Electrophysiological brainstem dysfunction in a child with Leigh disease

ELSEVIER

pyruvate dehydrogcnase complex (P chrome oxidase (complex IV). The bolic defects suggests that Leigh disease is not ;I biochemical enti? but is rather a disorder triggered by seseral metabolic defects that affect pyruvate oxidation or the respiratory chain. It is characterized by distinctive pathological abnormz!:ities associated with symmetrical and focal lesions in the brainstem tegmentum and basal ganglia. Symmetrical low-density areas on a cranial computed tomography (CT) scan and an increased signal in the basal ganglia, especially in the put n, on a T,-weighted magnetic resonance imaging ( I) scan are the most definite diagnostic findings [I]. M-Isopropyl-[ “‘I]p-iodoamphetamine ([ ““IlIMP) single-photon emission computed tomography (SPECT) has been used to assess disturbances in cerebral blood flow. Studies suggest that [ “31]IMP SPECT may be useful for examining the pathological characteristics of mitochondrial diseases [2-A]. Evidence suggests that electrophysiological studies of tion, including auditory brainstem re, short-latency somatosensory evoked pos) and electrically elicited blink reflexes (BRs), may be use 1 for classifying disease severity in patients with Leigh isease 15-71. All night polysomnography (PSG) is als seful for testing brainste [ 8- 121. We a:,sessed brainstem dysfunction using neuroii! an 8-year-old girl radiological and multimodality t with Leigh disease caused by a C deficiency.

The

paricnr

&;I\

horn

dcllvcry. A\ birlh. werght circumference was 3 1 cm. pwmls. cercbcllar

;II 30 lveCh\ al’l~r ;I nornxll prqnancy b;is 2.720 gm. Il!ngth was 5 I CIIl. WJ She W;I> the lira

Her fillher ~;lh h~dth~. hut ataxia and disturhcd ocular

child

her

of’ nonconsnnFuin~(~~l~

m~lh~‘r

IIlOVCSIIL’II1\

and hcd

ill

hUd IhOlll

~X~h’l.l~IlCC’d 20

yl!iH3

01

age: a diagnosis of adult-onset Leigh di\ca\c ~llr\OCiillLXl WI& H)I4(’ deficiency was confirmed by ;1 muscle biopsy. I’hc piltiltnl exhibited

ological brainstem dysfunction in a child with Leigh disease. Pediatr Neurol 1997; 16:329-333.

normal

developmental

generatiLed tonic-clonic shown to be hypotonic. development

milestones

in early

infancy.

but she expcrienccd

3

convulsion at I.7 months of age, when she Wit\ Alier this convulsive episode. her psychomotor

gradually became disturbed. A neurological examin;ltion she was 6 years of age showed mildly disturbed vcrtlc~l

perfhrmedwhen

peculiar movcmcnt\ accompanied rellexes were normally elicited 7 year\ reduced;

hy \trahi\mus. Corneid at (hat time but diappeared

and audiohlmh &hen she wa

of age. The gag reflex was preserved. Her mu\& she was hypotonic and exhihitcd a frogieg pow-e

IllaS\

wa

Leigh disease, which usually afl’ects infants and children but can occur at any age. is caused by congenital mitochondrial abnormalities, sue as deficiencies in the

extremities. rjlc I\Ilcp,

From the :‘:Department of Clinical Neuropathology: Tokyo Metropolitan Institute for Neuroscience; Department of’ Pediatrics: Tokyo: Metropolitan Medical Center for Severely Handicapped: Tokyo; and i Department of Pediatrics: the Hikari-no-Ie; Saiti~m;l. Japan.

Communications should he addressed lo: Dr. Hayashi; Department of Clinical Neuropathology; Tokyo Fuchu-41. Metropolitan Iratitute for Neuroscience; I7-h Musashi-d;ri; Tokyo 183. Japan. Received June 28, 1996; accepted December 2, I99h.

0 1997 by Elsevier Science PII SO887-8994(97)00020-9

Inc. All rights reserved. 0 0887-8994/97/$17.00

The deep tendon reflexes ;lnli ilnklC\. hut no cWnW

Araki

et al: MultimodalIty

4

the

were attenuutcd and symmetric It plrtntar re\ponW UerC elicited.

Tests

in Leigh

Disease

329

C~~ebcllar

signs

and involuntary

movements

were

absent,

touch senses were intac‘t. Serurn and cerebrospinnl Iactnte imd pyruvute were significantly elevated. muscle

biopsy

specimen

showed

a marked

and pain and

fluid (CSF) level of Examination of iI

decrease

in PDHC

activity.

Cranial CT performed at I year of age showed the presence of atrophy in the t’rontal irnd parietul cortices and crescent-shaped areas of low density in the bikral

putiunen.

An

4~0~4

symm~tricul

T,

lllitlhrilin

IcgnKntum

(Fig

iICCl~~l~llliiliO~l in IIIC I’lolltill (I$!,

MRI

scim

prolongi\tion I A, B); 1“‘I IOtWi.

performed

i\t 7 years

of iI@c

in the putumcn. thi\li~mi. and IIMP SPitCT 410wt~d i\rciih it’ IOW

hIhill

lllillilllli.

&lll~liil.

iltltl lllidl~lXill

I(‘,.

ABR\.

SSI’I’S , ;111d HI<\

signal avcri\ycr 2.000 click.\

\+LW ~vi\lui\Ic~l

!N~h~n-K~lld~n, wore

dcliveV:J

b ith iI N~ur~)lX\h

K clinical

‘I’l~hyl~. ,li~l~i\rl). For iI+e~CSh~llC~lIoI’ Al312~. bb **Iwaaiibcr::J ..I

L\) eiah

e;u’ lhrmgh

hoiIdphOn~~

ut iI rot\: of IO/s itnd im intensity

of 00 dBSL.

iI ~&kc electrode i\t the vcrtcx For SSEPs. s(lui\rc-wirvc pulses

thut rckrrcd IO the ciuWe king tested. with a 0.2~ms duration were delivered at

iI r;W of’ J/4 to the median intcnlrrty

wi\b adjusted

Recording

111~ spinoua

hil;Wri~l

Erh’\

nerve just proximal

to produce

electrodes

\yhtCm),

were (Erhl,

i\ small

pluctld

proccs\

points

Si.gnid~ wcro recorded

i\t FL. C3.

Al’ the fifth Erb2).

to the wrist. muscle

‘k

twitch

C3

polarity

\c!rIchra

of the wilvc

was indicated. ABRs and SSEPs we’re recorded during at Icat twice IO confirm reproducibility. To elicit BRs. 4upraorhital intervals.

ncrbcs Stimuli

and RZ at just recording m~sculus

stimulirtcd admmiared

miiximill

clcctrotlc~ orbiculuris

IlOW. PSG comprktld

clcctronlyc)grains and bil&r;ll

were were

:md nearly

and SSEPS were

tWO-~hi\nncl brachii

examined

age. The BR M’~S examined. i1ge.

330

PEDIATRIC

Ic\~cIs

IO-20 ISCY).

ilnd

compm~cnts

sl(Jw-wavc sleep the right and lcti

for 0.7 ms iIt 2-s that maintained RI OII rcpciItcd

triuls.

The

Uilh lIlilCCJ on Illt? LIIlpc’I’ Ll\pJCt Ot thC I;llCl;ll oculi imd wi\h rel’ercnced to the latcri\l s(ufllcc of’ 111~ ( EMGh)

biceps

&~trically ;It an intensity stnble

The stirnub of the thumb.

(Int~rnntional

ccrvicid

from

I~)ci~t4 mu~lcs. twice.

EEGs.

clcctrooculo~r3ni~.

1~ the subIll~nti~l, ;IS previously when

the l)i~ticnt

NEUROLOGY

Vol.

16 No. 4

wil\

Analysis of ABRs when the patient was 6 years of age showed bilateral wave components I, III, and V with normal latency: the amplitudes of waves II1 and V were markedly decreased as compared with the amplitude ol wave I. Except for wave I on the right-side-stimulated test, wave components were absent when the patient was 7 years of age (Fig 2A). When the patient was 6 years of age. SSEPs were clicitcd at Erh’s points at N 13 on the Fr.-Sc5 m.l al N I K on the C3- or C4-contralatcri\l Et-b’s I>oinls, but IIOI a~ N20 on the C3- or C4-Fl. Right-sidcstimulated SSEPs wcrc not obscrvcd at N 18 and N20 at 7 years ot’ age: normal SSEPs wcrc clicitcd at Erb’s point!: and at N 13 (Fig 2B). Only the R 1 component on the left-side-stimulated test was observed when the BR was examined when the patient was 7 years of age (Fig 2C). PSG showed that the percentages of slow-wave sleep and rapid eye movement (REM) sleep were severely reduced to < 10% (Fig 3A). The number of rapid eye movements (REMs) (275 pV amplitude and 270” angle of rise) pet minute during REM sleep was significantly lower than that in controls. The average frequency of the twitch movements (TMs) lasting CO.5 s and the localized movements (Lhls) lasting >().S s in submental muscle were decreased as compared with that in controls. Muscular atonia was obxcrvcd during REM sleep (Fig 3 rccordcd from c ~ubnicntal niusclc also showed atonia durmg non-RE sleep.

i\nd \urf;\cc rwtus

reported

and PSG \vils pert’ormcd

esults

uh&miillus IX- 1’1. ABR\

6 and 7 ycilrh once

01

at 7 years (j!

Struciural lesions in the brainstem have been detectelf by CT and MRI in patients with Leigh disease [ 11 The

usel*llllless of’ [ “‘I IlMP SPECT for characterization of Leigh disease has no[ b2en extensively investigated [2-41. Fujii et al. reported that 1“‘I]IMP SPECT showed decreased perfusion in the frontal cortex and basal ganglia in 3 patients with Leigh disease, but they did not address the brainstem change 141. In the present patient, SPECT images showed areas of low accumulation in the midbrain together with decreased perfusion in the frontal cortex and basal ganglia. ABRs are associated with prolonged wave V latency, a significantly reduced ratio of the amplitude of wave V to wave I, or a complete absence of wave component V in patients with Leigh disease [S-71. These findings are de ed in the early stage of suggesting that Rs are useful for evahiat process. The cortical components of SSE are usuallly absent in patients with Leigh disease, and spinal c responses may also be involved in some patients These A characteristics are consistent with the findings in the present f:ase. A

appeared to be related to a clinical status. Analysi of disturbances in the

Araki

et at: Multimodality

Tests in Leigh

Diseaw

331

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3

2

4

6

5

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sleep--

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tone, the abnormal non-REM sleep atonia W;LSobserved in our patient. In addition, we have observed similar non-REM sleep ,itonia in epileptic patients, especially in those with ntyoclonus of’ brainstent origin (S. Arahi, M. aruki, unpublished observaliuyashi, .4.. V;~ka, tions). and non-REM sleep atonia nright be suggestive of a brainstcm lesion. ‘Th\: present findings su~gcst that MRI, SPECT. and various electrophysiological tests, including muftimodality evoked potenti& and RX, provide integrated and comprehensive information conccxting brainstern dysfunction in patients with Leigh disease.

ph:tsrc muscle activity originate in the brainstem [ IO, I ! I. The control of musculcr tone during sleep is aOi.xted in patients with severe athetoid cerebral paisy a\sociuted with brainstem dyc;‘unction !12]. These findings strongly suggest that the decreases in RI34 steep i:41’. tht: dccrcasc!: in KEhrl~,atId TMs, and the abnormalitic a in muscle tone observed during steep in our patient by the brainstem lesion. Although may havoc reflected the disturbed ocular movement ased REMs rul’e;lot always .:orreiated with gaze palsy :7j. Although such antiepileptic drugs tis valproate and ~xbamizepinc may affect muscle

332

PEDIATREC

NElXOLOC;Y

Vol.

I6 No

~1

111 Barkovich di\ordcr+,: analysis

AJ.

Good

of t!rcir

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and ima@ng

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chlrr;lcteri&h.

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with lactic a&do& 1c)XW I :35X-6 I .

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and !,trokclikc

accumulation

of

with

mitoch~~ndrial

cpi+.J&s

(MFL

4s).

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