Document

J Head Trauma RehabilVol. 24, No. 3, pp. 155165

Copyright c 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins

Traumatic Brain Injury and SleepDisturbance: A Review ofCurrent Research

Henry J. Orff, MS; Liat Ayalon, PhD; Sean P. A. Drummond, PhD

Objective: To summarize the current literature regarding the significant prevalence and potential consequencesof sleep disturbance following traumatic brain injury (TBI), particularly mild TBI. Design: PubMed andOvid/MEDLINE databases were searched by using key words sleep disturbance, insomnia, TBI, brain injury,and circadian rhythms. Additional sources (eg, abstracts from the annual Associated Professional Sleep Societiesmeeting) were also reviewed. Results: Sequelae of TBI include both medical and psychiatric symptoms and frequentcomplaints of sleep disturbance. Sleep disturbance likely result from and contribute to multiple factors associatedwith the injury, all of which complicate recovery and resolution of symptoms. Interestingly, research now seems toindicate that mild TBI may be more correlated with increased likelihood of sleep disturbance than are severe formsof TBI. Conclusions: Sleep disturbance is a common consequence of TBI, but much more research is required toelucidate the nature and extent of this relation. Research needs to focus on (1) uncovering the specific types, causes,and severity of TBI that most often lead to sleep problems; (2) the specific consequences of sleep disturbance in thispopulation (eg, impaired physical or cognitive recovery); and (3) the most effective strategies for the treatment ofsleep-wake abnormalities in this population. Keywords: delayed sleep phase, insomnia, sleep disturbance, traumatic braininjury

TRAUMATIC BRAIN INJURY (TBI) is a leadingcause of death and permanent disability in theUnited States. The primary causes of TBIs are falls(28%), motor vehicle accidents (20%), being hit by ob-jects (19%), and assaults (11%).1 TBI can be classifiedas mild, moderate, or severe, most often by GlasgowComa Scale score (mild = 1315; moderate = 912; se-vere = 8 out of 15). Symptoms of mild TBI (mTBI) in-clude headache, confusion, lightheadedness, dizziness,blurred vision, tinnitus, bad taste in the mouth, fatigueor lethargy, change in sleep patterns, behavioral or moodchanges, and trouble with memory, concentration, at-tention, or thinking.2 In addition to these symptoms,individuals with moderate or severe TBI may also expe-rience headaches that intensify or do not go away, re-peated vomiting or nausea, convulsions or seizures, aninability to awaken from sleep, dilation of one or both

Author Affiliations: Joint Doctoral Program in Clinical Psychology, SanDiego State University/University of California, San Diego (Mr Orff);Research Service, VA San Diego Healthcare System & Department ofPsychiatry, University of California, San Diego (Dr Ayalon); andPsychology Service, VA San Diego Healthcare System & Department ofPsychiatry, University of California, San Diego (Dr Drummond).

This study was supported by F31 MH077411-01A1 (H.J.O.) and NationalSleep Foundation Pickwick Fellowship (L.A.).

Corresponding Author:Sean P. A. Drummond, PhD, Department of Psychia-try, 9151B University of California, San Diego/VA San Diego Healthcare Sys-tem, 3350 La Jolla Village Dr, San Diego, CA 92161 ([email protected]).

pupils of the eyes, slurred speech, weakness or numbnessin the extremities, loss of coordination, and confusion,restlessness, or agitation.

Sleep disturbance is one of the most common yetleast studied of the post-TBI sequelae. Recent researchsuggests that 30% to 70% of patients experience sleepproblems following TBI and that these sleep disturbanceoften exacerbate other symptoms and impede the reha-bilitation process and the ability to return to work.3 In-terestingly, it has been shown that it is mTBI that is mostfrequently associated with sleep disturbance as opposedto severe TBI.4,5 While the importance of sleep prob-lems in the general population of TBI patients has beenknown for some time, recent events such as the wars inthe Middle East have brought renewed attention to thisissue. Many veterans have sustained a TBI, and the treat-ment of sequelae associated with this type of injury hasbecome a major health policy concern.

PURPOSE OF REVIEW

This review addresses the etiology and implicationsof sleep problems in TBI across 4 general domains ofcurrent scientific inquiry and observation: subjectiveimpression of poor sleep; objective changes in sleep-related parameters; alterations in circadian rhythms; andneurophysiologic and/or neuropsychologic abnormali-ties associated with TBI. Both nonpharmacologic and

155

156 JOURNAL OF HEAD TRAUMA REHABILITATION/MAYJUNE 2009

pharmacologic treatment options for sleep problems inthis population are then presented, as well as limitationsand areas for future research.

For this review, PubMed and Ovid/MEDLINEdatabases were searched by using the following keywords: sleep disturbance, insomnia, TBI, braininjury, and circadian rhythms. Each key word wascrossed with the others and the abstracts of manuscriptsresulting from this search were reviewed by the first au-thor. The review was limited to those studies that focusedspecifically on sleep and TBI. Note that many of thestudies reviewed included patients with TBI of varyingseverities, and they typically did not report results sep-arately for each severity type. Intervention studies wereincluded provided that the primary aim of the study wasnot limited to comparing effectiveness of pharmaceu-tical agents. Additional studies were sourced from ab-stracts from the Associated Professional Sleep Societiesmeetings and published in the journal Sleep over the pastdecade. Also, only articles published in English languagejournals over the past decade (since 1997) and those thatcould be searched electronically were included in the re-view. In all, 33 articles met these criteria and were selectedfor this review (Table 1). Articles were later groupedby domain of inquiry for easier synthesis and readabil-ity. While it is possible that some studies were missedwith this search method, this review provides a broadoverview of the current state of knowledge regardingsleep disturbance and its relation to TBI and recovery.

TBI AND SUBJECTIVELY REPORTEDSLEEP DISTURBANCE

One of the most common and well-documented syn-dromes seen in patients with TBI is insomnia, a disor-der inherently defined by patient self-report. The diag-nostic criteria for insomnia are a problem of initiatingand/or maintaining sleep for at least 1 month accompa-nied by subjective impairment in daytime functioning.37

Evidence showing that insomnia is a problem for TBIpatients has come from several studies. For example, ina questionnaire study of 452 TBI patients, up to 50% ofindividuals reported insomnia symptoms and 29.4% ful-filled the diagnostic criteria for an insomnia syndrome.6

For those who met criteria for insomnia, sleep prob-lems were a severe, chronic, and untreated condition inalmost 60% of cases. Risk factors associated with insom-nia were mTBI, higher levels of fatigue, depression, andpain. In another study of 50 postacute TBI admissionsand a comparison group of 50 rehabilitation outpatients,30% of all patients were found to suffer from insomnia,while an additional 12% experienced a degradation ofsleep quality as measured by the Pittsburgh Sleep Qual-ity Index.7 In this sample, sleep initiation was a problemalmost twice as often as sleep duration.

In a longitudinal study of admissions to a rehabili-tation unit, Clinchot et al8 found that 50% of patientsreported difficulty sleeping, 64% reported waking up tooearly, 25% described sleeping more than usual, and 45%complained of problems falling asleep. Overall, 80% ofsubjects reporting sleep problems also reported prob-lems with fatigue. Furthermore, in a study by Parcelland colleagues,9 63 patients with TBI recruited after dis-charge from rehabilitation and 63 age- and sex-matchedcontrols from the general community were comparedon sleep variables. Patients were shown to have a signif-icantly higher frequency of reported sleep disturbancefollowing their TBI (80%), and they reported more night-time awakenings and longer sleep-onset latency. In com-parison, sleep problems were only reported by 23% ofindividuals in the control group. In keeping with otherstudies, participants with a more mild form of TBI re-ported sleep changes more frequently.

Insomnia not only represents a problem immediatelyfollowing injury but also appears to persist for monthsand years after a TBI. For example, in a review of medicalrecords from 175 patients diagnosed with mTBI taken at2 time intervals (interval 1 = mean 10.7 days vs interval2 = mean 6.3 weeks postinjury), Chaput et al13 foundthat complaints of sleep disturbance were reported by11.1% and 34.7% of patients. Overall, there was a 2-to 3-fold increase in the prevalence of sleep disturbancefrom 11 days to 6 weeks postinjury. In a study of sleepcomplaints in 39 patients with chronic postconcussionsyndrome and a control group of 27 patients with or-thopedic injuries, the former reported more difficultyinitiating and maintaining sleep at night and greater dif-ficulty with sleepiness during the day over a mean 2-yearpostinjury period.10

Among 19 adolescent patients who were 3 years post-mTBI without any discernible clinical sequelae, com-plaints of sleep disturbance could be confirmed by bothpolysomnographic (PSG) and actigraphic (ie, daily ac-tivity) monitoring.11 In addition, in a study of 22 hos-pitalized patients with TBI of recent onset (median3.5 months postinjury) and 77 discharged patients whohad sustained brain injury about 2 to 3 years earlier (me-dian 29.5 months), Cohen et al12 found high rates ofsleep complaints in both groups (72.7% and 51.9%, re-spectively). Difficulty initiating and maintaining sleepwere the most common complaints among hospital-ized patients (81.2%), whereas excessive daytime somno-lence was most common in discharged patients (72.5%).Notably, those discharged patients who reported sleepcomplaints also reported greater neurobehavioral im-pairments and poorer occupational outcomes.

Among the typical consequences of poor nighttimesleep in any population are complaints of daytime fa-tigue or excessive sleepiness. Not surprisingly then, thereis also a relationship between sleep disturbance and

Traumatic Brain Injury and Sleep Disturbance 157

TAB

LE1

Trau

mat

icbr

ain

inju

ryan

dsl

eep

dist

urba

nce

sum

mar

yof

revi

ewed

artic

les

Au

tho

rS

amp

le/a

ge

Sev

erit

yTi

me

sin

cein

jury

Mea

sure

sR

esu

lts

TBIa

ndsu

bjec

tive

slee

pdi

stur

banc

eO

uelle

tet

al6

n=

452

/16+

yTB

I(m

ixed

)m

ean

=7.

85y

ISI,

MFI

,sle

ep,p

sych

olog

ican

dpa

rtne

rqu

estio

nnai

res

Inso

mni

ais

apr

eval

ent

cond

ition

follo

win

gTB

IFi

chte

nber

get

al7

n=

50TB

Ipat

ient

s/36

.5y

n=

50pa

tient

sw

ithsp

inal

cord

inju

ry/3

8.2

yn

=25

patie

nts

with

mus

culo

skel

etal

inju

ries/

47.3

y

TBI(

mix

ed)

2w

k53

mo

PS

QI,

slee

pdi

ary

30%

ofpa

tient

ssu

ffer

edfr

omin

som

nia

Clin

chot

etal

886

patie

nts/

14+

yTB

I(m

ixed

)1

yP

hone

inte

rvie

wne

urop

sych

olog

icm

easu

res

Hig

hpr

eval

ence

ofsl

eep

prob

lem

saf

ter

brai

nin

jury

Par

cell

etal

9n

=63

patie

nts/

32.5

y(

1.7)

TBI(

mix

ed)

301

194

dS

leep

diar

y,E

pwor

thS

leep

ines

sS

cale

TBIg

roup

repo

rted

long

ersl

eep

late

ncie

san

dm

ore

awak

enin

gsn

=63

cont

rols

/30.

5y

(1.

2)P

erlis

etal

10n

=39

patie

nts/

41y

(14

.1)

mTB

I2

ypo

st-in

jury

Que

stio

nnai

reP

atie

nts

had

mor

esl

eep

prob

lem

san

dda

ytim

esl

eepi

ness

n=

27co

ntro

ls/3

7y

(15

)K

aufm

anet

al11

n=

19pa

tient

s/10

16.

5y

mTB

I3

ypr

ior

tost

udy

PS

G,a

ctig

raph

yin

take

ques

tionn

aire

Pat

ient

ssh

owed

low

ersl

eep

effic

ienc

ies

and

mor

ew

ake

time

n=

13P

SG

cont

rols

/sam

eag

esn

=15

actig

raph

yco

ntro

ls/s

ame

ages

Coh

enet

al12

n=

22re

cent

/med

ian

=29

yTB

I(m

ixed

)M

edia

n=

3.5

mo

Que

stio

nnai

reIn

som

nia

asso

ciat

edw

ithre

cent

inju

ryex

cess

ive

slee

pine

ssw

ithpa

stin

jury

n=

77di

scha

rged

/med

ian

=26

ym

edia

n=

29.5

mo

Cha

put

etal

13n

=17

5pa

tient

s/48

.9y

mTB

I10

dan

d6

wk

Riv

erm

ead

Pos

tC

oncu

ssio

nQ

uest

ionn

aire

Sle

epco

mpl

aint

ssh

ow2-

to3-

fold

incr

ease

betw

een

time

1-2

Bel

mon

tet

al14

Rev

iew

artic

leTB

I(m

ixed

)N

otsp

ecifi

edM

ultip

lem

easu

res

Fatig

ueis

pres

ent

in43

%7

3%of

patie

nts

Mas

elet

al15

n=

71/3

2y

(11

)TB

I(m

ixed

)3

mo

27y

PS

G,M

SLT

,act

igra

phy

PS

QI,

Epw

orth

Sle

epin

ess

Sca

leM

SLT

confi

rms

dayt

ime

hype

rsom

nia

inTB

Ipat

ient

sde

spite

nose

lf-re

port

edco

mpl

aint

sLu

ndin

etal

16n

=12

2pa

tient

s/37

.3y

n=

35co

ntro

ls/3

9y

mTB

1,7,

14d,

and

3m

opo

stin

jury

Riv

erm

ead

Pos

tC

oncu

ssio

nQ

uest

ionn

aire

poor

mem

ory,

slee

ppr

oble

ms,

fatig

uem

ost

com

mon

sym

ptom

sin

mTB

IB

aum

ann

etal

17n

=53

patie

nts/

37y

TBI(

mix

ed)

6m

opo

stin

jury

Com

pute

dto

mog

raph

y,la

bora

tory

test

s,M

SLT

,E

pwor

thS

leep

ines

sS

cale

62%

ofpa

tient

sha

da

slee

p-w

ake

com

plai

nt,d

aytim

esl

eepi

ness

mos

tco

mm

on(c

ontin

ues

)

www.headtraumarehab.com


TAB

LE1

Trau

mat

icbr

ain

inju

ryan

dsl

eep

dist

urba

nce

sum

mar

yof

revi

ewed

artic

les

(Con

tinue

d)

Au

tho

rS

amp

le/a

ge

Sev

erit

yTi

me

sin

cein

jury

Mea

sure

sR

esu

lts

TBIa

ndob

ject

ive

slee

pdi

stur

banc

eK

aufm

anet

al11

n=

19pa

tient

s/10

16.

5y

n=

13P

SG

cont

rols

/sam

eag

esn

=15

actig

raph

yco

ntro

ls/s

ame

ages

mTB

I3

ypr

ior

tost

udy

PS

G,a

ctig

raph

yin

take

ques

tionn

aire

Pat

ient

ssh

owed

low

ersl

eep

effic

ienc

ies

and

mor

ew

ake

time

than

did

cont

rols

Sch

reib

eret

al18

n=

26pa

tient

s/31

.6y

(8.

8)n

=26

cont

rols

/33.

8y

(7.

8)m

TBI

12m

o21

yP

SG

,MS

LTS

ubje

ctiv

ean

dob

ject

ive

slee

pdi

stur

banc

ein

patie

nts

Gos

selin

etal

19n

=10

patie

nts/

not

repo

rted

n=

11co

ntro

lsm

TBI

Pas

tye

ar

2ni

ghts

PS

Gan

d10

min

day

PS

G,E

pwor

thS

leep

ines

sS

cale

,PS

QI

Abn

orm

alw

akin

gE

EG

(mor

ede

lta,

less

alph

a)

Laia

ndC

astr

iott

a20

n=

7/50

y(

19.9

)TB

I(m

ixed

)1

29y

Med

ical

revi

ewP

SG

/MS

LTP

atie

nts

with

hype

rsom

nia

atgr

eate

rris

kfo

rap

nea

Cas

trio

tta

etal

21n

=87

/18

yTB

I(m

ixed

)>

3m

oP

SG

/MS

LTE

pwor

thS

leep

ines

sS

cale

,PO

MS

,Fu

nctio

nalO

utco

mes

ofS

leep

Que

stio

nnai

re,

psyc

hom

otor

vigi

lanc

eta

sk

Pat

ient

sat

grea

ter

risk

ofsl

eep

diso

rder

spo

stin

jury

Verm

aet

al22

n=

60/2

069

yTB

I(m

ixed

)3

mo

2y

PS

G,M

SLT

,Epw

orth

Sle

epin

ess

Sca

le,B

DI,

Glo

bal

Ass

essm

ent

ofFu

nctio

ning

,H

amilt

onA

nxie

tyS

cale

Sle

epdi

sord

ers

corr

elat

edw

/TB

Ibu

tno

tw

ithou

tse

verit

y

Bra

dsha

wet

al23

n=

182

patie

nts/

21y

(3.

9)n

=14

5co

ntro

ls/2

3y

(4.

4)m

TBI

Rec

ent

Epw

orth

Sle

epin

ess

Sca

le,

PS

QI

Mor

epr

eexi

stin

gsl

eep

com

plai

nts

and

dayt

ime

slee

pine

ssin

patie

nts

Oue

llet

and

Mor

in24

n=

14pa

tient

s/30

.4y

(9.

7)n

=14

cont

rols

/30

y(

10.1

)TB

I(m

ixed

)7

41m

oP

SG

,sle

epdi

ary,

ISI,

MFI

,BD

I,B

eck

Anx

iety

Inve

ntor

yS

igni

fican

tdi

ffer

ence

sin

subj

ectiv

ebu

tno

tob

ject

ive

slee

pdi

stur

banc

ebe

twee

ngr

oups

Aur

ora

etal

25n

=9/

245

3y

TBI(

mix

ed)

Med

ian

=7

yP

SG

,PS

QI,

dayt

ime

MS

LT,

Epw

orth

Sle

epin

ess

Sca

le,

Glo

balF

atig

ueIn

dex

Poo

rsu

bjec

tive

but

norm

alob

ject

ive

slee

pdi

stur

banc

ein

patie

nts

Kor

inth

enbe

rget

al26

n=

98/3

13

ym

TBI

24h

and

46

wk

late

rE

xam

inat

ion,

inte

rvie

ww

akin

gE

EG

23of

98pa

tient

sha

dsl

eep

prob

lem

sat

follo

w-u

pC

hung

etal

27n

=7/

336

8y

Hea

din

jury

P

ast

hist

ory

Epw

orth

Sle

epin

ess

Sca

le,

Sta

nfor

dS

leep

ines

sS

cale

,P

OM

S,T

oron

toA

lexi

thym

iaS

cale

,Fat

igue

Sev

erity

Sca

le

No

asso

ciat

ion

betw

een

subj

ectiv

ere

port

san

dP

SG

mea

sure

men

ts

(con

tinue

s)


TAB

LE1

Trau

mat

icbr

ain

inju

ryan

dsl

eep

dist

urba

nce

sum

mar

yof

revi

ewed

artic

les

(Con

tinue

d)

Au

tho

rS

amp

le/a

ge

Sev

erit

yTi

me

sin

cein

jury

Mea

sure

sR

esu

lts

TBIa

ndci

rcad

ian

dist

urba

nce

Qui

nto

etal

2848

-yol

dm

an(c

ase

repo

rt)

TBI(

seve

re)

4y

prio

rN

euro

logi

cex

amin

atio

nse

lf-re

port

Pat

ient

exhi

bite

dsi

gnifi

cant

dela

yed

slee

pph

ase

post

inju

ryN

agte

gaal

etal

2915

-yol

dgi

rl(c

ase

repo

rt)

TBI(

mix

ed)

Pos

tinju

ryP

SG

,act

igra

phy

mel

aton

in,

tem

pera

ture

Pro

min

ent

dela

yed

slee

pph

ase

post

-TB

IA

yalo

net

al30

n=

42/2

6y

mTB

I1+

mo

PS

G,a

ctig

raph

yte

mpe

ratu

rean

dm

elat

onin

,ME

Qm

TBIl

eads

toin

crea

sed

chan

ceof

circ

adia

nde

lay

Ste

ele

etal

31n

=10

patie

nts/

38.8

y(

4.3)

n=

10co

ntro

ls/3

7.8

y(

4.4)

TBI(

mix

ed)

741

194

dS

aliv

a,m

elat

onin

,ME

QN

oev

iden

cefo

rci

rcad

ian

chan

gefo

llow

ing

TBI

TBIa

ndne

urop

hysi

olog

ic/n

euro

psyc

holo

gic

dist

urba

nce

Bau

man

net

al32

44pa

tient

s/m

ean

=36

y29

cont

rols

/mea

n=

44y

TBI(

mix

ed)

14

dC

ereb

rals

pina

lflui

dhy

pocr

etin

Hyp

ocre

tinle

vels

low

erin

95%

ofpa

tient

sw

ithm

oder

ate

tose

vere

TBI

Bau

man

net

al33

n=

96/3

8y

(16

)n

=65

(at

6-m

ofo

llow

-up)

TBI(

mix

ed)

4d

and

6m

oP

SG

,Mai

nten

ance

ofW

akef

ulne

ssTe

st,M

SLT

,E

pwor

thS

leep

ines

sS

cale

,la

bora

tory

test

s,qu

estio

nnai

res

TBIc

orre

late

dw

ithsl

eep-

wak

epr

oble

ms,

poss

ible

role

for

hypo

cret

in

Frie

boes

etal

34n

=13

/27.

3y

(6.

2)TB

I(m

ixed

)2.

54.

6m

oP

SG

,hor

mon

ete

sts,

Ham

ilton

Dep

ress

ion

Sca

leS

leep

-end

ocrin

ech

ange

sob

serv

edm

onth

saf

ter

TBI

Bre

edet

al35

n=

258

patie

nts/

237

3y

n=

65co

ntro

lsTB

I(m

ixed

)M

ean

=18

mo

Med

ical

inte

rvie

ws,

Qua

lity

ofLi

feB

rain

Inju

ryS

cree

ning

Que

stio

nnai

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these daytime symptoms in TBI patients. Fatigue maybe present in as many a 43% to 73% of patients andis one of the primary symptoms in 7% of patients re-gardless of injury severity, time since injury, gender,or medications.14,15 Lundin et al16 found that poormemory, sleep disturbance, and fatigue were the mostcommonly reported symptoms following TBI. Whilethese complaints declined postinjury, correlations be-tween symptoms and disability were still evident at3 months postinjury. Furthermore, patients with earlyhigh symptom load were found to be at risk for develop-ing persisting complaints. In a study by Baumann andcolleagues,17 33 of 53 patients (62%) were found to havea sleep disorder following TBI, of whom 29 (55%) re-ported increased fatigue or excessive daytime sleepinesscompared with pre-TBI. In this study, Epworth Sleepi-ness Scale scores (a measure of trait sleepiness) were ab-normally elevated (>10) in 14 patients (26%), suggest-ing that many patients exhibited high levels of daytimesleepiness (especially those with mTBI as compared withthose with moderate/severe TBI).

Overall, subjectively reported sleep disturbance is oneof the most commonly described problems in TBI pa-tients. The literature reviewed in this section is particu-larly convincing because numerous studies seem to beproviding replicable findings of insomnia in TBI pa-tients. Most of the studies surveyed (especially the studyof Ouellet and Morin)24 had reasonably large samplesizes and utilized a variety of measures to assess sleepdisturbance. In addition, daytime fatigue and sleepinesswere also common findings in these studies. Interest-ingly, it is the research on subjectively defined sleep prob-lems that has brought attention to the observation thatmTBI is more clearly associated with insomnia than se-vere forms of TBI. While the exact cause of subjectivelyreported sleep difficulties and daytime sleepiness is notknown, these problems obviously affect patients bothcognitively and psychologically as they recover fromtheir injuries and impede attempts to return to normalactivities.

TBI AND OBJECTIVELY MEASUREDSLEEP DISTURBANCE

Despite the wealth of information supporting the pres-ence of subjective sleep complaints in TBI patients, ev-idence for measurable objective deficits in sleep hasbeen harder to identify. Some evidence of objectivechanges in sleep quantity and quality has been found byKaufman and colleagues11 in a study of 19 adolescents(3 years post-mTBI) who complained of sleep distur-bance and a group of control participants. Question-naire results revealed that patients subjectively reportedmore severe sleep complaints, a result that was corrob-orated by PSG measurements. In fact, PSG recordings

revealed that in comparison with controls, mTBI wasassociated with lower sleep efficiency, more nocturnalwake time, and more awakenings lasting longer than3 minutes. In a study by Schreiber and colleagues,18

26 mTBI patients with normal brain computed tomo-graphic and negative encephalographic (EEG) studieswere compared with a matched group of healthy con-trols. Patients in this study also showed altered sleeparchitecture, with significantly higher percentage of non-rapid eye movement (NREM) stage 2 than did controlsand significantly lower percentage of rapid eye move-ment (REM) sleep. In addition, Gosselin et al19 foundevidence of objective changes in the EEG during wake-fulness in athletes with concussion relative to controlathletes. In particular, athletes with concussion wereshown to have significantly more delta activity and lessalpha activity during wakefulness. This pattern has beenseen in sleep-deprived and sleep-disordered populationsand suggests that abnormal waking EEG may play a sig-nificant and/or unique role in the symptoms associatedwith TBI, especially daytime dysfunctions and sleepinessexperienced in this population.

Of note, some patients with sleep disturbance afterTBI may experience sleep problems other than insom-nia. Lai et al20 found an increased risk of sleep disorders,including sleep apnea. In addition, several patients inthis study also had a prior history of sleep disorders,which the authors suggest might have contributed tothe TBI. Castriotta et al21 and Verma et al22 have sim-ilarly reported high numbers of sleep disorders such asobstructive sleep apnea, periodic limb movements, andnarcolepsy in patients with TBI. Such findings have ledsome to propose that preexisting sleep disorders and sub-jective daytime sleepiness may be more common in pop-ulations with brain injury and may actually represent arisk factor for accidents or behaviors that predispose tohead injury.23

Contrary to these findings, several studies have failedto find clear evidence of objective sleep impairments inpatients with mTBI. For example, Ouellet and Morin24

found that TBI patients with insomnia, relative tohealthy controls, showed a tendency to overestimatethe subjective impression of their sleep disturbance ascompared with PSG measurements. Despite reports ofsignificant sleep disturbance on subjective measures, pa-tients showed no differences from controls in percentageof stage 2, slow-wave (stages 3 and 4), or REM sleep onPSG measurements. Patients did, however, have a higherproportion of stage 1 sleep, more awakenings lastinglonger than 5 minutes, and shorter REM sleep latencies.Such a pattern of mild sleep disturbance that is overesti-mated on subjective measures is consistent with the over-all insomnia literature, suggesting that the experience ofinsomnia may be similar in persons with and withoutTBI. In a study by Aurora and colleagues,25 5 men and


4 women (aged 2453 years) with a median time frominjury of 7 years were studied with PSG measurements.Results indicated that subjects had normal sleep efficien-cies (median of 90.7%); the median amounts of stage 1,stage 2, slow-wave, and REM sleep were 1.9%, 32.5%,43.8%, and 18.0%, respectively. The authors concludedthat while TBI patients may suffer from subjective com-plaints of fatigue and poor nocturnal sleep, they never-theless manifest relatively normal sleep architecture.

Several other investigations also seem to support thisobservation of a disparity between subjective and objec-tive measures of sleep disturbance following TBI. For ex-ample, Korinthenberg and colleagues26 studied 98 chil-dren (aged 313 years) within 24 hours after a minor headinjury and 4 to 6 weeks later. At follow-up, 23 of 98 stillexhibited posttraumatic complaints with headache, fa-tigue, sleep disturbance, anxiety, and affect instability.These posttraumatic symptoms, however, did not corre-late with somatic, neurologic, or EEG findings observedimmediately after the injury or at the follow-up inves-tigation. Chung et al27 found that subjective reports ofdaytime sleepiness and fatigue in patients with head in-jury were not well substantiated when compared withovernight PSG sleep measures and physiologic tests ofdaytime sleepiness.

Despite containing nearly an equal number ofmanuscripts as the section on subjective sleep distur-bance, the evidence for objective sleep problems inmTBI is the most equivocal of any of the outcome mea-sures reviewed here. Inconsistencies in the literature maybe due to multiple factors such as (1) small sample sizesin most studies (with a few notable exceptions), (2) morevariability in the age ranges across studies (including alarger number of children and adolescents), and (3) useof samples with mixed severity of injury. On the otherhand, the variability in TBI severity and the time sinceinjury are about the same in this set of articles as is inthe reports on subjective sleep disturbance. However,subjective and objective discrepancies in sleep distur-bance, such as those observed in TBI patients, are notat all inconsistent with the general literature on insom-nia. Nonetheless, the largest studies in this section sug-gest that TBI patients do experience objective sleep dis-turbance and/or sleep disorders postinjury.21,22,26 Theother intriguing hypothesis that warrants more longitu-dinal research is the notion that preexisting sleep distur-bance may be associated with increased risk of TBI.23

TBI AND CIRCADIAN CHANGES

Recent research has provided evidence that, ratherthan insomnia per se, sleep disturbance following TBImay be associated with alterations in the timing andrhythm of sleep. Such alterations can result in a mis-match between an individuals biological sleep-wake

schedule and his or her desired 24-hour environmentaland social schedule.38,39 Of the circadian dysrhythmias,delayed sleep phase syndrome is the most common andis often misinterpreted as insomnia by patients and clini-cians alike. In fact, the estimated prevalence of circadiandisorders among patients who initially complain of in-somnia is 7% to 10%.38,39 Patients with circadian rhythmsleep disorders (CRSDs) often exhibit altered rhythmsof melatonin secretion and body temperature.40,41 Con-sistent with these notions, recent case studies of CRSDsfollowing TBI have reported evidence of delayed sleepphase,28 delayed sleep phase with delayed melatoninand body temperature rhythms,29 and a non24-hoursleep-wake pattern with abnormal melatonin rhythm.42

Recent work by Ayalon and colleagues30 found thatmTBI might actually contribute to the emergence ofCRSDs. In this latter study, 2 types of disturbanceswere observed: delayed sleep phase syndrome and irreg-ular sleep-wake pattern; these types differed in subjectivequestionnaire scores and had distinct profiles of mela-tonin and temperature circadian rhythms. The authorsalso reported that 15 of 42 patients (36%) with com-plaints of insomnia following mTBI were more properlydiagnosed with CRSDs. The frequency of CRSDs inthis sample is considerably higher than the prevalence ofthese disorders among the general population of patientsattending sleep clinics who complain of insomnia.38,39

Not all research, however, supports the idea that TBIleads to circadian disturbances. In a study of 10 patientsin a postacute TBI group compared with matched con-trols, Steele and colleagues31 found that the TBI and con-trol groups reported similar habitual sleep times as mea-sured with a Morningness-Eveningness questionnaire.Furthermore, the timing of melatonin onset did not dif-fer between the groups. While the small sample size mayhave contributed to the lack of group differences, thepreliminary conclusion of the authors is that this studyfailed to provide conclusive objective evidence of a shiftin circadian timing of sleep following acute TBI.

In summary, a growing body of evidence suggests thatfor some patients, circadian disturbances may play a rolein sleep problems subsequent to TBI. Unfortunately, theliterature in this area is sparse, and the 2 primary investi-gations reviewed here (studies of Ayalon et al and Steeleet al)30,31 came to opposite conclusions as to the roleof circadian dysrhythmia in TBI patients. It is obviousthat future studies are needed on this connection and itslimits.

TBI AND NEUROPHYSIOLOGIC/NEUROPSYCHOLOGIC DISTURBANCES

Recent research is beginning to demonstrate thatTBI may be implicated in neurophysiologic changesthat affect the regulation of sleep and wakefulness. For



example, Baumann and colleagues32 studied 44 consec-utive patients with acute TBI and controls and foundhypocretin-1 levels to be abnormally low in 95% ofpatients with moderate to severe TBI and in 97% ofpatients with posttraumatic brain changes as indicatedby computed tomographic scan. In a follow-up study,Baumann and colleagues33 observed low cerebral spinalfluid hypocretin-1 levels in 4 of 21 patients 6 monthsfollowing a TBI (mixed severities) as compared with 25of 27 patients in the first days after TBI. Furthermore,significantly lower levels of hypocretin-1 were associ-ated with posttraumatic excessive daytime sleepiness.These data suggest that hypocretin-1 deficiency afterTBI may reflect hypothalamic damage in patients withacute TBI. Such deficiencies would be expected to con-tribute to sleep disturbance via hypocretins role in pro-moting wakefulness (eg, the study of Mignot et al).43

More specifically, abnormally low levels of hypocre-tin would be expected to contribute to daytime sleepi-ness and fatigue, 2 common complaints in patients withmTBI.

Sleep-endocrine alterations have also been shown tobe present several months after severe TBI and ex-hibit a pattern of sleep EEG parameters and noctur-nal hormone secretions similar to that seen in patientswith remitted depression.34 Frieboes et al34 proposethat hypothalamic-pituitary-adrenal overdrive and long-term modulation of hypothalamic and pituitary recep-tors may lead to either permanent sleep-endocrine alter-ations (a neurobiologic scar) or perhaps hypothalamic-pituitary damage due to diffuse thinning out of neurons(eg, growth hormone secreting cells). Similar researchhas shown that patients with TBI are more likely thanhealthy, age-matched peers to report problems with theirmetabolic/endocrine and neurologic systems.35

Current research also indicates that deficits in cogni-tive performance may be related to the degree of sleepdisturbance resulting from TBI. In a study of 87 pa-tients with mild to severe TBI admitted to a compre-hensive outpatient neurorehabilitation program, hierar-chical regression analysis revealed that poor performanceon selected measures of cognitive functioning was signif-icantly related to sleep disturbance, accounting for 14%of variance beyond that accounted for by injury severityand gender.4 These results suggest that sleep disturbanceamong patients with mTBI may be associated with im-paired neuropsychologic functioning. Sleep disturbancehas also been shown to correlate with posttraumatic am-nesia. In a study of 9 patients in a rehabilitation unit,sleep efficiency was positively correlated with ratings oforientation and significantly predicted clearance of post-traumatic amnesia.36

Overall, it appears that TBI can induce measurableneurophysiologic changes that may lead to objective

alterations in sleep-wake regulation. In particular, theworks of Baumann et al32 and Friebos et al34 provide con-vincing evidence that TBI results in endocrine changesthat might explain sleep disturbance in this population.In addition, the literature reviewed here suggests thatsleep changes may contribute to cognitive performancedeficits in persons with TBI. While only a few studiesindicated a link among TBI, sleep problems, and neu-ropsychologic performance, such results should not besurprising, given the established role that sleep plays incognition. One issue in need of further investigation isthe amount of variance in neuropsychologic impairmentthat can be directly and uniquely attributed to sleep dis-turbance, independent of other factors.

TREATMENT OF SLEEP PROBLEMSASSOCIATED WITH TBI

As researchers debate the complex issues surroundingthe underlying etiology and course of symptoms result-ing from TBI, clinicians must focus on how best to treatsleep disturbance in this population. Overall, the TBI-related sleep disturbance most strongly supported in theliterature are consistent with insomnia and delayed sleepphase syndrome. Fortunately, there are many provenpsychologic and pharmacologic interventions that canhelp patients with these sleep disturbance. In fact, sev-eral cognitive-behavioral techniques (CBTs) have beeneffective in improving sleep in patients with insomniaand thus hold particular promise for persons with TBI.Unfortunately, we found only a single report in whicha CBT for insomnia was applied with individuals withTBI (ie, the work of Ouellet and Morin).44 In this casestudy, a patient treated with a CBT had reductions insleep-onset latencies from 47 to 18 minutes, nocturnalawakenings dropped from 85 to 28 minutes, and sleepefficiencies increased from 58% to 83%. These resultswere well maintained at 1- and 3-month follow-up assess-ment. Furthermore, there are several therapies that havebeen effective in the treatment of CRSDs and which mayhave applicability in this population. For example, brightlight therapy will aid in the consolidation of sleep in pa-tients with CRSDs.44 Given that alterations in melatoninfunctioning also lead to sleep-phase alterations seen inTBI patients, treatment with exogenous melatonin couldbe useful in adjusting sleep-phase problems seen in thispopulation.

Despite the effectiveness of CBTs for the treatmentof sleep disturbance, prescription and over-the-countermedication remain the most common and accessibleforms of treatment for most individuals recovering fromTBI. In fact, hypnotic medications may be prescribed inas many as 20% of TBI patients.45 While medications


have been effective in treating sleep disturbance inhealthy individuals, such treatment effects have notbeen studied in TBI patients. Use of hypnotic medica-tions may also be associated with daytime drowsiness,dizziness or lightheadedness, and cognitive and psy-chomotor impairments, all of which are likely to be par-ticularly detrimental for this population.

LIMITATIONS AND FUTURE DIRECTIONS

TBI is a common and economically costly health-care issue in the United States today, with sequelae thatare numerous and include both medical and psychiatricsymptoms. It is associated with frequent complaints ofsleep disturbance that likely result from and contributeto multiple interrelated factors associated with the in-jury, all of which complicate recovery and resolution ofsymptoms. While current research is beginning to elu-cidate the nature of the relationship between TBI andsleep disturbance, the literature is hampered by manymethodologic concerns. As seen in this review, studiesover the last decade vary considerably across importantfactors such as sample size, age, injury severity, types ofmeasures/assessments performed, and the length of timebetween injury and evaluation. In addition to variabilityin study design, reporting of important factors such asthe number of prior TBIs, patient treatment regimen,medication use, past/current medical and/or psychiatricstatus, etc varied considerably among articles (and oftenwere not reported at all), making it difficult to evaluatethe role of these variables in sleep-related outcomes andcomplicating comparisons between studies.

There are, of course, several other limitations to the lit-erature. For example, very little attention has been paidto symptoms associated with a specific type or locationof injury, making logical cross-comparisons of studiesalmost impossible. Second, studies have not adequatelyinvestigated the effects of TBI on sleep on the basis oftime since injury (immediate vs long term). Third, therelative role of physiologic and/or psychologic factorsin the emergence of sleep disorders (ie, due to physicalinjury in sleep/arousal brain regions vs trauma/stress)has not been fully explored. Fourth, whether impairedsleep is the result of or the cause of other TBI-relatedsymptoms and whether impaired sleep may even in-crease likelihood of injury is yet to be determined. Fifth,TBIs typically result in multiple sequelae, such as pain,mood problems, posttraumatic stress disorder, and sleepdisturbance. Hence, teasing apart comorbid symptomsand studying their contributory effects to illness and re-covery are difficult processes at best. Finally, for obviousreasons, premorbid sleep patterns in individuals who suf-fer a TBI are rarely assessed. Clearly, knowledge of such

status might have implications for the understanding ofpost-TBI functioning.

Another important limitation is the inability of re-search to explain why mTBI seems to be more com-monly associated with sleep disturbance than more se-vere forms of TBI. While this fact may seem counter-intuitive, it does appear that mTBI is correlated withincreased likelihood of insomnia or delayed sleep phasesyndrome. While no clear explanation for this link hasbeen established, one could speculate as to the potentialreasons for its occurrence. First, it may simply be a factthat more severe brain injuries result in more complexissues during the recovery process of patients. In suchcases, rehabilitation is focused on matters such as reestab-lishing the ability to conduct activities of daily livingand reduction of long-term disability. Thus, sleep distur-bance is less likely to become a focus of treatment and/orget reported. Second, differences in the nature of injuriesmay play a role in the development of sleep disturbance.Perhaps, more diffuse injuries (eg, axonal shearing) thatoccur in mTBI lead to impairment in global functioning(eg, arousal) more so than acute or focal traumas. Third,severe injuries may produce more permanent changes inbrain function, as opposed to mild injuries, and this dif-ference may alter in some meaningful way the recoveryprocess, causing sleep problems to occur more often inone group than another. Finally, differences in the waybrain injuries are treated may lead to differences in self-reported postinjury symptoms. Recent research by Cha-put et al13 has found that individuals with mTBI weremore likely to report mood and sleep problems 6 weeksafter injury than in the time immediately following theinjury. The author (personal communication) concludedthat sleep problems manifested at a later time becausepatients with mTBI are often rapidly discharged fromcare (as opposed to those with more severe injuries). Insuch cases, the appearance of sleep problems later inthe course of recovery might be due to patients runningout of medication and not receiving adequate follow-upservices.

In conclusion, it is obvious that TBI is associated withsleep disturbance. However, it is also clear that muchmore research needs to be done to understand the ex-tent of this relationship. More important, research needsto focus on uncovering the specific types, causes, andseverity of TBI that most often lead to sleep problems,as well as the most appropriate treatment strategies forthe resultant sleep-wake abnormalities. It is hoped thatrecent public attention regarding the significance of TBIwill spur support of research that is essential both to im-proving conceptualizations of this complex issue and toimproving therapeutic strategies that could benefit thosewho suffer from this debilitating condition.



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