ヘルペス脳炎の治療

1. ヘルペス脳炎の治療
2017/3/24
⼭本舜悟

2. 脳⽣検で証明されたHSV脳炎
ビダラビンとプラセボの⽐較ND JOURNAL OF MEDICINE Aug. 11, 1977
, a
giv-
de-
at a
ra-
so-
ke,
ys.
oup
ra-
and
re-
es-
at-
pa-
ore
by
ra-
ob-
ess-
in-
Table 1. Summary of Mortality* Data in Patients Treated with
Adenine Arabinoside (Ara-A)and Placebo.
BIOPSY ARA-A PLACEBO
TOTAL MORTALITY TOTAL MORTALITY
STUDIED DEAD RATE% STUDIED DEAD RATE%
Positivet 18 s 28 10 7 70
Negative 11 I 9 11 3 27
Totals 29 TI
*Mortality rates calculated at I-mo interval after onset of therapy by chi-square analy-
ses. Statistical evaluation: Ara-A vs placebo, biopsy positive, P = 0.03; Ara-A vs place-
bo, biopsy negative, P =0.27; biopsy negative vs biopsy positive, placebo, P =0.05; bi-
opsy positive (Ara-A) vs biopsy negative (placebo), P = 0.98; & biopsy positive (place-
bo) vs biopsy negative (Ara-A), P • 0.005.
t I case positive at autopsy was negative at biopsy.
analysis in that they were not randomized. Of the re-
maining 50, 29 received adenine arabinoside, and 21
were given placebo. Of 28 patients who were brain-bi-
opsy positive 18 received drug. Adenine arabinoside
significantly reduced the mortality rate of proved her-
pes simplex encephalitis from 70 to 28 per cent
(P = 0.03). However, when the data were adjusted for
increased severity, significance was further enhanced
The New England Journal of Medicine
Downloaded from nejm.org at HAUPTBIBLIOTHEK UNIV ZUERICH on December 25, 2014. For personal use only. No other uses without permission.
From the NEJM Archive. Copyright © 2010 Massachusetts Medical Society. All rights reserved.
tion of function.
Laboratory Observations
Brain tissue (biopsy and autopsy) was minced in standard cell
culture mediums (as employed at each participating unit) and in-
oculated as a 10 per cent (wt/vol) homogenate into eight tubes of
various types of cell cultures sensitive for isolation of herpes sim-
plex virus. We employed standard virologic procedures for process-
ing urine, throat swabs and occasionally white blood cells and
stools. All cultures were observed for a minimum of four weeks be-
fore being discarded as negative. Herpes isolates were typed in the
laboratory of A. Nahmias (Emory University, Atlanta, Georgia)
with a membrane immunofluorescent procedure, as previously de-
scribed. '0
We performed toxicology monitoring on admission (pretreat-
ment) and at serial five-day intervals for 25 days. These measures
included, in addition to clinical assessments, the following: com-
plete blood counts (quantitative assessments ofreticulocytes, plate-
lets, white blood cells, with differential counts, hemoglobin and
hematocrit); serum glutamic oxalacetic transaminase; bilirubin; to-
tal protein; blood urea nitrogen; creatinine; lactic dehydrogenase;
alkaline phosphatase; and routine urinalysis.
Data Management
Data from the case-reporting forms were collected, collated and
prepared for computerization at the Central Unit, University of
Alabama in Birmingham. Chi-square analyses were routinely em-
ployed in statistical assessments, with t-test or multivariant regres-
sion analyses applied as specifically indicated.
RESULTS
Mortality and Morbidity Data
Mortality data according to treatment and biopsy
category are summarized in Table 1. Fifty-two pa-
tients completed the study; two were excluded from
Since reduction in mortality resulting from ade-
nine arabinoside treatment of herpes simplex enceph-
alitis proved to be significant, these control studies
had to be terminated for ethical reasons, even though
the number of placebo-treated patients was small.
Statistical assessment of the impact of treatment on
morbidity was therefore impossible in that only three
placebo-treated patients survived. Figure 1 summar-
izes morbidity in the two treatment groups with
proved herpes simplex encephalitis. Morbidity was
z
w
a:
!zw
u
a::
w
a..
100
NIAID STUDY
N=IS N= 10
ARA-A• PLACEBO•
THERAPY
• P=0.03 AT DAY30
D ALIVE,NO OR MINOR
SEQUELAE
[[) ALIVE, MODERATE
SEQUELAE
ALIVE,SEVERE
SEQUELAE
• DEAD
Figure 1. Morbidity and Mortality in Biopsy-Proved Herpes
Simplex Encephalitis.
New England Journal of Medicine. 1977;297:289–94.
ビダラビン投与で死亡は減る
が，重い後遺症は残る

3. ヘルペス脳炎疑い患者
脳⽣検後にビダラビン開始
脳⽣検でHSV陽性ならビダラビン継続，陰性なら終了
England Journal of Medicine
March 31, 2016. For personal use only. No other uses without permission.
2010 Massachusetts Medical Society. All rights reserved.
he pa-
or ad-
medi-
weight
xceed-
s re-
we dis-
ve bi-
ments
ed by
sed on
ystem
semi-
re be-
in in-
axial
these
isease
h and
omic-
ed on
r one
were
. Pa-
were
s. Pa-
home
they .
y dis-
ortive
s a 10
least
on these 75 patients with similar data obtained from
18 vidarabine recipients and 10 placebo recipients
studied previously.' The mortality rate in herpes sim-
plex encephalitis in the present study was 33 per
cent one month after treatment and 39 per cent six
and 12 months after treatment. In the prior study,
mortality rates with therapy were not notably differ-
ent (28 per cent and 44 per cent at one month and six
months, respectively) from those in the current study.
100
80
0,
·~
;;.
5 60
(/)
!!
<:
.!!
0 40
a.
20
0
..•.
"~i
~-------
N=/8
.. N=/0
"-·------
30 60 90 120 /50
Days After Enrollment
Figure 1. Survival of Patients with Biopsy-Proved Herpes
Simplex Encephalitis.
A follow-up evaluation of patients treated with vidarabine
(squares) demonstrated a survival rate of 61 per cent. The
survival rates in the treated group (triangles) and placebo
group (circles) from the previously reported trial1 were 56 per
cent and 30 per cent, respectively.
・132例中75例で脳⽣検でHSV陽性
・■が本研究のHSV陽性，ビダラビン治療群
・▲はNEJM. 1977;297:289‒94. のビダラビン群
・●はNEJM. 1977;297:289‒94.のプラセボ群
New England Journal of Medicine. 1981;304:313–8.

4. 年齢が⽣命予後に影響
New England Journal of Medicine. 1981;304:313–8.

5. 脳⽣検でHSV陰性だった症例の原因
New England Journal of Medicine. 1981;304:313–8.

6. HSV脳炎（脳⽣検または⾎清・髄液の抗体産⽣で証明）
アシクロビル vs ビダラビンのRCT
・死亡はアシクロビル群19％（5/27），ビダラビン群50％（12/24）
リスク⽐0.37（95％信頼区間0.15-0.90, p=0.04）
・6ヶ⽉後に通常の⽣活に戻っている割合は
アシクロビル群56％（15/27），ビダラビン群13％(3/24）,
リスク⽐4.44（95％信頼区間 1.46-13.5, p=0.002）
Lancet. 1984;2(8405):707–11.

7. 脳⽣検で証明されたHSV脳炎
アシクロビル vs ビダラビンのRCT
・死亡（18ヶ⽉）はアシクロビル群28％(9/32)，ビダ
ラビン群54％(20/37)，リスク⽐ 0.52 (95%信頼区間
0.28-0.98)
New England Journal of Medicine. 1986;314:144–9.

8. 性器ヘルペスのある妊婦から帝王切開で出産
した新⽣児がビダラビン予防投与中に播種性
HSV感染症を発症した
JAMA. 1988;259:1054–5.

9. 後遺症はアシクロビル投与群，GCS ＞6群，若年群で
少なかった
New England Journal of Medicine. 1986;314:144–9.

10. ビダラビンはアシクロビルと比べ
て明らかに治療効果が落ちる！

11. ビダラビンは海外では使用されなくなった
• “As vidarabine is no longer available in any form, having been
replaced by aciclovir and other potent antiviral drugs active
against herpesviruses”
Grayson, M L. Kucers' The Use of Antibiotics Sixth Edition, 6th Edition. CRC Press.

12. 治療期間

13. アシクロビル10⽇間
治療後4⽇⽬に再燃
VanLandingham KE, Marsteller HB, Ross GW,
Hayden FG. Relapse of herpes simplex
encephalitis after conventional acyclovir therapy.
JAMA. 1988;259:1051–3.

14. ⽇本の⼩児のHSV脳炎
再燃例の治療期間の平均は11⽇間，再燃なしの平
均は14⽇間→14⽇間未満は再燃のリスク？
Ito Y, Kimura H, Yabuta Y, Ando Y, Murakami T, Shiomi M, et al. Exacerbation of herpes simplex
encephalitis after successful treatment with acyclovir. CLIN INFECT DIS. 1999;30:185–7.

15. HSV脳炎の治療期間は現在は14-21⽇間が
推奨されているが･･･
• 2008年のIDSAガイドラインでは14-21⽇間治療を推奨
Tunkel AR, Glaser CA, Bloch KC, Sejvar JJ, Marra CM, Roos KL, et al. The Management of
Encephalitis: Clinical Practice Guidelines by the Infectious Diseases Society of America.
CLIN INFECT DIS. 2008;47:303‒27.
• 14⽇間治療で再燃
Yamada S, Kameyama T, Nagaya S, Hashizume Y, Yoshida M. Relapsing herpes simplex
encephalitis: pathological confirmation of viral reactivation. J Neurol Neurosurg Psychiatr.
2003;74:262‒4.
• 15⽇間，20⽇間，21⽇間治療で1例ずつ再燃例の報告
Sköldenberg B, Aurelius E, Hjalmarsson A, Sabri F, Forsgren M, Andersson B, et al.
Incidence and pathogenesis of clinical relapse after herpes simplex encephalitis in adults.
J Neurol. 2006;253:163‒70.
• 治療終了前に髄液のHSV-PCR陰性化を確認した⽅がよいかも
Herpes. 2004;11 Suppl 2:57A‒64A.
CLIN INFECT DIS. 2008;47:303‒27.

16. 新⽣児のHSV感染症
• 14-21⽇間の静注アシクロビ
ルの後，半年間アシクロビル
内服を継続した⽅が神経学的
予後がよかった
Kimberlin DW, Whitley RJ, Wan W, Powell DA, Storch G, Ahmed A, et al. Oral acyclovir
suppression and neurodevelopment after neonatal herpes. N Engl J Med. 2011;365:1284–92.

17. アシクロビル耐性HSVの脳炎？
• アシクロビル耐性HSVはAIDS患者で粘膜病変を繰り返す⼈で出
現することはあるが，免疫正常者では⾮常に稀
Chaudhuri A, Kennedy PGE. Diagnosis and treatment of viral encephalitis.
Postgraduate medical journal. 2002;78(924):575‒83.
• 2010年に免疫正常でアシクロビル投与歴のない⼈でアシクロビ
ル耐性HSVによる脳炎が初めて報告
Schepers K, Hernandez A, Andrei G, Gillemot S, Fiten P, Opdenakker G, et al.
Acyclovir-resistant herpes simplex encephalitis in a patient treated with anti-tumor
necrosis factor-α monoclonal antibodies. J Clin Virol. 2014;59:67‒70.
• ⽇本での免疫正常でアシクロビル投与歴のない⼈のアシクロビ
ル耐性HSVによる脳炎の報告は⾒つけられず

18. アシクロビル耐性
HSV脳炎
• day 6の髄液HSV-PCRのtiter
がday2よりも増加していたこ
とから耐性が疑われた
Schepers K, Hernandez A, Andrei G, Gillemot S, Fiten P,
Opdenakker G, et al. Acyclovir-resistant herpes simplex
encephalitis in a patient treated with anti-tumor necrosis
factor-α monoclonal antibodies. J Clin Virol. 2014;59:67‒70.

19. アシクロビルで治療された35例のHSV脳炎
良好な転帰でも治療後の発熱期間は約7⽇間
literature, a marked decrease should make us consider other
diseases18
.
As was mentioned above, CSF PCR for HSV is the diagnostic
method of choice, with a sensitivity of 98% and a specificity
of 94%. However, negative PCR results should be interpreted in
keeping with clinical suspicion18
. False-negative PCR results can
encephalitis up to the start of treatment8,10,21
. Among all these
prognostic factors, the only one clinicians can influence is early
establishment of antiviral treatment. In our series, the majority of
patients started treatment with acyclovir on the first day after
admission, and it may be for this reason that a delay in starting
antiviral treatment did not have a significant influence on our
ARTICLE IN PRESS
Table 4
Univariate analysis of factors associated with the prognosis at 6 months
Good outcome (Rankin p2), n ¼ 25 (71%) Poor outcome (Rankin X3), n ¼ 10 (29%) pÃ
Age (years) 48.12717.68 68.4720.34 0.007
Duration of symptoms before admission (days) 4.9672.81 4.972.13 0.928
Duration of symptoms before treatment (days) 5.5673.03 5.472.72 0.872
Duration of fever after initiating treatment (days) 6.8474.69 14.1176.64 0.003
Sodium levels in serum at admission (mmol/l) 134.8874.9 136.475.34 0.418
Leukocyte count in serum at admission (cells/ml) 9232.472911.58 10270.0073299.835 0.46
Sex (males) 16 (64%) 6 (60%) 0.049
Debilitating diseases 4 (16%) 1 (10%) 0.553
Headache 20 (80%) 4 (40%) 0.021
Nausea and vomiting 10 (40%) 5 (50%) 0.292
Disorientation 14 (56%) 6 (60%) 0.567
Behavioral changes 13 (525) 6 (60%) 0.184
Seizures 10 (40%) 4 (40%) 0.652
Decreased level of consciousness 14 (56%) 2 (20%) 0.071
Neurological deficit 15 (60%) 3 (30%) 0.146
Treatment for cranial hypertension 7 (28%) 4 (40%) 0.689
Antiepileptic drugs 16 (64%) 7 (70%) 0.530
Serum hemoglobin levels at admission (g/dl) 12.971.4 13.5370.95 0.225
Serum albumin levels at admission (g/l) 36.8874.53 32.674.76 0.02
Values are expressed as the mean7standard deviation (SD).
à Univariate analyses were calculated using the Mann-Whitney U test, w2
or Fisher exact test, as appropriate.
A. Riera-Mestre et al. / Enferm Infecc Microbiol Clin. 2009;27(3):143–147146
Riera-Mestre A, Gubieras L, Martínez-Yelamos S, Cabellos C, Fernández-Viladrich P. Adult herpes simplex
encephalitis: fifteen years' experience. Enfermedades Infecciosas y Microbiología Clínica. 2009;27:143–7.

20. 予後不良因⼦
• 年齢が⾼いこと，発症時の意識レベルが悪いのは予後不良因⼦
New England Journal of Medicine. 1986;314:144‒9.
• 治療の遅れは予後不良因⼦
Hughes PS, Jackson AC. Delays in initiation of acyclovir therapy in herpes simplex
encephalitis. The Canadian journal of neurological sciences Le journal canadien des
sciences neurologiques. 2012;39:644‒8.
• 発症から受診までの時間が⻑いこと，MRIで病変が広範囲であ
ることは予後不良因⼦
Sili U, Kaya A, Mert A, HSV Encephalitis Study Group. Herpes simplex virus
encephalitis: clinical manifestations, diagnosis and outcome in 106 adult patients. J
Clin Virol. 2014;60:112‒8.