Letters to the Editor

210

JAKE TIMOTHY

CRAIG WINTER
INDRAJIT DAS
NUSRAT KHAN
JACKIE DE BELLEROCHE.
Departments of Neurosurgery, The Brook General
Hospital, The Royal London Hospital, and the
Departments of Biochemistry and Psychiatry,
Charing Cross and Westminster Medical School
Correspondence to: Dr Jake Timothy, Department
of Neurosurgery, Leeds General Infirmary, Great
George Street, Leeds LS 1 3EX, UK.
1 Gilad G, Gilad V. Polyamines in neurotrauma.
Ubiquitous molecules in search of a function. Biochem Phannacol 1992;44:401-7.
2 Shohami E, Nates JL, Glantz L, et al. Changes
in brain polyamine concentrations following
head injury. Exp Neurol 1992;117:189-95.
3 Koski P, Helander IM, Sarvas M, Vaara M.
Analysis of polyamines as their dabsyl deriva-

tives by reversed phase high performance liquid chromatography. Anal Biochem 1987;
164:261-6.
4 Gilad GM, Gilad VH, Wyatt RJ. Accumulation of exogenous polyamines in gerbil brain
after ischaemia. Mol Chem Neuropathol 1993;
18:197-210.

Hatred of the hemiparetic limbs (misoplegia) in a 10 year old child
Injury to the right parietal region in adults
may cause disorders of visuospatial ability in
drawing and construction, neglect of the left
side of space, denial of left hemiparesis
(anosognosia), and sometimes an active
hatred of the paralysed limb (misoplegia),
occasionally associated with a personification of a limb (calling it "the nuisance"), or
attempting to injure the paralysed left
limbs.' 3Although misoplegia is reputed to
be fairly common,3 it seems not to have been
reported in adults since the classic work of

Critchley.2
These neuropsychological signs have been
far less often reported in children. There
have been reports of left neglect and extinction in children,45 together with reports of a
general tendency in children with head injury
to deny their deficit. However, there seem to
be no previous reports of anosognosia
proper, or misoplegia, in children in relation
to the classic pattern of right parietal neuropsychological deficits.
A 10 year old right handed boy, with no
previous neurological history of note, had an
episode of acute loss of consciousness
(Glasgow Coma Scale score 6) after a
spontaneous intracerebral haemorrhage.
Brain CT showed a lesion in the deep
white matter and basal ganglia of the right
temporoparietal region (figure).
He had a dense left hemiparesis with
reduced sensation, hemianopia, and a tendency to ignore things on the left side (for
example, failing to dress his left limbs). His
mother reported that he seemed to have
regressed emotionally (for example, he had
episodes of swearing, tantrums, and impulsive behaviour). He had become more self
centred, often feeling that he had been "left
out". His physiotherapist and occupational
therapist reported that it was impossible to
please him, as he found their treatment
"wrong" or "faulty". This was dramatically
different from his premorbid state, where he
was described as a normal and emotionally
stable child. Corroborating accounts of his
change in behaviour were reported by his
school teachers, although they noted no
decline in his general intellectual abilities,

and he returned to his old class at school.
His mother reported that everything was
"a laugh", and that you could not hold a
serious conversation with him (although his
serious side "came back" when he was "in
trouble"). His physiotherapist reported that
he avoided conversations about his hemiparesis, "as if it wasn't there", and instead
talked excessively about other things. In an
early physiotherapy session he insisted that
he could run, but soon tripped and fell as a
result of his hemiparesis. He had been a
member of a football team and maintained
that he would be able to return to the team,
but he was clearly unable to play and was
not selected. He then asserted that the team
was inferior, and promised to find a better
team. Both his physiotherapist and occupational therapist reported that it was difficult
to gain his cooperation in therapy because of
his denial of deficit. However, apart from
anosognosia, he showed no other delusional
beliefs.
In sharp contrast with this denial of
deficit, his family, physiotherapist, and occupational therapist also reported that he held
some unusual attitudes towards his left side.
He was angry about his left limbs, often
"hated" them, blamed them, and wanted to
get rid of them. In the acute period in hospital he once actually threw himself out of his
bed, on to his left side, in an attempt to
injure his left arm and leg. He would often
bend the fingers of his left hand backwards,
attempting to break them. Both his mother
and his physiotherapist reported him as saying that he "would rather destroy it, if he
couldn't use it". They also reported that he
expressed a desire that his left side might be
replaced, with that of his mother.
He was assessed by us three months after
the cerebrovascular accident, at which stage
the left hemianopia and hemiparesis were
still present, although the paresis had
improved slightly so that he could now walk
(with typical circumduction in gait). His left
arm had recovered proximal movement, but
he still had very poor control over his hand
and finger movements. During our assessment his speech was entirely normal, as was
his recent memory and recognition of well
known faces. However, he performed poorly
on drawing and constructional tasks (the
block design subtest of the WISC-III, scaled
score 5), showing some features of constructional dyspraxia, as well as occasionally

omitting components on the left. He showed
further features of hemispatial neglectmissing some words on the left in reading,
bisecting lines well to the right of true centre
(mean line length 9*7cm, mean bisection
position 59 7% from the left) and omitting
items on the left in a figure cancellation task
(Bell test, 11 of 16 targets identified in the
left hemispace, 17 of 17 in the right).
At this stage he was anosognosic for his
hemiparesis and neglect, but was aware that
his drawing and constructional abilities
seemed poor. Although he agreed that his
left arm was "not the same" as before the
injury, he denied that it caused him any disability. Asked directly to judge whether he
might be able to use his arm to open a door,
he said that this would not be a problem.
When challenged to do this, he found it
impossible, and solved the problem by using
his right (good) hand to wrap the fingers of
the left hand around the handle, and then
pulled the door open using his body.
As regards the misoplegia, he said that he
hated his arm and leg because he couldn't
use them, and that he wanted to break them.
He believed that, if the bones were broken,
"the muscles might grow back together
again", and he would be miraculously
healed. Concerning his wish to have the left
side replaced with that of his mother he confirmed that he had, quite naturally, asked
her to do this.
This patient therefore showed the classic
pattern of neuropsychological deficits seen
after right parietal lesion in adults: misoplegia, anosognosia, left hemispatial neglect,
and constructional apraxia.' 3 The case
seems to be the first in which misoplegia has
been reported in a child. It has been suggested that signs of denial of deficit are common in all children after brain injury, but it
is of clinical relevance to be able to differentiate between different forms of denial of illness. A pattern of neuropsychological deficit
known to be associated with anosognosia,
involving signs such as left neglect, visuospatial errors, and constructional apraxia,
would be a suitable marker in making a distinction between anosognosia as part of a
right parietal syndrome, and denial of deficit
for other reasons (for example, as part of a
frontal syndrome, or as a purely psychogenic
defence mechanism).
The nature of the misoplegia in this case
seems to be largely the same as that found in
adults,' I in that it involved a hatred for the
left limbs, and a desire to injure them. In one
respect, however, his attitude was different
from that of misoplegic adults, in that he
expressed a desire for the limbs to be
"replaced", and it is surprising that his
mother was chosen as the source of the
exchanged body parts.
Another interesting feature of the case is
the finding that anosognosia and misoplegia
coexisted in one patient. This is surprising
given that they reflect polar opposites in attitude to the disabled limbs. However, we
noted during our assessment that the
anosognosia and misoplegia were never present simultaneously. Rather he often switched
between hating the left limb and denying his
hemiparesis.
We thank Emily Le Marie and Jannette Bell for
their reports on the patient, and Professor
Christine Temple for her assistance with the literature on neglect in children.

Brain CT of patient.

AVRON D MOSS
Child and Family Consultation Service,
Royal London Hospital,
Whitechapel, London El IBB, England

211

Letters to the Editor
OLIVER H TURNBULL
Department ofPsychology,
King's College,
Aberdeen University,
Aberdeen AB 9 2UB, Scodand
Correspondence to: Dr 0 Tumbull.
1 Bisiach E, Vallar G. Hemineglect in humans.
In: Boller F, Grafman J, eds. Handbook of
neuropsychology. Vol 1. Amsterdam: Elsevier,
1988.
2 Critchley M. Misoplegia, or hatred of hemiplegia. Mt Sinai Jf Med 1974;41:82-7.
3 Fredericks JAM. Disorders of the body
schema. In: Vinken PJ, Bruyn GW, Klawans
HL, Fredericks JAM, eds. Handbook of clinical neurology. Amsterdam: Elsevier, 1985.
4 Ferro JF, Martins IP, Tavoro L. Neglect in
children. Ann Neurol 1984;15:281-4.
5 Thompson NM, Ewing-Cobbs L, Fletcher JM,
Miner ME, Levin HS. Left unilateral neglect
in a preschool child. Dev Med Child Neurol
199 1;33:636-44.

Valproate induced encephalopathy
treated with carnitine in an adult

Hepatotoxicity due to valproate often necessitates discontinuation of the drug. We
report a patient with unstable epilepsy in
whom valproate was an irreplaceable component of anticonvulsant treatment. Hepatic
encephalopathy was reversed and remained
controlled by combining carnitine supplementation with an essentially unchanged
valproate schedule.
A 35 year old previously healthy woman
developed status epilepticus secondary to
viral encephalitis initially requiring mechanical ventilation and phenobarbitone concentrations of over 100 mg/l with phenytoin to
maintain seizure control. Phenytoin was discontinued due to rash and replaced by carbamazepine, which was subsequently
withdrawn due to abnormal liver function
tests and sedation. Valproate was initiated in
combination with phenobarbitone. Isolated
generalised breakthrough seizures sometimes associated with urinary tract infections
continued during a period of rehabilitation.
Thirteen months after her initial illness,
she was again admitted after three days of
increasing confusion, drowsiness, and
tremulousness without seizure activity. On
examination, delirium with asterixis raised
the clinical
suspicion of hepatic
encephalopathy. Routine blood tests including white blood count and liver function
tests were normal, and anticonvulsant concentrations were therapeutic (phenobarbitone 34-2 mg/l, valproate 83 mg/l). Serum
ammonia on admission was 43 mol/l (normal < 33 umolI1), rising to 215 ,umol/l by
the next morning. Serum free carnitine was
7 6 umol/l (normal 19 0-60-0 pmol/l) and
total
carnitine
154 ,umol/l
(normal
30-0-730 gumolI1). Phenobarbitone was
maintained and valproate decreased from
3 g to 2-75 g a day with supplemental L-carnitine added (330 mg four times daily). The
delirium and asterixis resolved over the next
three days permitting discharge on the
fourth hospital day with normal serum
ammonia (25 pmolIl) and therapeutic valproate concentrations (93 mg/l).
Valproate has been shown to cause
reduced serum carnitine concentrations and
hyperammonaemia in certain children when
compared with the administration of other
antiepileptic drugs.' However, not all valproate induced hepatotoxicity is carnitine
related. Children at greatest risk are those

receiving a multidrug anticonvulsant regimen. The condition usually develops within
a few months of starting valproate.
Carnitine supplementation has been used
to prevent hepatotoxicity in children considered at increased risk due to suspected mitochondrial disorder, malnutrition, mental
retardation, high dose valproate treatment,
or a history of hepatotoxicity to the valproate.2 Treatment with oral carnitine has
also been reported to reverse this hepatotoxicity in children despite continued
valproate.3
Less is known about the relation between
valproate induced hepatotoxicity and carnitine deficiency in adults. Reduced free carnitine concentrations have been reported in
76-5% of adults receiving anticonvulsant
drug regimens including valproate compared
with 21-5% of adults on schedules without
valproate.4 Coma from valproate induced
camitine deficiency in adults is reported to
respond rapidly to discontinuation of the
drug.5
This case shows that certain adults receiving valproate are, like children, at risk for
camitine deficiency and hyperammonaemia
with its clinical accompaniment. The incidence among encephalopathic adults on valproate is unknown. This patient further
illustrates that identification and correction
of a drug induced deficiency may allow continuation of treatment without disturbing
control of an unstable seizure disorder.
Much as folate is used in chronic phenytoin
administration, supplemental carnitine
should be considered in adult patients with
epilepsy at risk for hyperammonaemia.
DAVID BEVERSDORF
COLIN ALLEN
Section of Neurology,
Department of Medicine
RICHARD NORDGREN
Department ofPediatrics,
Dartmouth-Hitchcock Medical Center,
1 Medical Center Drive,
Lebanon NH 03756, USA

Correspondence to: Dr D Beversdorf, Department
of Neurology, University of Florida College of
Medicine, SW 1600 Archer Road, Gainesville,
FL 32610, USA.
1 Thom H, Carter PE, Cole GF, Stevenson KL.
Ammonia and carnitine concentrations in
children treated with sodium valproate compared with other anticonvulsant drugs. Dev
Med Child Neurol 199 1;33:795-802.
2 Sugimoto T, Nishida N, Murakami K, et al.
Valproate-induced hepatotoxicity: protective
effect of L-carnitine supplementation. J7pn Y
Psychiatry Neurol (Tokyo) 1990;44:387-8.
3 Vance CK, Vance WH, Winter SC, Opala G,
Szabo A. Control of valproate-induced hepatotoxicity with carnitine. Ann Neurol 1989;
26:456.
4 Rodriguez-Segade S, Alonso de la Pefia C,
Tutor JC, et al. Camitine deficiency associated with anticonvulsant therapy. Clin Chim
Acta 1989;181:175-82.
5 Triggs WT, Bohan TP, Lin S-N, Willmore LI.
Valproate-induced coma with ketosis and
camitine deficiency. Arch Neurol 1990;47:
1131-3.

Increased serum neopterin concentrations in a patient with Creutzfeldt-Jakob
disease

Spongiform encephalopathies or prion diseases affect both human beings and animals.
The human transmissible spongiform
encephalopathies include Kuru, CreutzfeldtJakob disease, and the GerstmannStraussler-Scheinker syndrome (GSS), and
fatal familial insomnia; all these diseases are
associated with the accumulation of /3pleated amyloid protein in the brain.'

Besides genetic abnormalities, epidemiological studies disclosed that a transmissible
agent is involved in the spread of
Creutzfeldt-Jakob disease,' and small viruslike structures in brains from sporadic and
familial Creutzfeldt-Jakob disease and GSS
have been described.2 More recently the
possible association between bovine spongiform encephalopathies and CreutzfeldtJakob disease received much attention.
In a study comprising patients with neurodegenerative disorders we had the opportunity to examine a 67 year old woman who
was clinically suspected of having
Creutzfeldt-Jakob disease. She had shown
rapidly progressive dementia, typical EEG
patterns, and myoclonus; intercurrent illness
was apparent. The woman died five months
after the onset of clinical symptoms. At
necropsy, performed by one of us (KJ), diffuse spongiform changes were found in the
cerebral cortex, thalamus, striatum, and
cerebellum associated with neuronal loss
and astroglial proliferation, confirming the
diagnosis of Creutzfeldt-Jakob disease.
Blood specimens were obtained two months
and one month before death. Among other
routine laboratory tests, neopterin concentrations were measured by enzyme linked
immunosorbent assay (ELISA; BRAHMSDiagnostica, Berlin, Germany). Neopterin
concentrations were 16-3 nmol/l (first occasion) and 12-4 nmol/l (second occasion),
clearly raised compared with the serum
neopterin concentrations in healthy controls
(mean (SD) 5-4 (2 3) nmol/1).3
Increased neopterin concentrations are
indicative of activation of cell mediated
immunity in humans, because large amounts
of neopterin are released from human
monocytes and macrophages on stimulation
with interferon-y.4 Similarly, increased
neopterin concentrations are often found in
body fluids of patients with infections,
autoimmune disorders, or certain types of
malignancies, usually correlating with the
extent and the activity of the diseases and
giving prognostic information.3 4 Also in various infections of the CNS increased
neopterin concentrations, preferentially in
the CSF, have been reported.' Thus
increased serum neopterin is by no means
specific for Creutzfeldt-Jakob disease but
provides a hint that the cell mediated
immune system was chronically activated in
our patient with late stage Creutzfeldt-Jakob
disease. This is surprising as there is no evidence so far that prion diseases are associated with abnormal cellular immunity. We
are unable to deduce at which stage of disease immune deterioration may start in
Creutzfeldt-Jakob disease, when an increase
of serum neopterin may begin, and whether
the presence of any transmissible agent was
the cause of increased neopterin in the
patient. Further studies involving larger
numbers of patients are required to answer
these questions.
F LEBLHUBER
J WALLI
Department of Gerontology,
Landesnervenklinik Wagner-Jauregg,

Linz, Austria
G P TILZ
Department of Internal Medicine,
University of Graz, Graz, Austia
_K JELLINGER
Department of Neurology and
Boltzmann
Institute ofNeurobiology,
Ludwig
Lainz-Hospital, Vienna, Austria

H WACHTER
D FUCHS
Institute of Medical Chemistry and Biochemistry and
Ludwig Boltzmann Institute of AIDS-Research,

University ofInnsbruck,
Innsbruck, Austria