B Vitamin deficiency and neuropsychiatric syndromes in alcohol misuse.

Abstract

Alcohol misuse and alcohol withdrawal are associated with a variety of neuropsychiatric syndromes, some of which are associated with significant morbidity and mortality. B vitamin deficiency is known to contribute to the aetiology of a number of these syndromes, and B vitamin supplementation thus plays a significant part in prophylaxis and treatment. In particular, the Wernicke Korsakoff syndrome (WKS). due to thiamine deficiency, is a common condition in association with alcohol misuse, and is associated with high morbidity and mortality. Nicotinamide deficiency may result in a rarer condition, alcoholic pellagra encephalopathy, which often has a similar clinical presentation to WKS. This review considers the role of B vitamins in the aetiology and treatment of neuropsychiatric syndromes associated with alcohol misuse, with particular emphasis on WKS.

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Alcohol & Alcoholism Vol. 33, No. 4, pp. 317-336, 1998
INVITED REVIEW
B VITAMIN DEFICIENCY AND NEUROPSYCHIATRIC SYNDROMES IN
ALCOHOL MISUSE
CHRISTOPHER C. H. COOK*, PHILLIP M. HALLWOOD1 and ALLAN D. THOMSON2
Kent Institute of Medicine and Health Sciences, University of Kent at Canterbury, Kent CT2 7NR, 'Link Pharmaceuticals Ltd,
Horsham, W. Sussex and 2Greenwich District Hospital, London SE1O, UK
(Received 11 July 1997; in revised form 16 January 1998)
Abstract — Alcohol misuse and alcohol withdrawal are associated with a vanety of neuropsychiatric
syndromes, some of which are associated with significant morbidity and mortality B vitamin deficiency
is known to contribute to the aetiology of a number of these syndromes, and B vitamin supplementation
thus plays a significant part in prophylaxis and treatment. In particular, the Wemicke-Korsakoff
syndrome (WKS), due to thiamine deficiency, is a common condition in association with alcohol misuse,
and is associated with high morbidity and mortality. Nicotinamide deficiency may result in a rarer
condition, alcoholic pellagra encephalopathy, which often has a similar clinical presentation to WKS.
This review considers the role of B vitamins in the aetiology and treatment of neuropsychiatric
syndromes associated with alcohol misuse, with particular emphasis on WKS.
INTRODUCTION
Alcohol misuse is associated with a range of
neuropsychiatric conditions, some of which have a
high morbidity and mortality. One of the most
serious of these is Wernicke's encephalopathy,
which is both common and potentially fatal, as
well as being associated widi a high level of
chronic morbidity amongst survivors, in the form
of Korsakoff s psychosis. Wernicke's encephal-
opathy is due to thiamine deficiency, and the
treatment of this condition thus focuses upon rapid
replacement of thiamine. Such treatment has the
potential to reduce substantially the very signifi-
cant morbidity and mortality associated with
Wernicke's encephalopathy
psychosis. For a variety of reasons, clinical
management of Wernicke's encephalopathy is
often confused, inappropriate
neglected. This review evaluates the research
literature in this field and makes recommendations
for clinical management of such patients. The
wider role of B vitamins in neuropsychiatric
and Korsakoffs
or entirely
•Author to whom correspondence should be addressed.
syndromes associated with alcohol misuse will
also be considered.
NEUROPSYCHIATRIC CONDITIONS
ASSOCIATED WITH ALCOHOL MISUSE
There are a large number of neuropsychiatric
conditions known to be associated with alcohol
misuse. Many of these conditions are directly due
to alcohol toxicity or withdrawal, but other factors,
including malnutrition, also play a part (see Table
1). In addition, there are neurological syndromes
secondary to other alcohol-induced disorders (e.g.
hepatic encephalopathy)
trauma (e.g. head injury) (see review by Rubino,
1992). This review will focus mainly upon those
syndromes in Table 1 which are associated with
vitamin deficiencies. However, other syndromes
in Table 1, especially delirium tremens, may be
difficult to differentiate diagnostically from those
that are vitamin related. All of these other
syndromes, especially alcohol withdrawal, may
also commonly be co-morbid with the vitamin-
related syndromes.
There has been a 65% increase in the reported
incidence of alcoholic psychoses (ICD-9 code
and alcohol-related
317
© 1998 Medical Council on Alcoholism
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Table I. Neuropsychiatric conditions associated with alcohol misuse
n
n
x
n
Neuropsychiatnc syndromeAetiological factors
Common name
ICD-10*
DSM-IVtAlcohol Vitamin deficiency
Intoxication
Alcohol misuse
Alcohol dependence
Alcohol withdrawal
Alcohol-withdrawal
seizures
Delirium tremens
Alcoholic psychosis
Wemicke's
encephalopathy
Korsakoffs psychosis
FIO.O Acute alcohol intoxication
F10.1 Harmful use of alcohol
F10.2 Alcohol-dependence syndrome
F 10.30 Alcohol withdrawal state —
uncomplicated
F 10.31 Alcohol withdrawal state —
with convulsions
F10.4 Alcohol withdrawal state — with
delirium
FI0.5 Alcoholic psychotic disorder
G31.2 Degeneration of nervous system
due to alcohol I
F10.6 Alcoholic-amnestic syndrome
Alcoholic dementia F10.73 Alcoholic dementia
Cerebellar
degeneration
—
303.00 Alcohol intoxication
291.0 Alcohol intoxication delirium
305.00 Alcohol abuse
303.90 Alcohol dependence
291.8 Alcohol withdrawal
291.0 Alcohol-withdrawal delirium
291.3/291.5 Alcohol-induced psychotic
disorder
291.1 Alcohol-induced persisting
amnestic disorder
291.2 Alcohol-induced persisting
dementia
Alcohol consumption
Alcohol consumption
Regular heavy alcohol
consumption
Alcohol withdrawal
Alcohol withdrawal
Alcohol withdrawal
Alcohol intoxication/
withdrawal
Chronic heavy drinking
Chronic heavy drinking
Chronic heavy drinking
Chronic heavy drinking
—
? Pyridoxine
—
Thiamine
Thiamine
—
? Thiamine
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Marchiafava—Bignami
disease
Central pontine
myelinolysis
Alcoholic amblyopia
Alcoholic pellagra
encephalopathy
Peripheral neuropathy
Other
F10.71 Personality or behaviour
disorder due to alcohol
F 10.72 Residual affective disorder due
to alcohol
F 10.74 Other persisting cognitive
impairment due to alcohol
F10.5 Late onset psychotic disorder
due to alcohol
F10.8 Other mental and behavioural
disorders due to alcohol
F10.9 Unspecified mental and
behavioural disorder due to alcohol
Chronic heavy drinking
Chronic heavy drinking
Chronic heavy drinking
Alcohol misuse
Chronic heavy drinking
291.8 Alcohol-induced mood disorder
291.8 Alcohol-induced anxiety disorder
291.8 Alcohol-induced sexual
dysfunction
291.8 Alcohol-induced sleep disorder
291.9 Alcohol-related disorder not
elsewhere specified
Thiamine B|2
Nicotinamide
Thiamine
Folate
? Nicotinic acid
? Pyridoxine
? Pantothenic acid
*World Health Organization (1992). tAmencan Psychiatric Association (1994). ^Although it would appear that Wemicke's encephalopathy should be classi-
fied under G31.2 in 1CD-10, this is a broader category, which would also include other forms of damage to the nervous system due to alcohol. There is no
specific category for Wemicke's encephalopathy under either ICD-IO or DSM-IV.
8
o
r
2
a
n
H
n
C
73
O
T3
n
n
<
2a
73
oI
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320
C. C. H. COOK el al.
Table 2. Finished consultant episodes for ordinary and day
case admissions by main diagnosis, National Health
Service hospitals, England 1988-1989 to 1993-1994
Year
1988-1989
1989-1990
1990-1991
1991-1992
1992-1993
1993-1994
Alcoholic
psychoses
ICD-9 code
291
2487
3215
3578
4030
4234
4098
Delirium
tremens
ICD-9 code
291.0
438
565
631
720
699
750
Alcohol
dependence
syndrome
ICD-9 code
303
19 200
20 530
20 598
18 579
19414
20 950
Source: Hospital Episode Statistics, Department of
Health.
291) (World Health Organization, 1978) in gen-
eral, and a 70% increase in delirium tremens (code
291.0), specifically in England over the period
1988-1989 to 1993-1994, despite the fact that
both admissions for alcohol dependence (see
Table 2) and alcohol consumption patterns
(Thomas et al., 1994; Bennett et al., 1995) have
remained relatively static over this time period.
ICD-9 code 291 'Alcoholic Psychoses' is a
rather nebulous grouping which specifically
includes Korsakoffs psychosis (code 291.1), but
none of the other vitamin-related neuropsychiatnc
syndromes in Table 1. (In the ICD, it seems that
these are meant to be classified elsewhere, with
neurological disorders.)
Recent data from Scotland indicate that the
majority (83%) of cases of delirium tremens occur
in general hospitals (only 17% occurring in
psychiatric hospitals) and that a significant
proportion (perhaps up to 50%) occur in patients
not considered to be alcohol-dependent (CRAG/
SCOTMEG Working Group on Mental Illness,
1994) — probably reflecting the poor recording of
alcohol histories. Management of these conditions
is, therefore, not within the sole ambit of psychia-
trists, but is widely applicable to all healthcare
providers dealing with patients who misuse
alcohol.
WERNICKE-KORSAKOFF SYNDROME
One of the most serious neuropsychiatnc con-
ditions associated with alcohol misuse is the
Wernicke-Korsakoff syndrome (WKS), which
causes significant morbidity and mortality (Victor
et al., 1989). Wemicke's encephalopathy is due to
thiamine deficiency and is characterized, 'classi-
cally' by clouding of consciousness (acute confu-
sion/delirium), ocular
ophthalmoplegia), and ataxia. The onset of
Wernicke's encephalopathy is commonly, but
not always, associated with alcohol withdrawal
and may occur in patients who do not misuse
alcohol at all (e.g. in those with gastric carci-
noma). If high-dose parenteral thiamine is not
given urgently, the biochemical abnormalities that
thiamine deficiency causes can lead to irreversible
brain damage. This damage either leads to death,
with mortality rates of 17%-20% being reported,
or in 85% of survivors, to the chronic form of the
syndrome, Korsakoffs psychosis, characterized
by short-term memory loss, but with relative
preservation of other intellectual functions. Some
25% of patients developing Korsakoffs psychosis
require long-term institutionalization as a result of
this selective organic brain damage (Victor et al.,
1989).
There are two commonly held fallacies con-
cerning Wernicke's encephalopathy; firstly that it
is a rare condition (Torvik et al., 1982; Thomson
and Pratt, 1992) and, secondly, that the triad of
symptoms originally described by Wernicke in
1881 (ophthalmoplegia, confusion, and ataxia) are
invariably present (Harper et al., 1986).
signs (nystagmus,
Epidemiology
Unfortunately UK hospital admission data for
Korsakoffs psychosis (ICD-9 code 291.1) are not
readily available, and Wernicke's encephalopathy
is not specifically classified under ICD-9. The
proportion of 'alcoholic psychoses' contributed by
the WKS, and thus the contribution of this
syndrome to the increase in UK admissions for
alcoholic psychoses in recent years, is therefore
unknown.
The incidence of Korsakoffs psychosis in
Glasgow in recent years is reported to have
shown a marked increase (Ramayya and Jauhar,
1997). These authors conducted a retrospective
analysis of all admissions between 1990 and 1995
in the East End of Glasgow (adult population
160 000) and identified 47 new cases of Korsa-
koffs psychosis in this 6-year time period. The
number of new cases per year were two in 1990,
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ALCOHOL, B VITAMIN DEFICIENCY AND NEUROPSYCHIATRIC SYNDROMES
321
Table 3. Prevalence of Wemicke's encephalopathy at post-mortem examination (from published studies)
Study
Cravioto et al. (1961)
Victor et al. (1989)
JeUinger (1976)
Victor and Laureno (1978)
Harper (1979)
Torvik et al. (1982)
Harper (1983)
Hauw et al. (1988)
Harper et al. (1986)
Lindboe and Loberg (1989)
Harper et al. (1995)
Country
USA
USA
Austria
USA
Australia
Norway
Australia
France
Australia
Norway
France
Post-mortem
examinations
(n)
1600
1539
1009*
3548
2891
8735
4677
8200
285
6964
256
Identified cases of
Wemicke's
encephalopathy
(n)
28
29
11
77
51
70
131
111
6
52
1
Prevalence
(%)
1.7
1.9
1.1
2.2
1.7
0.8
2.8
1.4
2.1
0.8
0.4
1 Elderly patients with dementia.
seven in 1991, three in 1992, 10 in 1993, 12 in
1994, and 13 in 1995. These figures reveal a rise
in incidence from 12.5 per million in 1990 to
81.25 per million in 1995. However, diagnosis in
this study was of Korsakoff s psychosis according
to 'classical criteria' and the figures would there-
fore presumably represent a gross underestimate
of the total prevalence of brain lesions of the
Wernicke-Korsakoff type.
In Australia, hospital admissions for Wemicke's
encephalopathy represent a low proportion of total
admissions. In a prospective study, Wood et al.
(1986) found that 32 such patients were admitted
to a general hospital over a 33-month period. This
represented 0.07% of the total admissions, 1.7% of
patients admitted with alcoholism, and 13% of
patients admitted with alcoholic psychoses. How-
ever, in this study, the presence of ophthalmo-
plegia was held to be essential to confirm the
diagnosis, and this would probably have under-
estimated the total prevalence (see later). In a
retrospective study, Ma and Truswell (1995) found
that admissions for WKS to 17 general hospitals in
Sydney decreased from 0.032% to 0.023% of total
admissions over the period 1978-1993. The
decrease may have been attributable to the intro-
duction of thiamine enrichment of bread flour in
1991, although national alcohol consumption also
decreased by 24% over the period in question.
However, Wernicke's encephalopathy is widely
underdiagnosed (see later) and so these figures are
also likely to represent an underestimate of the
true prevalence.
In necropsy studies representative of the general
population, around 1.5% of brains show the
morphological lesions of WKS in and near the
mamillary bodies. Data from published studies are
summarized in Table 3. Harper has also collected
unpublished data, which show a prevalence of
0.5-1.3% (Austria), 0.1% (Belgium), 1.0%
(Czechoslovakia), 0.4-1.0% (France), 0.3-0.8%
(Germany), 0.5% (UK), and 0-1.0% (USA)
(Harper et al., 1995).
In alcoholics the condition is, however, much
more frequent (Torvik et al., 1982). In a study of
8735 serial post-mortem examinations Torvik
found 70 cases of Wernicke's encephalopathy in
561 alcoholics examined — a prevalence of
12.5%. There is also strong evidence that the
cerebellar lesions of Wemicke's encephalopathy
and those of 'alcoholic cerebellar degeneration'
represent the same disease process (Reuler et al.,
1985; Victor et al, 1989). In Torvik's study,
26.8% of 567 alcoholics examined showed
cerebellar atrophy. It is possible to calculate
from the published data that, in this study,
approximately 35% of alcoholics examined post-
mortem showed the classical lesions of Wer-
nicke's encephalopathy and/or cerebellar atrophy
(Torvik et al., 1982; Victor et al., 1989).
In 3.9% of alcoholics (22 patients) examined by
Torvik, the cause of death was diagnosed, post-
mortem, to be as a direct result of an acute episode
of Wemicke's encephalopathy (Torvik et al.,
1982). In Harper's studies of patients with
Wemicke's encephalopathy, over 20% died sud-
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322
C. C. H. COOK et al.
denly and unexpectedly. Harper also noted that
lesions described histopathologically as being
'chronic' Wernicke's encephalopathy may also
cause sudden death (Harper, 1979; Harper et al.,
1986).
Aetiology
The involvement of thiamine deficiency in the
aetiology of WKS was suspected over 50 years
ago. Bowman et al. (1939) showed some evidence
of a beneficial effect of parenteral thiamine in the
treatment of Korsakoff s psychosis with 'acute
onset'. These patients would possibly now be
diagnosed as suffering from Wernicke's encepha-
lopathy. At about the same time, Alexander (1939)
showed that pigeons fed on a thiamine-deficient
diet developed lesions identical in distribution,
morphology, and histology to those found in
human Wernicke's encephalopathy. Later, de
Wardener and Lennox (1947) showed that in
prisoners of war on a grossly deficient diet, the
genera] incidence of cases of Wernicke's en-
cephalopathy coincided in time with the incidence
of classical beriberi. There was also a close
association in individual cases (79%) with classi-
cal beriberi, and the syndrome responded to
treatment with thiamine.
Jollife et al. (1941) published a report of a series
of 27 cases of Wernicke's encephalopathy and
noted that, amongst those who recovered, the
development of Korsakoff s psychosis was 'the
rule'. Furthermore, they noted that Korsakoff s
psychosis generally did not respond to thiamine
supplementation (Jollife et al., 1941). Malamud
and Skillicom (1956) suggested that, in view of
the clinical association and the similar distribution
of the underlying lesions, Wemicke's encephalo-
pathy and Korsakoff s psychosis were manifesta-
tions of the same disorder, differing only in the
acuteness or chronicity of the underlying disease
process. The full history of the development of the
understanding of the link between Wemicke's
encephalopathy and Korsakoff s psychosis, and
the aetiology of WKS, have been reviewed by
Lishman (1981).
WKS has since been shown to be associated
with thiamine deficiency (Butterworth et al.,
1993), and the activity of thiamine-dependent
enzymes in the brain in Wernicke's encephalo-
pathy is known to be reduced by 70-97%
(Tallaksen et al., 1993). However, thiamine
deficiency and reduced activity of the dependent
enzymes are also seen in alcoholics without WKS
(Lavoie and Butterworth, 1995).
WKS is often precipitated, in those who are
alcohol-dependent, by the stress of an intercurrent
illness or it can also develop during or following
treatment of alcoholic seizures or delirium tre-
mens — conditions placing increased demands on
already depleted thiamine stores. For example,
Victor et al. (1989) found that, in a group of 50
hospitalized alcoholic patients with Korsakoff s
psychosis, the condition began in 38% of cases
with an attack of delirium tremens. Similarly, in
patients dying acutely during an episode of
delirium tremens, brainstem lesions differing
only quantitatively from those of Wernicke's
encephalopathy have been found (Anonymous,
1981). Because of the similarity, in both histo-
pathological and clinical presentations (see later),
a number of authors have postulated that these two
conditions may represent part of the same con-
tinuum (Anonymous, 1981; Victor et al., 1989).
There is a specific topographic pattern of
lesions in WKS which focuses on periventricular
regions including the mamillary bodies [which act
as a relay centre between hippocampal and
thalamic nuclei in one of the two memory circuits
(Meyer, 1958)], other hypothalamic structures,
periventricular thalamic nuclei, and structures in
the floor of the fourth ventricle (Thomson and
Pratt, 1992). Involvement of the dorso-medial
nucleus of the thalamus appears to be particularly
associated with memory disturbance (Victor,
1964).
It is possible that a minority of patients diag-
nosed clinically as having Korsakoff s psychosis
may in fact have a form of alcoholic dementia
(Cutting, 1978; Jacobson and Lishman, 1987). As
it currently appears that alcoholic dementia is not
due to thiamine deficiency (see later), this may
suggest that there is in fact a degree of aetiological
heterogeneity within the diagnosis of Korsakoff s
psychosis.
Clinical presentation
Harper, in a review of published pathological
studies, found that only 10% of patients with
Wernicke's encephalopathy had the full classical
triad of clinical signs. Thus, 23% had ataxia, 29%
had ocular signs and 82% presented with mental
changes i.e. confusion, drowsiness, obtundation,
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ALCOHOL, B VITAMIN DEFICIENCY AND NEUROPSYCHIATRIC SYNDROMES
323
pre-coma, and coma (Harper et al., 1986). It is
also now believed that Wernicke's encephalopathy
can evolve as 'minor' episodes of 'subclinicaT
encephalopathies in which all of the classical
features are absent (Reuler et al., 1985; Blansjaar
and Van Dijk, 1992). Because of the very non-
specific presentation of WKS in clinical practice,
and the wide differential diagnosis that exists,
ante-mortem diagnosis is reported to occur in only
around 5% of cases (Torvik et al., 1982).
In addition to the classical signs of Wernicke's
encephalopathy, patients may also present with a
history of alcohol misuse and otherwise un-
explained hypothermia and hypotension (Koeppen
et al., 1969). Hypothermia may also occur in the
absence of hypotension (Philip and Smith, 1973;
Hunter, 1976). Response to parenteral B vitamins
apparently occurs rapidly in some cases (Acker-
man, 1974; Reuler et al., 1985; Lindberg and
Oyler, 1990), but body temperature may take up to
2 weeks to return to normal (Hansen et al., 1984).
ALCOHOLIC PELLAGRA
ENCEPHALOPATHY
Alcoholic pellagra, first recognized in 1869, is
due to deficiency of niacin (and possibly other B
vitamins) in association with chronic alcohol
misuse. The signs and symptoms are generally
similar to those seen in 'endemic' pellagra, and in
acute and severe deficiency they may include an
encephalopathic syndrome characterized most
frequently by confusion, oppositional hypertonus,
and myoclonus (Serdam et al., 1988). Cogwheel
rigidity and grasping and sucking reflexes (Jollife
et al., 1940; Serdaru et al., 1988), hallucinations,
insomnia, tremor, ataxia, and urinary and faecal
incontinence (Ishii and Nishihara, 1981) are also
commonly seen. Peripheral neuropathy, seizures,
anxiety, depression, excitement, and neurasthenia
may also occur (Ishii and Nishihara, 1981). This
syndrome has been termed 'alcoholic pellagra
encephalopathy'.
Alcoholic pellagra encephalopathy is much less
common than WKS, with a prevalence of only
0.003% in one series of post-mortem examinations
(Hauw et al., 1988). However, it has been
suggested that routine multiple vitamin therapy
may have significantly reduced the incidence of
the syndrome in the USA and UK since the 1950s
(Lishman, 1981). There is also evidence that it
may be subject to even greater under diagnosis. In
one survey of 74 post-mortem examinations of
alcoholic patients who died in hospital, 20 (27%)
were found to have neuropathological features of
pellagra (Ishii and Nishihara, 1981).
The differential diagnosis from other neuropsy-
chiatric syndromes associated with alcohol misuse
can be difficult. For example, a diagnosis of
delirium tremens is often made (Ishii and
Nishihara, 1981). Furthermore, alcoholic pellagra
encephalopathy occurs not infrequently in combi-
nation with other alcoholic encephalopathies, and
treatment with thiamine and pyridoxine without
niacin appears to aggravate or precipitate the
condition (Serdaru et al., 1988). Characteristic
microscopic changes assist with diagnosis at post-
mortem examination, notably chromatolysis of
neurones in the central nervous system (CNS),
especially in the pons (Ishii and Nishihara, 1981;
Hauw et al., 1988).
Alcoholic pellagra encephalopathy responds
readily to treatment with nicotinic acid (Cleckley
et al., 1939), although a significant mortality is
still reported (Jollife et al., 1940; Gottlieb, 1944).
In one published case report, treatment with i.v. B-
complex vitamins (including both thiamine and
nicotinamide) led to the resolution of the pellagra
encephalopathy, but did not prevent the develop-
ment of Wernicke's encephalopathy (Teare and
Pollock, 1993). The exact dose of vitamins given
was not reported, but it would appear that the dose
of thiamine was insufficient as prophylaxis against
Wernicke's encephalopathy, whilst the dose of
nicotinamide was sufficient to treat the pellagra
encephalopathy. This would suggest that it may be
important that the treatment of alcoholic pellagra
encephalopathy should include high doses of
parenteral thiamine as well as nicotinamide.
OTHER VITAMIN-RELATED
NEUROPSYCHIATRIC CONDITIONS
ASSOCIATED WITH ALCOHOL MISUSE
As discussed above, alcoholic cerebellar degen-
eration may well be due to thiamine deficiency,
and may actually be a part of WKS. Peripheral
neuropathy is also commonly associated with
WKS, and was originally considered by Korsakoff
to be a part of his 'psychosis polyneuritica'. How-
ever, it also commonly occurs separately from
WKS and may be caused by folate deficiency
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324
C. C. H. COOK et al.
(Gimsing et al., 1989) and possibly pyridoxine,
pantothenic acid, or nicotinic acid deficiency as
well as (more commonly) thiamine deficiency
(Fennelly et al., 1964). It has also been suggested
that, in some patients without thiamine deficiency,
peripheral neuropathy may develop as a result of
an alcohol-induced defect in thiamine utilization
(Paladin and Perez, 1987).
Marchiafava-Bignami disease, central pontine
myelinolysis, and alcoholic amblyopia are all rare,
but have also been thought to be possibly due to
nutritional deficiencies associated with alcohol
misuse. These disorders have been reviewed by
Lishman (1987Z?).
Marchiafava-Bignami disease is associated
with CNS demyelination particularly affecting
the corpus callosum. It is very rare, and Victor
and Laureno (1978) found a prevalence of only
0.06% (two cases) in their series of 3548 post-
mortem examinations. Although it has been
suggested that there may be a nutritional origin
(Lishman, 1987£), this is not universally agreed
(Delmas-Marsalet et al., 1967), and at least one
published case report provides evidence of a lack
of response to i.v. vitamins, including high doses
of thiamine (Dceda et al., 1989).
Central pontine myelinolysis was first described
almost 40 years ago (Adams et al., 1959). It may
be associated with Wemicke's encephalopathy
both in the presence (e.g. Cole et al., 1964;
Rodriguez and Hankey, 1987) and absence (e.g.
Bergin and Harvey, 1992) of alcohol misuse. Post-
mortem examination reveals demyelination of the
pons, and the disease is usually thought to be very
rare. Victor and Laureno (1978) found a pre-
valence of only 0.3% (nine cases) in a series of
3548 post-mortem examinations. However, one
post-mortem survey revealed that demyelination is
not confined to the pons, and the authors were able
to identify 58 cases of central pontine and/or
extrapontine myelinolysis (a prevalence of 1.0%)
in a series of 5926 brain autopsies (Gocht and
Colmant, 1987). A nutritional basis has been
suggested, in view of the frequent association with
malnutrition (Cole et al., 1964), but more recently
the sudden correction of hyponatraemia has been
implicated (see discussion by Hankey in Rodri-
guez and Hankey, 1987, and also Norenberg et al.,
1982; Illowsky and Laureno, 1987; Brunner et al.,
1988), and an association with hypokalaemia has
also been observed (Bahr et al., 1990). Experi-
mental work with dogs has also supported the
possible importance of rapid reversal of the
hyponatraemia (Laureno, 1983). Neither malnutri-
tion nor hyponatraemia are invariable features of
this condition, and treatment with large doses of B
vitamins appears to be ineffective (Wright et al.,
1979). Possibly, thiamine deficiency may make
the myelin sheaths more sensitive to sudden
changes in serum sodium (Bergin and Harvey,
1992).
Alcoholic amblyopia presents as a painless
bilateral loss of vision in association with alcohol
misuse. The majority of patients are also smokers.
A variety of B vitamin deficiencies have been
implicated in the aetiology, although thiamine
appears to be the most important. The visual
impairment has been shown to respond to treat-
ment with thiamine or B-complex vitamins, even,
in some cases, when alcohol misuse continues
(Carroll, 1944, 1945; Primo, 1988). In one report
of two cases, reduced transketolase activity has
been demonstrated (Dreyfus, 1965).
It. has been suggested that thiamine deficiency
contributes to the aetiology of alcoholic dementia,
but serum thiamine correlates poorly with cogni-
tive deterioration (Molina et al., 1994), and is
therefore now not thought to play a major
aetiological role in this condition (Lishman,
1987a). However, the failure to correlate current
thiamine status with cognitive deterioration does
not preclude the influence of earlier damage
attributable to thiamine deficiency. It is also
important to remember that thiamine utilization,
rather than thiamine status per se, is the critical
aetiological factor.
A causal role of thiamine deficiency in delirium
tremens has now been excluded (Lishman, 1987a),
although this condition may often be confused
diagnostically with Wemicke's encephalopathy,
and the two conditions may also frequently coexist
(see earlier).
There is some evidence that pyridoxine defi-
ciency may increase the risk of alcohol withdrawal
fits, but the causal relationship does not appear to
be well established (see later). It has also been
suggested that i.v. pyridoxine produces dramatic
reversal of alcoholic intoxication, but numerous
studies have failed to replicate this finding (see
review by Bonjour, 1980).
A wider range of neuropsychiatric conditions
are also associated with B vitamin deficiencies,
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325
Table 4. Neuropsychiatric conditions associated with B
vitamin deficiency
B Vitamin
Thiamine (BO
Biotin
Pantothenic acid
Pyridoxine (B6)
B,2
Choline
Folate
Nicotinic acid
Riboflavin
Neuropsychiatric condition
Wemicke-Korsakoff syndrome
Leigh's disease (subacute necrotizing
encephalomyopathy)
Neurasthenia
Depression
Peripheral neuropathy
Anorexia, lassitude, sleeplessness
Fatigue, irritability
Peripheral neuropathy
Irritability, confusion and lethargy
Depression
Seizures (in infants)
Peripheral neuropathy
Neurasthenia
Depression
Psychosis
Dementia
Seizures
Subacute combined degeneration of
the cord
? Deficiency does not occur
Depression
Dementia
Peripheral neuropathy
Neurasthenia (in early stages)
Depression
Psychosis
Acute organic brain syndrome
Seizures
Spastic paralysis, ataxia, tremor
Retrobulbar neuritis
Deafness
Peripheral neuropathy
Lethargy, low mood,
hypochondriasis
but are not necessarily associated with alcohol
misuse. These are listed in Table 4 (see also
Lishman, 1987b).
Given the high prevalence of B vitamin defi-
ciencies in alcohol dependence (see below), it may
well be that more attention should be paid to the
detection of these conditions in patients admitted
for alcohol withdrawal.
B VITAMIN DEFICIENCY IN ALCOHOL
MISUSE AND DEPENDENCE
B vitamin deficiencies are common in alcohol-
ics (Thomson et al, 1987). Thiamine (B,) defi-
ciency has been reported in 30-80% of alcoholics,
folate deficiency in 60-80%, pyridoxine (B6)
deficiency in 50% (Thomson et al., 1987), and
riboflavin (B2) deficiency in 17% (Thomson et al.,
1996). Whilst much less common, nicotinic acid
deficiencies have also been reported (Thomson et
al., 1987).
A complete exposition on the role of the B
vitamins is beyond the scope of this review.
However, thiamine, pyridoxine, riboflavin, and
nicotinamide act as coenzymes and are involved in
glucose and lipid metabolism and the production
of amino acids and glucose-derived neurotrans-
mitters (Tower, 1956, 1958, 1976; Greenwood et
al, 1985a; Thomson et al., 1987, 1994; Thomson,
1990; Thomson and Pratt, 1992). The brain
depends on an adequate supply of glucose both
as an energy source and as a donor of carbon
fragments for protein, neurotransmitter and lipid
biosynthesis. Glucose utilization is B vitamin-
dependent and it is likely that a breakdown in this
complex metabolic process is a major factor in the
production of B vitamin-deficient brain damage
(Pratt et al, 1985; Thomson et al, 1987; Thomson
and Pratt, 1992).
The consequences of B vitamin deficiencies on
the central and peripheral nervous systems are
shown in Table 4. Given the overlap in sympto-
matology, and the fact that alcoholics are
commonly deficient in a number of the B vitamins
(Thomson et al., 1987), most authorities advocate
the use of B-complex vitamins in the management
of neuropsychiatric conditions associated with
alcoholism (Anonymous, 1979, 1981, 1991;
Guthrie and Elliot, 1980; Greenwood et al,
1985b; Thomson and Pratt, 1992).
Thiamine
The three major thiamine-dependent enzyme
systems are pyruvate dehydrogenase, transketo-
lase, and 2-oxo-glutarate dehydrogenase. Pyruvate
dehydrogenase is involved in the breakdown of
pyruvate to acetyl coenzyme A, which feeds into
the Krebs cycle, and is thus involved in energy
production. Transketolase is involved in the
pentose phosphate pathway, the maintenance of
myelin sheaths in the nervous system, lipid and
glucose metabolism, and branched chain amino
acid production. 2-Oxo-glutarate dehydrogenase is
involved in the tricarboxylic acid cycle, and
synthesis of glucose-derived neurotransmitters
[acetylcholine, y-amino butyric acid (GABA) and
glutamate] (Thomson et al, 1987; Thomson and
Pratt, 1992).
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326
C. C. H. COOK et al.
A considerable amount of research has recently
been conducted on transketolase, a key enzyme
involved in glucose metabolism within the CNS
(Pratt et al., 1985; Thomson et al., 1987, 1994;
Thomson and Pratt, 1992).
The apoenzyme of transketolase apparently
exists in two (or more) forms in different patients.
One component apoenzyme has its thiamine
diphosphate (TDP) coenzyme firmly bound,
while the other variant is a smaller molecule
which is inactive without added TDP, for which it
has reduced affinity (Pratt et al., 1985). This could
represent a genetic variant with altered TDP
binding predisposing the subject to brain damage
due to thiamine depletion. Equally, the transketo-
lase protein may be damaged by acetaldehyde or
reactive oxygen species; the fragments resulting in
altered binding with TDP. Under these cir-
cumstances, there would also be an increased
requirement for thiamine, hence predisposing
malnourished subjects to thiamine deficiency
and, subsequently, brain damage. As thiamine
receptor sites on the apoenzyme molecule become
vacant, due to thiamine depletion, the molecule
also becomes unstable and vulnerable to irrever-
sible damage. It may, however, be activated at
non-physiological levels of thiamine diphosphate,
i.e. at levels which cannot be achieved with orally
administered thiamine (Pratt et al., 1985; Thom-
son et al., 1994). This may explain the wide inter-
patient variation in amounts of thiamine required
to resolve the symptomatology of Wernicke's
encephalopathy (Blass and Gibson, 1977).
It was thought that the low affinity variant of
transketolase might be a mediator of genetic
susceptibility to Wernicke-Korsakoff psychosis
(Blass and Gibson, 1977; Martin et al., 1993).
However, although this enzyme variant is seen
commonly in patients with WKS, it is also found
in alcoholics without WKS, unaffected sons of
alcoholics (Mukherjee et al., 1987), and (less
commonly) in the normal population (Greenwood
et al., 1984). A comparison of DNA from two
WKS patients and two controls revealed no coding
differences specific to the WKS subjects (McCool
et al., 1993).
Pyridoxine
Pyridoxine (Bg) is unique amongst the B-
complex vitamins in that it is the only member
in which deficiency, or interference with its
function, commonly results in epileptiform seiz-
ures in all mammalian species, including man
(Tower, 1956, 1958, 1976). Seizure disorders
associated with inadequate B6 nutrition relate to
the function of the vitamin as a coenzyme for
glutamic acid decarboxylase (GAD), the enzyme
which synthesizes the inhibitory neurotransmitter
GAB A from glutamic acid (Tower, 1976). In
nutritional seizure states, clinical response and
normalization of electroencephalograms have
been shown to occur within minutes of adminis-
tration of parenteral pyridoxine — demonstrating
a functional interference with an essential meta-
bolic step which can be promptly reversed or
corrected by appropriate measures (Tower, 1956,
1958, 1976). We might speculate, therefore, that
pyridoxine deficiency could contribute to the
aetiology of alcohol-withdrawal seizures, and
there is some evidence in support of this conten-
tion.
In one early study, five patients with 'rum fits'
showed greater evidence of pyridoxine deficiency
than two patients with alcoholism and epilepsy,
six patients with alcoholism who had suffered no
fits, and one normal control (Lerner et al., 1958).
In another study, only one out of 23 male
alcoholics treated with 100 mg of pyridoxine
suffered a withdrawal fit, as compared with
seven out of 23 not given this treatment. Another
20 patients studied by the same author were all
given pyridoxine, and none of them suffered
withdrawal fits (Lunde, 1960). The sample sizes
in these studies were very small, but we have not
been able to find any larger or more recently
published studies.
Vitamin storage
The water-soluble vitamins are not extensively
stored by the body; for example, the body stores
around 25-30 mg thiamine, principally in the
heart, brain, liver, and kidneys. In healthy
individuals, daily turnover is approximately 1 mg
and a regular intake is required to maintain these
reserves (McCormick, 1988). Deficiency can
present within 2-3 weeks of intake ceasing
(Velez et al., 1985). In chronic alcoholics, this
problem is compounded for a number of reasons,
including inadequate diet, reduced absorption,
increased metabolic demands, and reduced hepatic
storage (Thomson and Majumdar, 1981; Green-
wood et al., 1985b). Whilst research has concen-
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327
trated on the storage, utilization, and role of
thiamine, the other B vitamins are known to be
adversely affected in alcoholics in a similar way
(Thomson et al, 1996).
TREATMENT OF B VITAMIN DEFICIENCY
AND WKS ASSOCIATED WITH ALCOHOL
MISUSE
In treating B vitamin-related neuropsychiatric
conditions associated with alcoholism, in view of
the high morbidity and mortality, the aim must be
to restore CNS B vitamin levels as rapidly as
possible in order to correct the concomitant
metabolic imbalance. Similar considerations will
apply to the prophylaxis of neuropsychiatric
conditions associated with alcohol misuse and
withdrawal. Although most research has focused
on thiamine and WKS, similar concerns relate to
other B vitamins (see Thomson et al., 1996), and it
would therefore appear reasonable to assume that
the same general principles should apply to them
too.
This review will focus upon B vitamin supple-
mentation, and other sources should be consulted
regarding the general management of alcohol
withdrawal (e.g. Turner et al., 1989; Edwards et
al., 1997). However, it is important to note that a
large carbohydrate load, administered parenterally
(e.g. as an i.v. glucose infusion) or by mouth will
increase the thiamine requirement and may
thereby precipitate or exacerbate Wemicke's
encephalopathy (see e.g. Lonsdale, 1978). Simi-
larly, oral hypoglycaemic agents may precipitate
Wemicke's encephalopathy (Kwee and Nakada,
1983).
In order to understand how this rapid restoration
of CNS vitamin levels may best be achieved, we
must consider research evidence in respect of
route of administration (oral vs parenteral), fre-
quency and dosage of administration and the
safety profile of the vitamins as commercially
available. This research evidence will then be
compared against current practice in the UK and
will be used to formulate recommendations for
good clinical practice in the prevention and
treatment of WKS.
Parenteral vs oral B vitamin supplementation
Absorption from the gastrointestinal tract.
Thiamine transport across the intestinal wall in
man is mediated via active, saturable, stereospe-
cific and sodium-dependent transport mechanisms.
Kinetic studies have shown that, in healthy volun-
teers, a 10-mg dose of thiamine maximizes oral
absorption i.e. increasing a single oral dose above
this level has no significant effect on plasma or
cumulative urinary thiamine levels under test
conditions. The maximum amount of thiamine
absorbed from single oral doses of 10 mg or
greater would appear to be between 4.3 mg and
5.6 mg (Thomson et al., 1970).
Absorption of thiamine appears to be indepen-
dently affected by ethanol and malnutrition
(Thomson et al., 1970; Greenwood et al, 1985b;
Thomson, 1990). In abstemious malnourished
alcoholics, the oral absorption of thiamine is
extremely variable (some patients showing little,
or no, absorption). However, absorption is
approximately 30% of that in healthy individuals
i.e. a maximum of 1.5 mg of thiamine can be
absorbed from a single oral dose of 10 mg or
greater. In the presence of alcohol, thiamine
absorption is further impaired. In one-third of
patients, a further 50% reduction in absorption
was found with concomitant administration of
alcohol and thiamine (Thomson et al., 1970).
Research would thus suggest that only 0.8 mg or
less of an oral dose of thiamine might be absorbed
in malnourished patients who have recently been
drinking and in some patients the amount absorbed
is extremely low. The daily thiamine requirement
is approximately 1-1.6 mg in healthy individuals.
Presumably the requirement is higher in patients
with Wemicke's encephalopathy, although little or
nothing is known about how much thiamine must
be absorbed in order to reverse or arrest the
condition. Neither has there apparently been any
research into the possible advantages of multiple
daily dosage of oral thiamine in prophylaxis
against Wemicke's encephalopathy. However,
where a therapeutic dose is required, the rapidity
of the requirement for thiamine repletion would
appear to preclude this option anyway.
Given these considerations, oral thiamine sup-
plementation in alcoholics (particularly if they
continue to drink) is likely to be quite inadequate.
It is therefore not surprising that cases of
Wemicke's encephalopathy have been described
in alcoholics taking high-dose B vitamin supple-
mentation orally (Chataway and Hardman, 1995).
It is perhaps surprising, however, that some
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328C. C. H. COOK et al.
patients apparently do show clinical improvement
on oral supplements (Meyer et al., 1985).
Furthermore, in one study of alcoholic patients,
an oral regimen of 50 mg thiamine daily for 5 days
did elevate erythrocyte levels of thiamine diphos-
phate (Baines et al., 1988). However, malnour-
ished subjects were excluded from the study group
and the levels of thiamine were elevated more
rapidly in a comparison group who were given
250 mg daily i.m.
Transport across the blood-brain barrier.
Thiamine has active and passive transport mech-
anisms across the blood-brain barrier. The active
mechanism is both rate-limited and saturable at
low thiamine levels (Greenwood et al., 1985b).
Active uptake occurs at a maximum rate of
approximately 0.3 (ig/h/g of brain tissue. This
rate is comparable to that calculated for brain
thiamine turnover, suggesting that thiamine trans-
port may be just sufficient to meet normal cerebral
requirements and that there may exist very little
excess capacity of the system (Butterworth, 1995).
Rapid correction of CNS vitamin levels, therefore,
requires a high plasma: CNS concentration gra-
dient to be established such that passive diffusion
is encouraged.
A number of published studies comparing the
effects of oral vs parenteral vitamin supplementa-
tion in chronic alcoholics have demonstrated the
beneficial role of high-dose parenteral therapy in
terms of restoration of CNS levels (Baker and
Frank, 1976; Thomson et al., 1983). Baker and
Frank (1976) studied the absorption, utilization,
and clinical effectiveness of various thiamine
derivatives. They showed that, in contrast to
parenterally administered water-soluble thiamines
(thiamine hydrochloride and thiamine pyrophos-
phate), oral administration of water-soluble thi-
amine neither elevated thiamine activity in
cerebrospinal fluid nor restored transketolase
activity to normal in alcoholics with thiamine
deficiency.
Thomson (1969) and Thomson et al. (1983)
evaluated thiamine supplementation in six thia-
mine-deficient alcoholic patients with Wernicke's
encephalopathy. Patients initially received 50 mg
of thiamine hydrochloride orally followed 24 h
later by 50 mg of thiamine propyl disulphide (a
fat-soluble form which behaves like a parenteral
presentation). This latter product was in develop-
ment in Japan in the 1960s but has never been
commercially available as a pharmaceutical pro-
duct. It is, however, available 'over the counter' as
a food supplement in the USA. Blood and CNS
thiamine and pyruvate levels were measured by
the above authors post-treatment. Oral thiamine
hydrochloride had little or no effect on either CNS
or blood vitamin status. Pyruvate levels in blood
and CNS (a marker of carbohydrate metabolic
degradation) only fell significantly following
administration of bioavailable thiamine. The
authors also noted a marked improvement in
clinical symptoms (ataxia, confabulation, ocular
palsy, etc) following repeated therapy with the
bioavailable form of thiamine, but not with oral
thiamine hydrochloride.
Frequency of administration of parenteral B
vitamin supplements
Blood thiamine levels fall to baseline values
between 6 and 24 h after administration of the
bioavailable form (Thomson et al., 1983). Unpub-
lished data using radiolabelled thiamine in defi-
cient alcoholics have also demonstrated that
thiamine plasma levels decline to 20% of peak
values within 2 h of parenteral administration
(Thomson, 1969). Thus, the 'window' for passive
diffusion to occur appears to be relatively short. In
order to restore CNS B vitamin levels in patients
with WKS, parenteral vitamins should therefore
be administered twice or three times daily.
Dosage of parenteral B vitamin supplements
No formal, dose-ranging, placebo-controlled
studies have been conducted on the use of
parenteral B-complex vitamins in alcoholics.
Knowledge concerning the appropriate dosage is,
therefore, largely based on data from uncontrolled
trials and empirical clinical practice. In reviewing
these publications, it is also important to distin-
guish those circumstances where the vitamin
supplements were being used prophylactically,
and those where they were being used in treatment
of established or suspected WKS.
Prophylaxis. One study of 12 patients (Majum-
dar, 1980) has described a prophylactic regime of
one pair of Parentrovite ampoules of high-potency
parenteral B-complex vitamins once daily for 5
days in 'at-risk' alcoholics undergoing detoxifica-
tion. The regimen was apparently clinically effec-
tive in preventing the development of WKS, and
transketolase activity was restored to normal in
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ALCOHOL, B VITAMIN DEFICIENCY AND NEUROPSYCHIATRIC SYNDROMES
329
seven patients with marginal/low levels of activ-
ity. Parentrovite was similar to the only high-
potency parenteral B complex
currently available in the UK (Pabrinex). Both
preparations contain(ed) 250 mg of thiamine
hydrochloride in addition to other B vitamins
(4 mg riboflavin, 50 mg pyridoxine hydrochloride,
and 160 mg nicotinamide) and 500 mg ascorbic
acid.
Another study suggested that one pair of
ampoules of high-potency parenteral B-complex
vitamins once daily for 5 days did not restore
vitamin status as measured by the activity of
thiamine-dependent enzymes (Brown et al., 1983).
A later study, measuring thiamine diphosphate
directly, showed that a similar regime, using i.m.
administration, was effective (Baines et al., 1988).
The latter study seems therefore to suggest that
such a regime might be effective prophylactically,
although the former study did not. However, the
discrepancy might be explicable on the basis that
normal thiamine levels may still be associated
with impaired utilization of thiamine due to a
damaged apoenzyme.
Treatment. Data are extremely limited on
dosage and duration of therapy in this condition.
However, low-dose parenteral therapy does not
appear to be reliably effective in preventing
morbidity and mortality. Doses of between
100 mg and 250 mg of thiamine/day apparently
may not restore vitamin status (Brown et al.,
1983), or improve clinical signs (Tallaksen et al.,
1992) or prevent death (Harper et al., 1986).
Despite this, low doses are often used, and are
sometimes observed to be rapidly effective (Guido
et al., 1994), albeit in other cases recovery may be
delayed and incomplete (Cole et al., 1969; Evans
et al., 1985; Heye et al., 1994; Chataway and
Hardman, 1995).
Depending upon the severity of the presenting
neuropsychiatric condition, and the perceived
certainty of the diagnosis of Wernicke's encepha-
lopathy, a number of effective dosage regimens
have been described. These regimes have included
two pairs of i.v. high-potency B-complex vitamins
once or twice daily for 3—10 days (Hoher, 1962;
Von Hackstock, 1962; Victor et al, 1989). [The
paper by Von Hackstock (1962) refers to
diagnoses of 'delirium tremens', although the
delirium described was more probably a result of
Wernicke's encephalopathy.]
preparation
In confirmed
Wernicke's encephalopathy, doses of up to 1 g
of thiamine may be required, initially, to achieve a
clinical response (Nakada and Knight, 1984;
Lindberg and Oyler, 1990). However, the Paren-
trovite and Pabrinex Data Sheets recommend,
respectively, two to four pairs i.v. high-potency
ampoules 4- to 8-hourly for 2 days, with one pair
i.v. high-potency ampoules to be given subse-
quently for 5-7 days and two to three pairs of
ampoules 8-hourly for an unspecified length of
time, regardless of the presenting symptom(s).
There is evidence that response to high-dose
parenteral B-complex vitamins varies with the
presenting condition
responding more rapidly than confusion (Thomson
et al., 1983; Harper et al., 1986; Victor et al.,
1989). A noticeable improvement in delirium/
acute confusion is, however, said to occur in the
majority of cases within 1-2 days (Wood and
Currie, 1995). In some cases, repletion of other
vitamins (e.g. folate/B]2) may also be necessary
before a clinical response is achieved (Cole et al.,
1969).
e.g. ophthalmoplegia
Safety profile of parenteral B vitamin
supplements
In January 1989 the UK Committee on Safety of
Medicines (CSM) warned of the risk of serious
allergic reactions that may occur during, or shortly
after, the administration of Parentrovite (Commit-
tee on Safety of Medicines, 1989) — the thiamine
component being thought to be responsible for
these reactions (Wrenn and Slovis, 1992).
Between 1970 and 1988, the Committee received
90 reports of adverse reactions associated with
Parentrovite (72 associated with i.v. administra-
tion and 18 with the i.m. preparation). The most
frequently reported reactions were anaphylaxis (41
cases), dyspnoea/bronchospasm (13 cases), rash/
flushing (22 cases). The proportion of anaphyl-
actic and serious allergic reactions is reported to
be significantly greater for the i.v. route than for
the i.m. route (58 vs 3, respectively P < 0.001)
(O'Brien, 1995). To put this into context, between
0.5-1 million pairs of ampoules of each prepara-
tion of Parentrovite were sold annually in the UK
in the 19 years that the CSM Current Problems
adverse event data were collected. There were thus
approximately four reports of an anaphylactoid
reaction for every 1 million pairs of i.v. ampoules
sold and one report per 5 million pairs of i.m.
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330
C. C. H. COOK et al.
ampoules sold. It would appear, therefore, that
serious allergic reactions are very infrequent and
significantly less likely to occur with the i.m.
presentation.
Two retrospective studies on the safety of
parenteral thiamine (which is used, exclusively,
in the US) provide similar findings (Wrenn et al.,
1989; Wrenn and Slovis, 1992). The authors found
one case of generalized pruritis in 989 patients,
receiving a total of 1070 doses of thiamine (Wrenn
et al., 1989) and no significant allergic reactions in
more than 300 000 patients treated with parenteral
thiamine (Wrenn and Slovis, 1992). As Wrenn
stated, 'This compares to a 1% to 10% chance of
allergic reaction to penicillin, a 2% to 3% chance
of a contrast media reaction, and a 1% to 18%
chance of an allergic response to streptokinase'
(Wrenn and Slovis, 1992).
Current management in the UK
The utilization of parenteral B-complex vita-
mins has altered markedly in the UK over the past
10 years. It is not entirely clear why this may have
occurred, although two possible contributory
factors may be identified: (1) parentrovite i.v.
and i.m. presentations were withdrawn, and dis-
continued worldwide, in November 1992 (due to
manufacturing problems). After a 9-month inter-
val an identical i.v. preparation, Pabrinex i.v., was
introduced. After another 10 months, an identical
i.m. preparation, Pabrinex i.m., was also made
available. (2) In 1989, a Committee on the Safety
of Medicines Current Problems warning was
issued relating to Parentrovite and allergic reac-
tions (Committee on Safety of Medicines, 1989).
In September 1994, a survey was conducted on
methods of thiamine replacement used for al-
coholics in hospitals in England and Wales (D.
Taylor and J. Marshall; personal communication).
Questionnaires were sent to 273 hospital chief
pharmacists who were asked to state the most
commonly used thiamine replacement regimen for
four indications: alcohol misusers admitted for
observation (e.g. detoxification); alcohol misusers
with suspected severe vitamin deficiency; those
with suspected Wemicke's encephalopathy; and
those with confirmed Wernicke's encephalopathy.
The findings showed a shift towards increased use
of oral supplements, and decreased use of
parenteral supplements, for all indications, even
for suspected and confirmed cases of Wernicke's
encephalopathy.
A similar decline in the use of parenteral
thiamine/B-complex vitamins in 'at-risk' alcohol-
ics has also recently been documented by those
working with patients who have sustained head
injury (Ferguson et al., 1996). Survivors of
traumatic brain injury commonly suffer from a
combination of cognitive and physical disabilities.
Alcohol is a significant factor in head injury,
influencing severity and frequency of injury, as
well as affecting course and outcome following
injury (Glucksman, 1994; Dikman et al., 1995).
One out of every two patients who sustain a head
injury is likely to have an alcohol problem
(compared with only about one in 10 in the
general population) and an alcoholic's risk of
subsequent head injury doubles with each injury
(Dikman et al, 1995).
In a 2-year survey (1993-1995) of traumatic
head injury admissions in Edinburgh, Ferguson et
al. (1996) found that, of 218 patients with a history
of alcohol consumption prior to their accidents,
only 11 received parenteral B-complex vitamins.
In the 83 patients classified as alcoholic (n = 4l)
or heavy/harmful drinkers (n = 42), only eight
(9.6%) received parenteral B-complex vitamins
and all but one received suboptimal therapy.
As can be seen in Fig. 1, the decline in sales of
parenteral high-potency B-complex vitamins pre-
dated the CSM adverse reaction warning, and
therefore may have reflected a more general
awareness of reported adverse reactions, or else
may have been due to other unknown factors.
Following the 9-10-month gap during which
parenteral high-potency
were not available in the UK, sales recommenced
at a level well below that which had existed prior
to the discontinuation of Parentrovite. The inter-
ruption of availability therefore appears to have
been a particularly significant factor affecting the
usage of high-potency B-complex vitamins. How-
ever, the perceived significance of the discon-
tinuation of Parentrovite may have been affected
by the prior publication of the CSM warning, and
it may be that it was the combination of both
factors which led to the failure of sales to recover
after the reintroduction of a parenteral B-complex
vitamin preparation in the form of Pabrinex.
As discussed, over the 6-year period for which
data are available, there has been a 65% increase
in reported admissions for cases of alcoholic
B-complex vitamins
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ALCOHOL, B VITAMIN DEFICIENCY AND NEUROPSYCHIATRIC SYNDROMES
331
- Parenteral Vitamin Sales In
pairs of ampoules (/10)
-Alcohol Dependence Syndrome
(/10)
-Alcoholic Rsychoses
•t.JW
4,000
3,500-
3,000
2,500
2,000 •
1,500 •
1,000 -
500 -
0-
1987-
1988
\
t
CSM current
problems
warning
1 1
\
withdrawn A .
'Pabrinex' \ ^ " ^
introduced
1 1 1
1988-
1989
1989-
1990
1990-
1991
1991-
1992
1992-
1993
1993-
1994
Year
Fig. 1. Admissions for alcoholic psychoses (ICD-9 code 291) and alcohol-dependence syndrome (ICD-9 code 303), in
National Health Service hospitals and sales of parenteral B-complex vitamins in England 1988-1989 to 1993-1994.
Source: Hospital Episode Statistics, Department of Healdi and sales data from IMS/Link. Note: Hospital Episode
Statistics are not available for the penod prior to 1988-1989. A change in ICD-9 and ICD-10 revisions for 1994-1995 and
ensuing major differences in coding definitions mean that data from 1994 onwards cannot be compared to previous data.
psychoses (ICD-9 code 291) and this is signifi-
cantly inversely correlated with the declining sales
of parenteral B-complex vitamins (r = -0.846,
95% confidence interval -0.983 to 0.431;
P = 0.034). The proportion of 'alcoholic psy-
choses' contributed by patients with WKS is
unknown. However, as discussed previously,
WKS cannot be easily diagnosed and may be
confused with delirium tremens (ICD-9 Code
291.0). It therefore appears that the CSM recom-
mendations have been misinterpreted by psychia-
trists in the UK, and that they have led to a change
to the use of oral thiamine supplements, in
preference to parenteral supplements, even where
that is inappropriate due to malnutrition or heavy
recent alcohol intake (O'Brien, 1995).
GENERAL CONCLUSIONS AND
RECOMMENDATIONS
B vitamin deficiencies are common in alcohol
misuse and dependence. WKS is also a common
condition, associated with significant morbidity
and mortality. Despite this, current practice in the
UK commonly appears to be inadequate when
viewed in the light of the published research
evidence. There is therefore clearly a need to
educate medical staff, and to establish agreed
by guest on July 15, 2011
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