Anticonvulsants for preventing seizures in patients with

chronic subdural haematoma (Review)

Ratilal BO, Costa J, Sampaio C

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2008, Issue 4
http://www.thecochranelibrary.com

Anticonvulsants for preventing seizures in patients with chronic subdural haematoma (Review)
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Anticonvulsants for preventing seizures in patients with chronic subdural haematoma (Review) i
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention review]

Anticonvulsants for preventing seizures in patients with

chronic subdural haematoma

Bernardo O Ratilal1 , Joo Costa2 , Cristina Sampaio3

1 Departmentof Neurosurgery, Hospital de So Jos, Lisboa, Portugal. 2 Laboratrio de Farmacologia Clnica e Teraputica , Faculdade
de Medicina Lisboa, Lisboa, Portugal. 3 Laboratrio de Farmacologia Clnica e Teraputica, Faculdade de Medicina Lisboa, Lisboa,
Portugal

Contact address: Bernardo O Ratilal, Department of Neurosurgery, Hospital de So Jos, Rua Jos Antnio Serrano, Lisboa, 1150-
199, Portugal. bratilal@yahoo.com. (Editorial group: Cochrane Injuries Group.)

Cochrane Database of Systematic Reviews, Issue 4, 2008 (Status in this issue: Edited)
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DOI: 10.1002/14651858.CD004893.pub2
This version first published online: 20 July 2005 in Issue 3, 2005. Re-published online with edits: 8 October 2008 in Issue 4, 2008.
Last assessed as up-to-date: 15 May 2005. (Dates and statuses?)

This record should be cited as: Ratilal BO, Costa J, Sampaio C. Anticonvulsants for preventing seizures in patients
with chronic subdural haematoma. Cochrane Database of Systematic Reviews 2005, Issue 3. Art. No.: CD004893. DOI:
10.1002/14651858.CD004893.pub2.

ABSTRACT
Background
Anticonvulsant therapy is sometimes used prophylactically in patients with chronic subdural haematoma, although the benefit is unclear.
Objectives
To establish the effectiveness of prophylactic anticonvulsants in patients with chronic subdural haematoma, for both pre- and post-
operative periods.
Search strategy
We searched the Cochrane Injuries Group Specialised Register, Cochrane Controlled Trials Register, MEDLINE, EMBASE, LILACS,
the American Association of Neurological Surgeons Database and abstract books of conference proceedings of the European Association
of Neurosurgical Societies. We also searched the references of all identified studies.
Selection criteria
Randomised controlled trials comparing any anticonvulsant versus placebo or no intervention.
Data collection and analysis
No trials met the inclusion criteria for the review.
Main results
No randomised, controlled trials were identified.
Authors conclusions
No formal recommendations can be made about the use of prophylactic anticonvulsants in patients with chronic subdural haematoma
based on the literature currently available. Non-controlled studies came up with conflicting results. There is an urgent need for well-
designed randomised controlled trials.
Anticonvulsants for preventing seizures in patients with chronic subdural haematoma (Review) 1
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
PLAIN LANGUAGE SUMMARY
Anti-epileptic drugs for preventing seizures in patients with long-term subdural haematoma

Chronic subdural haematoma (CSH) is a serious condition in which blood collects under the thickest membrane that surrounds the
brain, known as the dura mater. CSH is usually caused by minor head injuries in which a vein has torn, especially in the elderly or
patients with other brain problems. A CSH may cause seizures which can be dangerous.

Some doctors give patients anti-epileptic drugs such as phenytoin or phenobarbital to try to prevent seizures. However, most patients
with CSH will not have seizures and anti-epileptic drugs can have serious side effects. The review authors researched whether patients
with a CSH who received anti-epileptic drugs had fewer seizures than those who did not. Anti-epileptic drugs may be given before
or after surgery for the CSH. They searched the medical journal literature to find randomised controlled trials in which one group of
patients received a treatment (anti-epileptic drugs) and was compared with a similar group which received a non-active or different
treatment. The authors could find no randomised controlled trials. They did find other studies which were not as high quality evidence.
These had conflicting results regarding the benefit of anti-epileptics.
The review authors conclude that better research needs to be done on this topic and, for now, there is no clear evidence to support the
regular use of anti-epileptic drugs for patients with long-term subdural haematoma.

BACKGROUND
Chronic subdural haematomas (CSHs) are usually caused by mi-
nor head injuries and most result from tearing of a bridging vein.
The frequency of pre- and post-operative seizures in these patients
is not established. The overall incidence of seizures in patients with
CSH has been reported to vary from 2.3% to 17% (Luxon 1979;
Ohno 1993) with an incidence of post-operative seizures reported
from 1.0% to 23.4% (Grisoli 1988; Hirakawa 1972). The wide
variation in these numbers is probably related to the severity of
the head injury and the type of surgical procedure performed in
each study.
OBJECTIVES
The objective of this review was to establish the effectiveness of
prophylactic anticonvulsants in patients with CSH, for both pre-
and post-operative periods.
We intended to examine the following hypotheses:
the frequency of seizures is lower when prophylactic anticon-
vulsants are administered at the time of the diagnosis, com-
pared with placebo or no treatment, and administered either
in the pre- or post-operative period;

CSH typically occurs in people with prior brain atrophy, such complications are less frequent in those people to whom an-
as the elderly or chronic alcoholics, who are also more vulnera- ticonvulsants are first administered prophylactically.
ble to the potential side-effects of anticonvulsant drugs (Prabhu
2003). The efficacy of prophylactic anticonvulsive medication in
this pathology has been debated and its use is not consensual.
METHODS
There is a wide variation in practice. For some specialists, the low
incidence of seizures does not justify an anticonvulsant prophy-
laxis in patients with CSH caused by minor head injury (Ohno Criteria for considering studies for this review
1993). Others suggest that this prophylactic medication should be
considered only in alcoholic patients because of their higher risk of
Types of studies
seizure (Rubin 1993). Another study verified a significant increase
in morbidity and mortality associated with respiratory complica- All studies were required to be randomised controlled trials (RCTs)
tions and status epilepticus in patients with new-onset seizures. It comparing any anticonvulsant versus placebo or no intervention.
recommended the administration of anticonvulsants for a period
of six months following diagnosis in all patients with CSH (Sabo Types of participants
1995).
Inclusion criteria
Patients with cranial computerized tomography (CT) or mag-
Why it is important to do this review netic resonance imaging (MRI) compatible with an old subdural
To our knowledge, no systematic review of anticonvulsants for haematoma with radiological or clinical evidence of mass effect.
preventing seizures in patients with CSH has yet been done. The Exclusion criteria
present review aimed to fulfil this need. History of pre-existing seizures.
Anticonvulsants for preventing seizures in patients with chronic subdural haematoma (Review) 2
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Types of interventions
Administration of any anticonvulsant drug, at any dosage, begin-
ning at the time of the diagnosis and prolonged for any length of
time, compared with placebo or no anticonvulsant. Trials compar-
ing different anticonvulsants, different dosages, route of adminis-
tration or differences in timing or duration of administration were
excluded.
Types of outcome measures
Primary outcomes
frequency of pre-operative and post-operative seizures;
Secondary outcomes
frequency of specific anticonvulsant adverse side-effects
(safety of the administration);
all-cause mortality;
other complications: permanent neurological impairment,
long term epilepsy, CSH recurrence.
Search methods for identification of studies
No language restriction was applied to the search.
Electronic searches
We conducted a search from the following sources:
Cochrane Controlled Trials Register (CENTRAL in The
Cochrane Library, Issue 4, 2004);
MEDLINE (1966:3 to January 2005);
EMBASE (1974:3 to November 2004);
LILACS (1982:3 to January 2005);
Cochrane Injuries Group Specialised Register.
The search strategy is documented in Appendix 1.
Titles, keywords and abstracts of the citations downloaded from
the electronic searches were screened, and full copies of reports of
potentially suitable trials were obtained for further assessment.
Searching other resources
The search strategy also included:
reference lists of located trials and CSH review articles;
electronic search of meeting proceedings from the Ameri-
can Association of Neurological Surgeons (AANS) and hand-
search of the available abstracts from the meeting proceed-
ings from the European Association of Neurosurgical Soci-
eties (EANS);
personal communication with other researchers in the field.
Anticonvulsants for preventing seizures in patients with chronic subdural haematoma (Review)
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Data collection and analysis
Selection of studies
Two authors (Ratilal B, Costa J) independently assessed the stud-
ies identified by the search strategy to identify potentially suit-
able trials for the review according to the criteria outlined above.
Disagreements were resolved by discussion with a third author
(Cristina S).
Data extraction and management
The full papers were independently assessed for the type of partic-
ipants, the type and dose of anticonvulsant used, methodological
quality, the number of patients excluded or lost to follow-up, and
the outcome measures stated in the protocol. Sources of bias were
investigated.
Assessment of risk of bias in included studies
We intended that at least two authors would assess the internal
validity of individual trials, using the scale devised by Jadad 1996.
RESULTS
Description of studies
No trials were found that were eligible for inclusion in the review.
Risk of bias in included studies
No studies could be assessed.
Effects of interventions
The search strategy yielded a total of 107 references. We have not
found any randomised study comparing any anticonvulsant with
placebo or no intervention in CSH. No data could be analysed.
DISCUSSION
Given the conflicting results regarding the use of prophylactic an-
ticonvulsants in patients with CSH, it is disappointing that there
are no RCTs that evaluated their effectiveness in these patients.
Only three retrospective studies with a control group were identi-
fied.
Rubin 1993 conducted a retrospective analysis of 143 adult pa-
tients treated from January 1979 to July 1991 for CSH. Until July
1986, all patients had received prophylactic anticonvulsant drugs
from the time of surgery. After this date, drug therapy was given
only if seizure was present. Seizure was noted in 4.8% (4 of 83) of
the patients in the first group, compared with 3.4% (2 of 25) of
3
those who did not receive anticonvulsants. Before surgery 5.6%
of the patients had seizures, whereas after surgery this frequency
was 3%. Of the 83 patients who received anticonvulsants, eight
(9.6%) had non-serious drug-related adverse effects (mild allergic
reaction and phenytoin intoxication). According to the authors,
antiepileptic drugs should not be administered prophylactically in
patients with CSH because the risk of epilepsy is not high enough
to balance the morbidity caused by the anticonvulsants.
In the retrospective analysis of Ohno 1993, 129 patients treated
for CSH between August 1980 and March 1992 were studied.
Patients were usually given phenobarbital pre-operatively. Until
December 1987, 56 of 59 patients were given anticonvulsant post-
operatively. Prophylactic use of these drugs was subsequently dis-
continued, except in those patients with severe head injury (17
of 70 received prophylaxis). None of the 73 patients in total who
were given prophylactic antiepileptic drug treatment developed
seizures. Only two of 56 patients not given prophylaxis developed
early post-operative seizures. A total of four patients had seizures,
none of whom had received anticonvulsant drugs. The incidence
of seizures was considered low and similar to that previously re-
ported for minor head injury. The trialists suggest that routine use
of antiepileptic prophylaxis is not justified in patients with CSH
related with minor injuries.
Sabo (Sabo 1995 ) reported a retrospective analysis with histori-
cal controls of 98 patients treated surgically for CSH and exam-
ined the prevalence of seizure activity, morbidity, mortality and
the side-effects of anticonvulsant medication. Of the 92 patients
without pre-existing seizure, 42 (46%) received adequate prophy-
lactic phenytoin. Adequate prophylaxis included an initial dose
of phenytoin (15 mg/kg) and daily medication to adjust serum
drug levels within therapeutic range. The administration of this
drug was associated with three non-serious dermatological reac-
tions. One (2.4%) patient among the 42 who received prophylac-
tic anticonvulsants experienced seizure activity in comparison to
REFERENCES
Additional references
Grisoli 1988
Grisoli F, Graziani N, Peragut JC, Vincentelli F, Fabrizi AP, Caruso
G, et al.Perioperative lumbar injection of Ringers lactate solution
in chronic subdural hematomas: a series of 100 cases. Neurosurgery
1988;23(5):61621.
Hirakawa 1972
Hirakawa K, Hashizume K, Fuchinoue T, Takahashi H, Nomura K.
Statistical analysis of chronic subdural hematoma in 309 adult cases.
Neurologia medico-chirurgica (Tokyo) 1972;12(0):7183.
Anticonvulsants for preventing seizures in patients with chronic subdural haematoma (Review)
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
16 (32%) of 50 patients who did not receive adequate prophylaxis
(P<0.001). The onset of new seizures was found in 17 (18.5%) of
the 92 patients and was associated with increases in morbidity (P
= 0.036) and mortality (P < 0.005). Therefore, they recommend
the use of phenytoin prophylaxis in patients treated surgically for
CSH for six months following the diagnosis.
Other retrospective studies considered the incidence of seizures in
patients with CSH but have not included any control group for
anticonvulsant therapy (Hirakawa 1972 ; Luxon 1979 ; Kotwica
1991; McKissock 1960).
Given the lack of high-quality controlled trials and the clinical
heterogeneity of the data from the available studies pointing to
the possibility of bias, no meta-analysis was performed.
AUTHORS CONCLUSIONS
Implications for practice
No conclusions can be reached about the use of prophylactic an-
ticonvulsants in patients with CSH from the information cur-
rently available. Clinicians must balance potential benefit against
the possible risk of complications in each case.
Implications for research
Randomised clinical trials of prophylactic anticonvulsants in pa-
tients with CSH are required in order to gain a clear idea of the
effectiveness of this form of treatment.
ACKNOWLEDGEMENTS
We are grateful all members of the Cochrane Injuries Group in
London, namely Paul Chinnock and Katharine Ker for their con-
tinued assistance and to Karen Blackhall for conducting some of
the electronic searches.
Jadad 1996
Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gav-
aghan DJ, et al.Assessing the quality of reports of randomized clinical
trials: is blinding necessary?. Controlled Clinical Trials 1996;17(1):
112.
Kotwica 1991
Kotwica Z, Brzezinski J. Epilepsy in Chronic Subdural Haematoma.
Acta Neurochirurgica (Wien) 1991;113:11820.
Luxon 1979
Luxon LM, Harrison MJG Luxon LM, Harrison MJG. Chronic
subdural haematoma. Quarterly Journal of Medicine 1979;48(189):
4353.
4
McKissock 1960
McKissock W, Richardson A, Bloom WH. Subdural haematoma. A
review of 389 cases. Lancet 1960;1:13659.
Ohno 1993
Ohno K, Maehara T, Ichimura K, Suzuki R, Hirakawa K, Monma
S. Low incidence of seizures in patients with chronic subdural
haematoma. Journal of Neurology, Neurosurgery and Psychiatry 1993;
56(11):12313.
Prabhu 2003
Prabhu S, Zauner A, Bullock M. Surgical management of traumatic
brain injury. In: H. Richard Winn editor(s). Youmans Neurological
Surgery. 5th Edition. Vol. 4, Philadelphia: Saunders, 2003:514580.
Rubin 1993
Rubin G, Rappaport ZH. Epilepsy in chronic subdural haematoma.
Acta Neurochirurgica (Wien) 1993;123(1-2):3942.
Sabo 1995
Sabo RA, Hanigan WC, Aldag JC. Chronic subdural hematomas and
seizures: the role of prophylactic anticonvulsive medication. Surgical
Neurology 1995;43(6):57982.

Indicates the major publication for the study

Anticonvulsants for preventing seizures in patients with chronic subdural haematoma (Review) 5
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DATA AND ANALYSES
This review has no analyses.

APPENDICES

Appendix 1. Search strategy

The search strategy for MEDLINE and Central/CCTR is given below. It was combined with all three stages of the optimal trial search
strategy. The search strategy was modified for EMBASE and LILACS.
1. exp hematoma, subdural, chronic/
2. hematom*.tw
3. haematom*.tw
4. hemorrhag*.tw
5. haemorrhag*.tw
6. subdur* OR extracran*.tw
7. chron*.tw
8. or/2-5
9. #6 AND #7
10. #8 AND #9
11. #1 OR #10
12. exp anticonvulsants/
13. anticonvuls*.tw
14. antiepilepti*.tw
15. carbamazepine/
16. carbamazep*.tw
17. carbazepin.tw
18. carbatrol
19. finlepsin.tw
20. neurotol.tw
21. epitol.tw
22. amizepine.tw
23. tegretol.tw
24. phenytoin/
25. fosphenyt*.tw
26. diphenylhydant*.tw
27. fenitoi*.tw
28. antisacer.tw
29. difenin.tw
30. dihydan.tw
31. dilantin.tw
32. cerebyx.tw
33. phenytek.tw
34. epamin.tw
35. epanutin.tw
36. hydantol.tw
37. Valproic Acid/
38. valproic*.tw
39. valproat*.tw
40. divalproex.tw
41. propylpentanoic*.tw
42. ergenyl.tw
Anticonvulsants for preventing seizures in patients with chronic subdural haematoma (Review) 6
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
43. convulsofin.tw
44. depakote.tw
45. divalproex.tw
46. dipropyl*.tw
47. depakene.tw
48. depakine.tw
49. depakote.tw
50. depacon.tw
51. vupral.tw
52. clonazepam/
53. antelepsin.tw
54. rivotril.tw
55. primidone/
56. desoxyphenobarbital.tw
57. misodine.tw
58. primaclone.tw
59. sertan.tw
60. mizodin.tw
61. mysoline.tw
62. ethosuximide/
63. ethosuccimid. .tw
64. ethylmethylsuccimide.tw
65. suksilep.tw
66. suxilep.tw
67. zarontin.tw
68. gabapent*.tw
69. neurontin.tw
70. gabamox.tw
71. lamotrigin*.tw
72. lamictal.tw
73. topiramat*.tw
74. topamax.tw
75. vigabatrin/
76. sabril.tw
77. tiagabin*.tw
78. gabitril.tw
79. felbamat*.tw
80. felbatol.tw
81. levetiracet*.tw
82. keppra.tw
83. zonisamid*.tw
84. zonegran.tw
85. oxcarbazep*.tw
86. trileptal.tw
87. or/12-86
88. #11 AND #87
89. limit 88 to human

Anticonvulsants for preventing seizures in patients with chronic subdural haematoma (Review) 7
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
WHATS NEW
Last assessed as up-to-date: 15 May 2005

Date Event Description

16 June 2008 Amended Converted to new review format.

HISTORY
Protocol first published: Issue 3, 2004
Review first published: Issue 3, 2005

CONTRIBUTIONS OF AUTHORS
All correspondence: BR
Drafting of review versions: BR, JC, CS
Search for trials: BR, JC
Obtaining copies of trial reports: BR, JC
Selection of trials for inclusion/exclusion: BR, JC, CS
Extraction of data: BR, JC
Entry of data (in RevMan): BR, JC
Interpretation of data analyses: BR, JC, CS

DECLARATIONS OF INTEREST
None known.

SOURCES OF SUPPORT

Internal sources

Clinical Therapeutics Institute, Lisbon Faculty of Medicine, Portugal.

Anticonvulsants for preventing seizures in patients with chronic subdural haematoma (Review) 8
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
External sources

No sources of support supplied

INDEX TERMS
Medical Subject Headings (MeSH)
Anticonvulsants [ therapeutic use]; Hematoma, Subdural, Chronic [ complications]; Randomized Controlled Trials as Topic; Seizures
[etiology; prevention & control]
MeSH check words
Humans

Anticonvulsants for preventing seizures in patients with chronic subdural haematoma (Review) 9
Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.