Vitamin E Deficiency and Associated Neurological Deficits
in Children with Protein-energy Malnutrition
by V. Kalra,* J. Grover,** G. K. Ahuja,*** S. Rathi,* and D. S. Khurana*
* Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
** Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, India
*** Department of Neurology, All India Institute of Medical Science, New Delhi, India
Summary
Vitamin E is important in maintaining normal neurological structure and function. In this study, 100
children with protein-energy malnutrition (PEM) were studied and compared to a suitably agematched control group. Posterior column deficits, cerebellar deficits, and problems with fine motor
coordination were present to a significant degree in the PEM subjects. The presence of neurological
signs was correlated with various parameters of vitamin E deficiency, including low serum atocopherol levels and a low tocopherol/total Iipid ratio which was present in 92 per cent of subjects.
There was good concordance between vitamin E levels and vitamin E to serum Upid ratio in assessing
vitamin E deficiency. We conclude that vitamin E deficiency is prevalent, to a hitherto unsuspected
degree, in children with PEM and that these malnourished children have significant neurological
deficits attributable to low vitamin E levels. This observation is of clinical significance as the
neurological deficits are potentially reversible with vitamin E supplementation.
Introduction
Since the discovery of vitamin E,1 its physiologic role
has been controversial. There is evidence to suggest that
it may have a role in maintaining normal neurological
structure and function.2"3 Multiple disease states like abetalipoproteinaemia, chronic fat malabsorption, cystic
fibrosis, and primary isolated vitamin E deficiency all
reveal neurological deficits in vitamin E deficient
subjects. Studies indicate the potential reversibility and
preventability of the neurological symptoms with
appropriate and timely treatment.5'7 The therapeutic
implication justifies investigation of the role of vitamin E
as an important factor in human malnutrition.
Patients and Methods
Between June 1990 and December 1993, 130 children of
either sex between the ages of 3 and 8 years with
moderate protein-energy malnutrition (PEM) were
Acknowledgements
The authors are grateful to the Indian Council of Medical
Research (ICMR), New Delhi for funding the research project
on vitamin E deficiency in protein-energy malnutrition, Dr K. R.
Sundaram, Professor, Biostatistics Unit, All India Institute of
Medical Sciences helped in statistical analysis of the data. All
the patients who cooperated in the study are duly acknowledged.
Correspondence: V. Kalra, Additional Professor of Pediatrics,
All India Institute of Medical Sciences, New Delhi-110029,
India. Fax 0091 II 6862663.
Journal of Tropical Pediatrics
Vol. 44
October 1998
identified on the basis of weight-for-age criteria using
the norms of the Indian Academy of Pediatrics.
Children up to 80 per cent of the reference weight for
age (50th percentile of the Harvard standard) were
considered normal. Those between 50 and 70 per cent of
the reference were enrolled into the study. Patients were
recruited from the pediatrics out-patient clinics and rural
health centres of the All India Institute of Medical
Sciences, New Delhi, India. Children with acute severe
illness, neurological illnesses, and neurodevelopmental
and mental retardation were excluded.
Sixty healthy age-matched subjects with similar
exclusion criteria were selected as control subjects.
Controls were recruited from the immunization clinics at
both centres. From amongst the total of 190 subjects, 40
had to be excluded owing to either unwillingness to
participate, non-compliance, or follow-up dropout. This
left 100 PEM subjects and 50 controls.
A clinical examination was performed and anthropometric data collected on a predesigned form. All the
children were examined by two clinicians independently
and only those positive findings on which there was
interobserver agreement were recorded as positive.
Features suggestive of malnutrition and associated
vitamin deficiencies were recorded. A detailed neurological examination was performed on all subjects and
controls.
Serum a-tocopherol was measured by the modified
spectrophotometric technique of Hashim and Schuttinger.9 Total Iipid levels were measured using standard
kits and the ratio of serum a-iocopherol to total Iipid
was calculated as it is thought to provide a better
© Oxford University Press 1998
291
V. KALRAETAL.
TABLE 1
Abnormal neurological signs in control and PEM subjects
Abnormal neurological signs
Normal control
(n = 50)
PEM group
( n = 100)
p value
1(2)
2(4)
0
0
2(4)
3(6)
1(2)
1(2)
3(6)
1(2)
0
38 (38)
23 (23)
32 (32)
10(10)
28 (28)
43 (43)
17(17)
18(18)
26 (26)
20 (20)
27 (27)
<0.00l
<0.0l
<0.001
<0.05
<0.0l
<0.00l
<0.05
<0.05
<0.0l
<0.0l
<0.00l
Vibration sense
Joint position
Dysdiadokinesia
Intention tremor
Ataxia
Tandem walking
Two-point discrimination
Synkinetic movements
Finger agnosia
L-R discrimination
Hyporeflexia
Figures in parentheses are percentages.
approximation of vitamin E status. A ratio of less than
0.6 is reported to suggest vitamin E deficiency.10
Electroneurophysiological data included visual
evoked responses and brainstem auditory evoked
potentials.
Results
Birthweight and gestational age were similar among
PEM subjects and controls. Ten per cent of patients in
the PEM group had a history of perinatal illnesses or
insults, compared to 4 per cent of controls.
Presenting symptoms in the PEM group included
upper respiratory infections (72 per cent), diarrhoea (22
per cent), malabsorption (2 per cent), skin rash (13 per
cent), and urinary complaints 7 per cent. On examination, muscle wasting was seen in the majority (80 per
cent); other findings included anaemia (64 per cent),
clinical vitamin A deficiency (11 per cent), hair and skin
changes (9 per cent), pedal oedema (6 per cent),
stomatitis and cheilosis (8 per cent), rickets (2 per
cent), multiple vitamin deficiencies including vitamins
D, B, and A (6 per cent).
A detailed neurologic examination of the PEM
subjects revealed multiple subtle deficits pertaining to
the posterior columns, cerebellum, and co-ordination. A
comparison of the signs between PEM subjects and
controls is shown in Table I. Absent tandem walking,
diminished vibration sense, diminished joint/position
sense, dysdiadokinesia, ataxia, and hyporeflexia were all
found to be present to a statistically significant degree
( p < 0 . 0 l ) in the PEM group compared to controls.
Finger agnosia, impaired left-right discrimination, and
synkinetic movements were also present to a significant
degree in the PEM subjects. The distribution of abnormal
neurological signs was similar between different age
groups.
Mean serum or-tocopherol level in PEM subjects was
0.26 ± 0.11 mg/dl, compared to 0.41 ± 0.09 mg/dl in
controls. The accepted normal mean serum a-tocopherol
level reported in healthy children from infancy to 12
years is 0.50 mg/dl. l0 Recognized norms reported by
other workers range from 0.35 to 0.5 mg/dl. Therefore in
our study, we applied the lowest accepted norm to
identify vitamin E deficiency. As shown in Table 2, 92
per cent of malnourished children had serum ortocopherol levels of less than 0.35 mg/dl, while only 12
per cent of the healthy age-matched controls had low
levels. This highly significant difference ( p < 0 . 0 l ) is
indicative of the low levels of a-tocopherol seen in
TABLE 2
Serum a-tocopherol levels and vitamin E/lipid ratios in PEM and control groups
PEM group ( n = 100)
Serum a-tocopherol (mg/dl)
<0.35
>0.35
Vitamin E/tipid ratio
<0.3
0.3-0.6
>0.6
Control group (;i = 50)
92(92)
8(8)
6(12)
44(88)
II (M)
81 (81)%
8(8)
0
9(18)%
41 (82)
Figures in parentheses are percentages.
292
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Vol. 44
October 1998
V KALRA ET AL.
TABLE 3
Age profile of PEM subjects in relation to serum a-tocopherol
Serum a-tocopherol
(mg/dl)
3-4+ yrs (n = 42)
5-6+ yrs (n = 34)
7-8 yrs (n = 24)
Total
0
0
3
6
4
3
18
0
0
1
3
2
3
4
9
0
2
1
7
13
13
12
46
1
7
0.05-0.1
0 1-0.15
0.15-0.2
0.2-0.25
0.25-0.3
0.3-0.35
0.35-0.4
>0.40
1
5
6
5
19
1
5
moderate PEM. Lower serum a-tocopherol levels have
been reported in infancy and early childhood. 10 "
However, a detailed analysis of a-tocopherol levels in
PEM subjects with regard to age distribution revealed no
significant association in subjects 3 to 8 years of age
which comprised the study population (Table 3).
The ratio of serum a-tocopherol to total lipids (normal
>0.6) has been advocated as a better approximation of
vitamin E status, especially in hyperlipidaemic states
were mild vitamin E deficiency might be missed.12 The
a-tocopherol to total lipid ratio in PEM patients was
0.47 ± 0.14 compared to 0.72 ± 0.12 for age-matched
controls (/? < 0.01). In 92 per cent of PEM subjects,
compared to only 18 per cent of controls, the ratio was
less than 0.6 (Table 2). There was good concordance
between the low serum a-tocopherol and tocopherol/
total lipid ratio. Table 4 shows the strong relationship
between the presence of neurological signs and low
serum a-tocopherol levels.
Brainstem auditory evoked responses and visual
evoked responses (VER) were obtained in 15 PEM
patients and controls. The absolute peak latencies for
waves I-V were comparable to normative data in both
PEM and control subjects. The interpeak latencies were
normal in both groups. The VER revealed a mean peak
latency of 100 ms with an amplitude of 7.13/xV in PEM
subjects and was similar among controls. Thus, there
were no significant differences in brainstem and visual
evoked response latencies between subjects and controls.
Discussion
For several decades vitamin E deficiency has been
known to cause degeneration of the nervous system and
muscle in a variety of vertebrates.13 Chicks developed
encephalomalacia and ataxia when fed on deficient
diets.14 The neuropathological lesions associated with
vitamin E deficiency are characterized by axonal
degeneration in the posterior columns and a selective
loss of large calibre myelinated sensory axons in the
spinal cord and peripheral nerves.15 The primary
manifestations of prolonged vitamin E deficiency
include spinocerebellar ataxia, skeletal myopathy, and
retinopathy.1617 Hyporeflexia, diminished proprioceptive ability, as well as ophthalmoplegia, dysarthria, and
ptosis may be observed. Not all patients exhibit the entire
spectrum of deficits. The role of vitamin E as an
antioxidant currently accounts best for its protective
effects.3 Other important functions of vitamin E in the
nervous system include regulation of brain prostaglandin
TABLE 4
Neurological signs and serum a-tocopherol level-related parameters in the PEM group
Neurological sign
Vibration sense/joint
position
Dysdiadokinesia/intention
tremors
Ataxia/tandem walking
Two-point discrimination/
synkinetic movements/
finger agnoisa/L-R
discrimination
Hyporeflexia
Abnormal
(No of patients)
Vitamin E <0.35 mg/dl
Vitamin E/lipid ratio <0.6
Vitamin E <0.35 mg/dl.
ratio <0.6
47 (47)
44(44)
38 (38)
37 (37)
38 (38)
34(34) .
28 (28)
26 (26)
58 (58)
59 (59)
55 (55)
56 (56)
44(44)
45 (45)
44(44)
44(44)
27 (27)
25(25)
22 (22)
22 (22)
Figures in parentheses are percentages.
Journal of Tropical Pediatrics
Vol. 44
October 1998
293
V. KALKA ET A l -
and leukotriene synthesis and control of nucleic acid
synthesis and gene expression."
The most common cause of vitamin E deficiency is
usually malabsorption of vitamin E due to underlying
gastrointestinal, pancreatic, and hepatic disorders.2
Gastrointestinal disorders were the second most
common mode of presentation in our study group. In
patients with PEM, tocopherol depletion occurs due to
both poor vitamin intake and impaired intestinal
absorption which, in turn, may be due to a combination
of pancreatic insufficiency, decreased bile production,
and diarrhoea.20
The most common clinical sign observed in our
patient population was muscle wasting, found in 80 per
cent of PEM subjects. Protein calorie deficit along with
vitamin E deficiency may contribute to the muscle
wasting found in malnourished children as it is known
that deficiency of this vitamin can result in a skeletal
myopathy.17
The majority of patients with abnormal neurological
signs had both low vitamin E levels and a low vitamin E/
lipid ratio. With reference to posterior column signs, in
our patient population, impaired vibration sense and
hyporeflexia were highly significant statistically
(p < 0.001) while impaired joint position sense was
moderately significant (p<0.01) on comparing both
groups. Diminished vibration sense and abnormal joint
position sense as a consequence of low serum tocopherol
has been reported earlier.617 Hyporeflexia has been
reported as an initial sign of vitamin E deficiency in a
series of patients with chronic choleslasis.17
With regard to cerebellar signs, dysdiadokinesia and
impaired tandem walking were highly significant
statistically (p < 0.001) while ataxia was moderately
significant (p<0.01) and intention tremor the least
significant (p < 0.05). Impaired tandem walking has
been reported as one of the presenting features in adult
patients with chronic cholestatic disease with very low
vitamin E levels,23 but has not so far been reported in the
paediatric age group as a prominent feature of vitamin E
deficiency. Similarly, intention tremor has not been
described in pediatric patients as a feature of hypovitaminosis E, but it has been described in an adult
patient with very low vitamin E levels due to chronic
cholestasis.21
Among the so-called soft neurological signs, finger
agnosia and impaired left-right discrimination were
moderately significant (/?<0.0l) while impaired twopoint discrimination and synkinetic movements were
less significant (p < 0.05). Other investigators have
reported the presence of these signs in children with
PEM.22 None of these findings have been reported
previously as features of vitamin E deficiency and it can
be postulated that these are either additional findings
seen in vitamin E deficiency or are a consequence of the
other multiple deficiencies seen in PEM.
Other features of vitamin E deficiency such as
opthalmoplegia, ptosis, dysarthria, proximal weakness,
visual field loss, and, in advanced cases, pes cavus and
294
scoliosis, as reported by other investigators,17 were not
seen in this study.
Other studies have noted low vitamin E levels in
children with malnutrition23 but have not correlated
these to the presence or absence of neurological signs.
Experimental studies have shown impaired motor and
sensory nerve conductions in children and animals with
PEM. 4 The commonly reported motor weakness,
hypotonia and hyporeflexia seen in PEM24 may be the
result of multiple nutritional deficiencies in these
children. A direct correlation between abnormality of a
laboratory parameter and clinical signs is often not
absolute in clinical situations. The interplay of various
factors may be contributory. The presence of neurological signs similar to those reported in vitamin E
deficient states along with the presence of a-tocopherol
deficiency in this population suggest a possible association. Other nutritional deficiencies, except that of
vitamin B| 2 , are not known to cause posterior column
dysfunction. Vitamin E deficiency can be contributory to
the subtle neurological dysfunction observed.
Besides absolute reduction in serum a-tocopherol
levels, other methods have been described to evaluate
tocopherol deficiency. The ratio of vitamin E to total
serum lipid levels was proposed12 as the best method to
assess vitamin E status; other studies10'25 confirm its
superiority to other ratios such as vitamin Exholesterol,
vitamin E:(cholesterol + triglyceride), and so on. In our
study, the eight PEM patients who had normal levels of
vitamin E had a vitamin E:lipid ratio of >0.6.
Conversely, the six controls with low vitamin E levels
had a low serum vitamin E:lipid ratio of less than 0.6.
Therefore, both parameters, that is serum a-tocopherol
levels and serum o-tocopherol: lipid ratio show complete
congruence in determining vitamin E status.
A recent study reported abnormal brainstem auditory
evoked potentials in a group of children with cystic
fibrosis and attributed this to vitamin E deficiency.26
However, all our subjects had normal visual and auditory
evoked responses.
This study describes a-tocopherol status and its
possible interaction with other deficiencies to produce
the recognized neurological deficits seen with moderate
PEM. The recognition of vitamin E deficiency is
important because of the potential reversibility of
neurologic symptoms with vitamin E supplementation.
Studies to evaluate the reversibility of neurological signs
in malnutrition with vitamin E supplementation are
ongoing. Future larger community trials are warranted.
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