the development of subdural le-until September 2 0 1 0 included epileptic seizure in 4

sions was neuro-radiologically studied. The results

patients, auditory disorder in 0 , and death in 0 pa-

showed the compounded development of subdural le-tients.

sions in all of 8 patients. The details consisted of subdural abscess in 4 patients and subdural hygroma in 4

DISCUSSION

patients. The time of onset of subdural hygroma or ab-

We studied 8 patients with Hib meningitis in child-scess was 1 to 18 days after the initiation of treatment,

hood. We made early diagnoses of Hib using spinal flu-

which was diagnosed via neuro-radiological imaging

id via the latex method and treated with appropriate（Fig. 2）.

antibiotics according to sensitivity, but all of the pa-

Four patients with subdural abscess were initiallytients developed subdural lesions. Our cases indicate

treated with antibiotics that improved general condi-

that it is impossible to avoid the complication of devel-tions but failed to reduce the abscesses in size. Threeoping subdural lesions with the administration of theout of 4 patients with hematoma, drainage was per-currently available antibiotics alone with Hib meningi-

37（3）（2010）

Figure 2

Haemophilus influenzae meningitis associated with subdural lesions

177

Brain MRI FLAIR images（spin echo：TR＝9,000 msec/TE＝105 msec）with contrast agent（A/B：patient No.7, E/F：patient No.6）（C/D：patient No.7, G/H：patient No.6）revealed
enhancement image of miginx and severe subdural effusion in patients with Hib meningitis.
99m

Tc-ECD SPECT（C/D：patient No.7, G/H：patient No.6）exhibited hypoperfusion corticalareas consisted with adjacent to the subdural effusion.

tis.

pan, Hasegawa et al. reported in 2 0 0 4 that 2 1 . 3％ ofRegarding the diagnosis of Hib meningitis, it is nec-

the Hemophilus influenzae that was investigated inessary to be performed in spinal fluid to detect the2002 showed BLNAR, which is a problem, because thecausative bacterium, and appropriate treatment was

detection rate is very high 1 1 , 1 7）. After we diagnosed

given accordingly. Meanwhile, until the causative bac-Hib according to the latex rapid reaction, we suspected

terium was determined, treatment with an antibiotic

BLNAR and selected antibiotics such as MEPM andwas administered after the causative bacterium with

PAPM/BP as well as the fourth- or third-generation

empiric therapy. We performed latex agglutination us-

cephalosporins such as CZOP and CTX. Dexametha-

ing spinal fluid to make an earlier diagnoses of Hib andsone therapy was reported 2 1〜2 3） and was determined

initiated treatment with antibiotics. This kit was very

as effective in preventing auditory damage 8,9）. Howev-

useful, because very early diagnoses of causative bac-er, we could not avoid the complications of subdural le-teria that induced the bacterial infectious diseases

sions in all 8 patients.

could be made within about 15 minutes, and differen-

It has been reported that the complication of sub-tial diagnoses of pneumococcal organisms, Escherichia

dural lesions is often observed in Hib meningitis 2 4 , 2 5）,coli, meningococcus, etc., could also be simultaneously

and methods of treating it often become problematic

made in addition to Hib 18〜20）. For antimicrobial thera-

during the course of Hib meningitis. All of our Hib

py, the ampicillin, is generally regarded as effective,meningitis exhibited subdural lesions. Anzai et al. re-but in recent years, ampicillin-resistant Hib has be-

ported 9 cases of Hib meningitis with subdural abscesscome a problem. In our patients, BLNAR was also ob-

and performed subdural taps in 4 patients, and they

served in 4 patients. BLNAR was first reported inconcluded earlier intervention with subdural taps to1980 due to the increased use of treatment with sever-the subdural abscess might be prevented additional

al antibiotics. PBP-3 of penicillin-binding protein is in-complications 2 6）. According to our patients No. 4 , 5 , 8

volved in the mechanism of acquiring resistance. In Ja-

with only subdural hygroma showed amelioration

178

George Imataka

DJMS

through continuous treatment with antibiotics. In gen-development of Hib meningitis and Hib infections. At

eral, the expression of subdural abscess indicates insuf-

present, it is speculated that 8 . 6 to 8 . 9 people per

ficient treatment with antibiotics in meningitis. Howev-

100,000 people who are below the age of 5 years old

er, in the patients with subdural abscess, the lesions

are affected with bacterial meningitis per year in Ja-

did not ameliorate with the administration of antibiot-

pan 1 5）. Vaccination of the Hib is recommended for

ics alone, so we performed subdural taps in patients

younger children under 5 years old, but we treated

No. 3 , 6 , 7 . After we employed several subdural taps

Hib meningitis in a 7-year-old in patient No.2. The Ja-

accordingly, amelioration of the subdural abscess waspan Pediatric Society submitted a requisition paper toclinically observed.

the Ministry of Health, Labour and Welfare in June

The subdural lesions that were observed with diag-2005, requesting early approval. At the end of January

nostic imaging showed a contrast effect along the area

2007, the production of an Hib vaccine（ActHIB ®）wasaffected by meningitis. This is an image of meningitis

finally approved 17）. In the United States, regular vacci-

being capsulated due to inflammation of the meninx,

nation with Hib vaccines was introduced in 1987, thus

thus forming an abscess therein. When the inflamma-

resulting in a dramatic decrease to 1/100 of the infec-

tion of capsulated meningitis is observed, it is believedtions caused by Hib 3 , 7）. In the UK, vaccines were ap-

that the effect of an antibiotic did not extend to the in-proved in 1992, and the prevalence of Hib in patientsside of the capsule.

under 5 years old decreased to 0.6 per 100,000 people

CP shows high central transfer and is particularly

in 1998 3,4）. With the approval of Hib vaccine in Japan

administered for Hib meningitis 27,28）. Thus, the oral ad-

as a turning point, it is expected that Hib meningitis inministration of CP was selected as an antibiotic in pa-

Japan will dramatically decrease in the near future.

tients No. 3 , 6 . Side effects include liver, kidney, andHowever, Hib vaccination is currently voluntary. It is

gastrointestinal damage, hematopoietic damage, ana-

preferable for Hib vaccination to be incorporated into

plastic anemia, and Gray syndrome, but these side ef-

regular vaccinations as a government policy. To pre-fects were not observed in our subjects. Sofue-Hiraiwa

vent the Hib meningitis associated with subdural le-et al. reported successful treatment of four infants withsions, attention should be paid to the promotion of pre-subdural lesion with CP in Hib meningitis. Amongventive vaccinations of Hib vaccine.

them, two patients developed leucopenia and hypersensitive rash during the course of treatment, althoughthese adverse effects were promptly eliminated when
the drug was stopped

2 9）

Acknowledgement.

We would like to thank Kimiko

Ubukata, the Graduate School of Infection Control Sci-

. Intravenous administration

ences, Kitasato Institute for Life Sciences for executing

can also be selected as a method of administering CP,

genotype analysis of Hib and thanks to Katsuko Oku-

but it has been reported that oral administration canzumi, Dokkyo Medical University for her valuable su-

maintain a higher blood concentration

30）. The numberof our patients was small, but in our patients alone, theconcomitant use of subdural taps and CP was one ofpervision.
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