Original article

Thiamine for preventing dementia

development among patients with alcohol
use disorder: A nationwide population-
based cohort study
Author links open overlay panelWei-PoChouabYu-HanChangcHung-ChiLinadYi-HsinChangaYun-
YuChenaChih-HungKoacd
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https://doi.org/10.1016/j.clnu.2018.05.009Get rights and content

Summary
Objective of study

Alcohol use disorder is one of the most important factors contributing to dementia.
This study examined the protective effect of thiamine administration on the
incidence of dementia among patients with alcohol use disorder in Taiwan by
evaluating a nationwide database.

Methods

We retrieved data for this retrospective cohort study from the Longitudinal Health

Insurance Database 1995–2000. Patients receiving thiamine therapy after the
diagnosis of alcohol use disorder were recruited as the thiamine therapy (TT)
group, and the comparison group without TT (NTT group) included randomly
assigned and age-, sex-, and index year-matched individuals with alcohol use
disorder. Demographic data, comorbid medical disorders,
and psychotropic medication use were evaluated and controlled. The cumulative
defined daily dose (DDD) was analyzed to demonstrate the dose effect.

Results

Each group had 5059 patients. The TT group had a lower crude hazard ratio (0.76;
95% confidence interval: 0.60–0.96) of dementia than the NTT group. After
adjusting for demographic data, comorbidity, and psychotropic medication use, the
adjusted hazard ratio was 0.54 (95% confidence interval: 0.43–0.69). The
significance existed among TT subjects with cumulative DDD higher than 23.
The Kaplan–Meier analysis demonstrated a lower cumulative incidence of
dementia in the TT group than in the NTT group.

Conclusion

The results indicated that thiamine therapy could be a protective factor for
dementia development in patients with alcohol use disorder. Thiamine therapy
should be a crucial part of the treatment plan and health policies to prevent
dementia development or progression among patients with alcohol use disorder.

Comparative effects of alcohol and

thiamine deficiency on the developing
central nervous system
Author links open overlay panelAbdoulayeBâ

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https://doi.org/10.1016/j.bbr.2011.07.015Get rights and content

Abstract
The present study addresses the still unresolved issue of the character of alcohol–
thiamine metabolic interferences in the developing central nervous system (CNS).
Investigations compare developmental neurotoxicity evoked by three patterns of
maternal thiamine deficiency (pre, peri and postnatal), with two patterns of
maternal chronic alcohol intake (alcohol alone and alcohol + thiamine
cotreatment), on seven neurodevelopmental abilities in the offspring. The three
patterns of thiamine deficiency, pair-compared with controls, highlight four
sequences of development: (1) embryonic–perinatal sequence; (2) perinatal–
postnatal sequence; (3) “ontogeny in ontogeny out” sequence; (4) “off and on”
developing sequence. The results suggest a temporally- and regionally emergence
of structures and centers underlying functional maturation during CNS
ontogenesis. Furthermore, both developmental thiamine deficiencies and ethanol
exposure produce two waves of neurofunctional alterations, peaking at P15
(postnatal day 15) and P25, respectively. The first peak of vulnerability is a
prenatal event; it may interfere with the periods of intense cellular proliferation and
migration. The second peak represents both perinatal and postnatal events; it may
interfere with the periods of cellular differentiation, synaptogenesis, axonogenesis
and myelinogenesis. Alcohol + thiamine cotreatment fails to reduce the first peak,
but neutralizes essentially the second peak. The results suggest that alcohol
interferes with thiamine during cellular differentiation and membrane
developmental processes mainly. Indeed, among the three conditions of thiamine-
deficient diet, only perinatal thiamine deficiency exhibits a closer relationship with
developmental alcohol exposure. Together, these observations suggest that the
critical period for alcohol–thiamine antagonism occurs perinatally and affects
primarily cellular differentiation.

Highlights

► Developmental thiamine deficiencies highlight four sequences for CNS

development. ► Both alcohol and thiamine deficiency triggered two distinct
waves of alterations. ► The alcohol–thiamine antagonism during CNS ontogenesis
occurs perinatally.

Therapie. 2019 Sep 9. pii: S0040-5957(19)30140-4. doi: 10.1016/j.therap.2019.09.001. [Epub ahead

of print]

[Thiamin and alcohol use disorder: A national survey of

practice].
[Article in French]

Collet L1, Bisch M2, Viennet S2, Schwan R3, Paille F4.

Author information
1

Centre psychothérapique de Nancy, 1, rue du Docteur Archambault, BP 11010, 54521 Laxou

cedex, France. Electronic address: Laura.COLLET@cpn-laxou.com.

Centre de soins, d'accompagnement et de prévention en addictologie, centre hospitalier

régional universitaire, 54000 Nancy, France.

3
 Centre psychothérapique de Nancy, 1, rue du Docteur Archambault, BP 11010, 54521 Laxou
cedex, France; Centre de soins, d'accompagnement et de prévention en addictologie, centre
hospitalier régional universitaire, 54000 Nancy, France.

Service d'addictologie, hôpitaux de Brabois, centre hospitalier régional universitaire, 54511

Vandœuvre-lès-Nancy, France.

Abstract
OBJECTIVE:
The survey aimed to estimate, in the presence of alcohol use disorder, the frequency of
systematic prescription of thiamine, the factors associated with it, and those related to the
administration (oral, intravenous, intramuscular) when Wernicke's encephalopathy is suspected.

METHODS:
A self-questionnaire available on Internet was sent by e-mail to doctors and nurses taking care
patients with alcohol use disorder.

RESULTS:
In all, 565 professionals responded. The systematic prescription frequency of thiamine was
84.8 %, addiction care centers and medical-psychological centers prescribed it 5 times less than
in psychiatric hospitals (OR=0.2 IC [0.1-0.5] P<0.0001), and medicine/surgery/obstetrics (MSO)
services 10 times more than psychiatric hospitals (OR=10.7 IC [2.5-45.3] P<0.0001). The
prescription decreased with the exercise period, the interns prescribing it 10 times more
systematically (OR=10.9 IC [3.6-32.9] P<0.0001). In the presence of symptoms related to
Wernicke's encephalopathy, thiamine administration was mainly oral (67.1 %). Intravenous
administration was used more by the MSO services (OR=18.3 IC [10.2-32.7] P<0.0001), while
the intramuscular injection was used more in psychiatric hospitals (OR=4.6 IC [1.7-11.9]
P=0.0353).

CONCLUSION:
The prescription of thiamine is rather systematic. In contrast, intravenous administration is
underused, in the presence of symptoms related to Wernicke's encephalopathy, in favor of oral
administration, and the more specific use of the intramuscular injection in psychiatry.

J Altern Complement Med. 2015 Dec;21(12):740-7. doi: 10.1089/acm.2014.0353. Epub 2015 Oct 27.
Long-Term Treatment with High-
Dose Thiamine in Parkinson Disease: An Open-Label
Pilot Study.
Costantini A1, Pala MI1, Grossi E2, Mondonico S3, Cardelli LE4, Jenner C1, Proietti
S1, Colangeli M5, Fancellu R6.

Author information
1

1 Department of Neurological Rehabilitation, Villa Immacolata Clinic , Viterbo, Italy .

2 Bracco Foundation , Milan, Italy .

3 Centro Diagnostico Italiano , Milan, Italy .

4 Lab Analysis, Villa Immacolata Clinic , Viterbo, Italy .

5 University Studies Abroad Consortium , Viterbo, Italy .

6 Unit of Neurology, IRCCS San Martino University Hospital IST , Genoa, Italy .

Abstract
OBJECTIVES:
To investigate the potential clinical, restorative, and neuroprotective effects of long-term
treatment with thiamine in Parkinson disease (PD).

DESIGN:
Observational open-label pilot study.

SETTING:
Outpatient neurologic rehabilitation clinic.

PATIENTS AND METHODS:

Starting in June 2012, we have recruited 50 patients with PD (33 men and 17 women; mean age,
70.4 ± 12.9 years; mean disease duration, 7.3 ± 6.7 years). All the patients were assessed at
baseline with the Unified Parkinson's Disease Rating Scale (UPDRS) and the Fatigue Severity
Scale (FSS) and began treatment with 100 mg of thiamine administered intramuscularly twice a
week, without any change to personal therapy. All the patients were re-evaluated after 1 month
and then every 3 months during treatment.
RESULTS:
Thiamine treatment led to significant improvement of motor and nonmotor symptoms: mean
UPDRS scores (parts I-IV) improved from 38.55 ± 15.24 to 18.16 ± 15.08 (p = 2.4 × 10(-14), t test
for paired data) within 3 months and remained stable over time; motor UPDRS part III score
improved from 22.01 ± 8.57 to 9.92 ± 8.66 (p = 3.1 × 10(-22)). Some patients with a milder
phenotype had complete clinical recovery. FSS scores, in six patients who had fatigue, improved
from 53.00 ± 8.17 to 23.60 ± 7.77 (p < 0.0001, t test for paired data). Follow-up duration ranged
from 95 to 831 days (mean, 291.6 ± 207.2 days).

CONCLUSIONS:
Administration of parenteral high-dose thiamine was effective in reversing PD motor and
nonmotor symptoms. The clinical improvement was stable over time in all the patients. From our
clinical evidence, we hypothesize that a dysfunction of thiamine-dependent metabolic processes
could cause selective neural damage in the centers typically affected by this disease and might
be a fundamental molecular event provoking neurodegeneration. Thiamine could have both
restorative and neuroprotective action in PD.

THIAMINE
Wernicke–Korsakoff syndrome (WKS), commonly known as wet brain, is the combined
presence of Wernicke encephalopathy (WE) and alcoholic Korsakoff syndrome. Due to the close
relationship between these two disorders, people with either are usually diagnosed with WKS as
a single syndrome. The cause of the disorder is thiamine (vitamin B1) deficiency, which can
cause a range of disorders including beriberi, Wernicke encephalopathy, and alcoholic Korsakoff
syndrome. These disorders may manifest together or separately. WKS is usually secondary
to alcohol abuse. It mainly causes vision changes, ataxia and impaired memory.[1]
Wernicke encephalopathy and WKS are most commonly seen in people who are alcoholic.
Failure in diagnosis of WE and thus treatment of the disease leads to death in approximately
20% of cases, while 75% are left with permanent brain damage associated with WKS. [2] Of those
affected, 25% require long-term institutionalization in order to receive effective care.

Why Alcoholics Should Receive Vitamin B1 (Thiamine) by IV

Before any Glucose Infusions

Summary:
 It is well known that chronic alcoholics are at high risk for being deficient in
vitamin B1 (thiamine), which is known to put the patient at an increased risk
for Wernicke-Korsakoff Syndrome, cerebellar degeneration, and cardiovascular
dysfunction.
 The current standard of treatment for such patients is to give them thiamine
100 mg intravenously (IV) before administering glucose containing IV fluids
and then to continue this dose for several days.
 The inability of pyruvate to enter the TCA cycle causes the cell to convert the
pyruvate to lactate (or lactic acid) in order to be able to maintain glycolysis at a
minimum rate.  Therefore, if you feed the cell more glucose without giving the
needed thiamine to allow for the forward movement of cellular reactions for
complete ATP generation, you only increase the amount of lactic acid produced.
 This development of acidosis, the inability of the pentose phosphate pathway to
protect the cell from reactive oxygen species that damage cellular structures
and the mounting stress on the cell overall, results in either cell death or
activation of apoptosis.

Thiamin Deficiency
In addition to insufficient intakes of thiamin from the diet, the causes of thiamin deficiency include
lower absorption or higher excretion rates than normal due, for example, to certain conditions
(such as alcohol dependence or HIV/AIDS) or use of some medications [3].

In its early stage, thiamin deficiency can cause weight loss and anorexia, confusion, short-term
memory loss, and other mental signs and symptoms; muscle weakness; and cardiovascular
symptoms (such as an enlarged heart) [7].

The most common effect of thiamin deficiency is beriberi, which is characterized mainly by
peripheral neuropathy and wasting [1-3]. People with this condition have impaired sensory,
motor, and reflex functions. In rare cases, beriberi causes congestive heart failure that leads to
edema in the lower limbs and, occasionally, death [1,3]. Although beriberi is rare in the United
States and other developed countries, people in these countries do occasionally develop the
condition [17-20]. Administration of supplemental thiamin, often parenterally, quickly cures
beriberi [2,3].

A more common manifestation of thiamin deficiency in the United States is Wernicke-Korsakoff

syndrome [2]. This disorder is about 8–10 times more common in people with chronic alcoholism
than in the general population, but it can also develop in patients who have severe
gastrointestinal disorders, rapidly progressing hematologic malignancies, drug use disorders, or
AIDS [2]. In many patients, Wernicke-Korsakoff syndrome has two phases. The first, acute, and
life-threatening stage, Wernicke’s encephalopathy, is usually characterized by peripheral
neuropathy [3,21]. Without treatment, up to 20% of people with Wernicke’s encephalopathy die;
those who survive develop Korsakoff’s psychosis, although some people with Korsakoff’s
psychosis have not previously had Wernicke’s encephalopathy [22,23]. Korsakoff’s psychosis, an
effect of chronic thiamin deficiency, is associated with severe short-term memory loss,
disorientation, and confabulation (confusion between real and imagined memories) [1-3]. At this
chronic state of the disorder, parenteral thiamin treatment does not lead to recovery in about
one-quarter of patients [24].

The World Health Organization recommends daily oral doses of 10 mg thiamin for a week,
followed by 3–5 mg/daily for at least 6 weeks, to treat mild thiamin deficiency [25]. The
recommended treatment for severe deficiency consists of 25–30 mg intravenously in infants and
50–100 mg in adults, then 10 mg daily administered intramuscularly for approximately one week,
followed by 3–5 mg/day oral thiamin for at least 6 weeks.

Groups at Risk of Thiamin Inadequacy

The following groups are among those most likely to have inadequate thiamin status.

People with alcohol dependence

In highly industrialized countries, chronic alcohol use disorders appear to be the most common
cause of thiamin deficiency [1]. Up to 80% of people with chronic alcoholism develop thiamin
deficiency because ethanol reduces gastrointestinal absorption of thiamin, thiamin stores in the
liver, and thiamin phosphorylation [3,21]. Also, people with alcoholism tend to have inadequate
intakes of essential nutrients, including thiamin.

Older adults
Up to 20%–30% of older adults have laboratory indicators that suggest some degree of thiamin
deficiency [2,7]. Possible reasons include low dietary intakes, a combination of chronic diseases,
concomitant use of multiple medications, and low absorption of thiamin as a natural result of
aging [26,27]. Some small studies have found that the risk of deficiency is particularly high in
elderly people who reside in an institution [28,29].

People with HIV/AIDS

People with HIV infection have an increased risk of thiamin deficiency and its sequelae, including
beriberi and Wernicke-Korsakoff syndrome [1,30]. Autopsies of 380 people with AIDS found that
almost 10% had Wernicke’s encephalopathy [31], and some experts believe that thiamin
deficiency is underdiagnosed in this population [32]. The association between thiamin deficiency
and HIV/AIDS is probably due to malnutrition as a result of the catabolic state associated with
AIDS.

People with diabetes

Some small studies have found that thiamin levels in plasma are up to 76% lower in people with
type 1 diabetes than in healthy volunteers and 50%–75% lower in people with type 2 diabetes
[33,34]. Other studies have shown a higher risk of thiamin deficiency in people with type 1 and/or
type 2 diabetes based on tests of erythrocyte transketolase activity [35,36]. These lower thiamin
levels might be due to increases in clearance of thiamin by the kidneys. The relevance of these
effects to clinical prognosis or outcomes is not known.

People who have undergone bariatric surgery

Bariatric surgery for weight loss is associated with some risks, including severe thiamin
deficiency due to malabsorption that can lead to beriberi or Wernicke’s encephalopathy. A 2008
literature review identified 84 cases of Wernicke’s encephalopathy after bariatric surgery
(primarily gastric bypass surgery) between 1991 and 2008 [37]. About half of these patients
experienced long-lasting neurologic impairments. Micronutrient supplements that include thiamin
are almost always recommended for patients following bariatric surgery to avoid deficiencies
[38].

Thiamin and Health

This section focuses on four diseases or disorders in which thiamin does or might play a role:
Wernicke-Korsakoff syndrome, diabetes, heart failure, and Alzheimer’s disease.

Wernicke-Korsakoff syndrome
Wernicke-Korsakoff syndrome is one of the most severe neuropsychiatric sequelae of alcohol
abuse [39]. The authors of a 2013 Cochrane review of thiamin to treat or prevent Wernicke-
Korsakoff syndrome found only two studies that met their inclusion criteria, and one of these
studies has not been published [39]. These randomized, double-blind, placebo-controlled trials
compared 5 mg/day by mouth for 2 weeks or daily intramuscular doses of 5 to 200 mg/day
thiamin over 2 consecutive days in a total of 177 people with a history of chronic alcohol use. The
Cochrane review authors concluded that the evidence from randomized clinical trials is
insufficient to guide healthcare providers in selecting the appropriate dose, frequency, duration,
or route of thiamin supplementation to treat or prevent Wernicke-Korsakoff syndrome in patients
with alcohol abuse.

The authors of the European Federation of Neurological Societies guidelines for diagnosing,
preventing, and treating Wernicke’s encephalopathy note that even high doses of oral thiamin
supplements might not be effective in raising blood thiamin levels or curing Wernicke’s
encephalopathy [40]. They recommend 200 mg thiamin, preferably intravenously, three times
daily (total of 600 mg/day) until the signs and symptoms stop, along with a balanced diet. In its
guidelines for managing Wernicke’s encephalopathy in emergency departments, the Royal
College of Physicians in London supports the administration of oral thiamin hydrochloride (100
mg three times a day) in patients with adequate dietary intakes of thiamin and no signs or
symptoms of Wernicke’s encephalopathy [41]. However, the authors recommend parenteral
thiamin supplementation for patients at high risk, such as those with ataxia, confusion, and a
history of chronic alcohol misuse, because oral supplementation is unlikely to produce adequate
blood levels.

Diabetes
The proportion of people with type 1 or type 2 diabetes who have poor thiamin status based on
erythrocyte transketolase activity ranges from 17% to 79% in studies conducted to date [42]. In a
study of 76 consecutive patients with type 1 or type 2 diabetes, for example, 8% had mild thiamin
deficiency and 32% had moderate deficiency based on assays of the transketolase enzyme [35].

Some small studies have shown that oral supplementation with 150–300 mg/day thiamin can
decrease glucose levels in patients with type 2 diabetes or impaired glucose tolerance [43,44].
However, the authors of these studies did not assess the potential clinical significance of these
findings.

A few small randomized studies have assessed the effects of benfotiamine supplements on
diabetic neuropathy. Three studies found that, compared to placebo, 120–900 mg/day
benfotiamine with or without other B-vitamins decreased the severity of neuropathy symptoms
and lowered urinary albumin excretion (a marker of early-stage diabetic nephropathy) [45-47].
However, another study found no effect of 900 mg/day benfotiamine on urinary excretion of
albumin or kidney injury molecule-1, a marker of kidney injury [48].

Well-designed studies with larger sample sizes and longer durations are required to determine
whether thiamin supplements can reduce glucose levels in patients with diabetes or decrease
diabetic compications.
Heart failure
The rates of poor thiamin status in patients with heart failure have ranged in studies from 21% to
98% [49]. Explanations for this association include older age, comorbidities, insufficient dietary
intake, treatment with diuretics, and frequent hospitalizations [50].

The authors of one study reported that 33% of 100 patients with chronic heart failure had thiamin
deficiency compared to 12% of 50 healthy volunteers [51]. Rates of deficiency were even higher
when the investigators excluded those who used thiamin supplements. The different rates of
thiamin deficiency in patients with heart failure in these and other studies are probably due to
differences in nutrition status, comorbidities, medications and dietary supplements used, and
techniques used to measure thiamin status [50].

The authors of a systematic literature review and meta-analysis found two randomized, double-
blind, placebo-controlled trials of thiamin supplementation in people with heart failure that met
their eligibility criteria [52]. In these trials, thiamin supplements significantly improved net change
in left ventricular ejection fraction. The authors did not assess the clinical significance of this
finding, however.

More research is needed to determine whether thiamin supplements might benefit people with
heart failure, even if they have normal thiamin status.

Alzheimer’s disease
According to animal model studies, thiamin deficiency might play a role in the development of
Alzheimer’s disease [53]. For example, thiamin deficiency produces oxidative stress in neurons,
death of neurons, loss of memory, plaque formation, and changes in glucose metabolism—all
markers of Alzheimer’s disease. Autopsy studies have shown that transketolase and other
thiamin-dependent enzymes have decreased activity in the brains of people with Alzheimer’s
disease [54,55].

Few studies have assessed the prevalence of thiamin deficiency in people with Alzheimer’s
disease. One of these studies found that 13% of 150 patients with cognitive impairment and
acute-onset behavioral disturbances were considered thiamin deficient based on plasma levels
[26].

The authors of a 2001 Cochrane review assessed three double-blind, randomized trials
(including two crossover trials) that compared the effects of 3 g/day oral thiamin to placebo on
cognitive function in patients with Alzheimer’s type dementia [56]. The three studies randomly
assigned fewer than 20 patients each, and the two crossover studies did not include a washout
period [57-59]. The review authors stated that it was not possible to draw any conclusions from
these three studies because they were small and the publications describing them did not
provide enough detail to combine these data in a meta-analysis.

Larger, well-designed studies are needed to determine whether thiamin supplements are
beneficial for Alzheimer’s disease.
 Health Risks from Excessive Thiamin

The body excretes excess amounts of thiamin in the urine [2]. Because of the lack of reports of
adverse effects from high thiamin intakes (50 mg/day or more) from food or supplements, the
FNB did not establish ULs for thiamin [7]. They hypothesize that the apparent lack of toxicity may
be explained by the rapid decline in absorption of thiamin at intakes above 5 mg. However, the
FNB noted that in spite of the lack of reported adverse events, excessive intakes of thiamin could
have adverse effects.

Interactions with Medications

Although thiamin is not known to interact with any medications, certain medications can have an
adverse effect on thiamin levels. Some examples are provided below. Individuals taking these
and other medications on a regular basis should discuss their thiamin status with their healthcare
providers.

Furosemide
Furosemide (Lasix®) is a loop diuretic used to treat edema and hypertension by increasing
urinary output. Research has linked the use of furosemide to decreases in thiamin
concentrations, possibly to deficient levels, as a result of urinary thiamin loss [51,60,61]. Whether
thiamin supplements are effective for preventing thiamin deficiency in patients taking loop
diuretics needs to be determined in clinical studies.

Chemotherapy with Fluorouracil

Fluorouracil (also known as 5-fluorouracil; Adrucil®) is a chemotherapy drug that is commonly
used to treat colorectal and other solid cancers. The published literature includes several cases
of beriberi or Wernicke’s encephalopathy resulting from treatment with this drug, possibly
because the drug might increase thiamin metabolism and block the formation of TDP, the active
form of thiamin [62-65]. Thiamin supplements might reverse some of these effects.

Thiamin and Healthful Diets

The federal government’s 2015-2020 Dietary Guidelines for Americans notes that “Nutritional

needs should be met primarily from foods. … Foods in nutrient-dense forms contain essential
vitamins and minerals and also dietary fiber and other naturally occurring substances that may
have positive health effects. In some cases, fortified foods and dietary supplements may be
useful in providing one or more nutrients that otherwise may be consumed in less-than-
recommended amounts.”

 Format: Abstract

Send to

J Pharm Pract. 2019 Sep 8:897190019872584. doi: 10.1177/0897190019872584. [Epub ahead of print]

Evaluation of the Safety of Intravenous Thiamine Administration in
a Large Academic Medical Center.
Tjugum SL1, Hedrick TL1, Jean SJ1, Heeney SA1, Rohde KA1, Campbell-Bright SL1,2.

Author information
1

1 Department of Pharmacy, University of North Carolina Medical Center, Chapel Hill, NC,
USA.

2 Division of Practice Advancement and Clinical Education, University of North Carolina

Eshelman School of Pharmacy, Chapel Hill, NC, USA.

Abstract
BACKGROUND/OBJECTIVE:
Previous literature describes increased incidence of infusion-related reactions when
administering thiamine doses greater than 100 mg as an intravenous (IV) push. The purpose of
this evaluation was to assess the safety of administering higher doses of thiamine as IV push
compared to infusion.

METHODS:
A single-center, retrospective review was performed from June to October 2017. Included
patients were aged 18 years or older and received 1 dose of IV thiamine 200 mg or greater.
Patients were divided into 2 groups: group 1 included patients who received 200-mg IV push
and, group 2 included patients who received any dose greater than 200 mg. The primary
objective was to quantify and compare rate of adverse reactions between the 2 groups.
Institutional thiamine prescribing practices were examined. Wilcoxon Rank Sum and Fischer
exact tests were performed.

RESULTS:
Sixty-six percent of patients were male, and the median age was 55 years (interquartile range
[IQR]: 44-63). Fifty percent received 200-mg IV push, 20% received a combination of IV infusion
and IV push, and 30% received IV infusion. Adverse reactions possibly due
to thiamine administration occurred in 4 (2.0%) patients. One patient received 200 mg via IV
infusion, while 3 received 200 mg via IV push. There was no significant difference in adverse
reaction rate between IV push and IV infusion administrations (P = .640).

CONCLUSION:
Our results support administering thiamine doses of 200 mg or less as an IV push. Given lack of
robust safety data, it is recommended to continue to dilute doses greater than 200 mg and infuse
over 30 minutes.
KEYWORDS:
adverse drug reaction; medication safety; thiamine

Front Psychiatry. 2019 Apr 4;10:207. doi: 10.3389/fpsyt.2019.00207. eCollection 2019.

Neurological, Psychiatric, and Biochemical Aspects

of Thiamine Deficiency in Children and Adults.
Dhir S1, Tarasenko M1, Napoli E1, Giulivi C1,2.

Author information
1

Department of Molecular Biosciences, School of Veterinary Medicine, University of California,

Davis, Davis, CA, United States.

Medical Investigations of Neurodevelopmental Disorders (MIND) Institute, University of

California, Davis, Davis, CA, United States.

Abstract
Thiamine (vitamin B1) is an essential nutrient that serves as a cofactor for a number of enzymes,
mostly with mitochondrial localization. Some thiamine-dependent enzymes are involved in
energy metabolism and biosynthesis of nucleic acids whereas others are part of the antioxidant
machinery. The brain is highly vulnerable to thiamine deficiency due to its heavy reliance on
mitochondrial ATP production. This is more evident during rapid growth (i.e., perinatal periods
and children) in which thiamine deficiency is commonly associated with either malnutrition or
genetic defects. Thiamine deficiency contributes to a number of conditions spanning from mild
neurological and psychiatric symptoms (confusion, reduced memory, and sleep disturbances) to
severe encephalopathy, ataxia, congestive heart failure, muscle atrophy, and even death. This
review discusses the current knowledge on thiamine deficiency and associated morbidity of
neurological and psychiatric disorders, with special emphasis on the pediatric population, as well
as the putative beneficial effect of thiamine supplementation in autism spectrum disorder (ASD)
and other neurological conditions.
KEYWORDS:
Krebs cycle; autism spectrum disorders; brain; depressive disorders; encephalomyopathies;
pentose phosphate pathway; thiamine transporter

Korsakoff Syndrome
Timothy Covell; Waquar Siddiqui.

Author Information
Authors
Timothy Covell1; Waquar Siddiqui2.

Affiliations
1
 Mercy St. Vincent Medical Center

2
 UMKC

Last Update: May 5, 2019.

Go to:

Introduction
While there is no consensus for the actual definition of Korsakoff syndrome, it is generally
agreed to be a chronic neuropsychiatric syndrome due to thiamine (vitamin B1) deficiency.
[1] Damage to multiple areas on the brain leads to amnesia and confusion. While classically
associated with chronic alcohol use, Korsakoff syndrome can be the result of other processes
that ultimately lead to thiamine deficiency. Korsakoff syndrome is most often seen in the
context of chronic alcohol abuse and thought to be on the spectrum with Wernicke
encephalopathy. Wernicke encephalopathy is acute and often reversible while Korsakoff
syndrome is chronic and may be irreversible.[2] When Wernicke encephalopathy
accompanies Korsakoff syndrome, it is referred to as Wernicke-Korsakoff syndrome, and due
to the considerable overlap of the two diseases, this article will refer to the both of them when
evaluating and treating a patient.
Go to:

Etiology
Any condition leading to chronic thiamine deficiency can lead to Wernicke’s encephalopathy
and if untreated, to Korsakoff syndrome.[3]  The most common cause of Korsakoff syndrome
is chronic alcohol abuse. Alcohol interferes with GI tract absorption of thiamine as well as
interfering with the liver's ability to store thiamine. Additionally, accompanying malnutrition
often compounds the effects of alcoholism leading to further thiamin deficiency. Other causes
of Korsakoff syndrome include eating disorders, chronic vomiting (including hyperemesis
gravidarum), psychiatric disorders, chemotherapy, and cancer.[4][5]
Go to:

Epidemiology
The worldwide prevalence of Wernicke-Korsakoff syndrome is thought to be between 0 and
2%.  Those at higher risk include the homeless, elderly and psychiatric patients. Because
Korsakoff syndrome is grossly underdiagnosed and there is disagreement regarding precise
diagnostic criteria, there is little data on the incidence and prevalence.[1]
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Pathophysiology
Thiamine is an essential cofactor for multiple enzymes involved in brain cell metabolism.
[6] Without these enzymes, there is a reduction in metabolism of multiple cell components
and ATP. Thiamine mediates pyruvate metabolism, and its deficiency can lead to elevated
lactate, which can lead to edema, loss of neurons, and reactive gliosis throughout the brain.
The cognitive deficits seen in Korsakoff syndrome are thought to be primarily due to damage
to the following areas- the anterior nucleus of the thalamus, mammillary bodies, and corpus
callosum.[7] There is also evidence of decreased glucose metabolism in the cerebral cortex.
[8] Cerebellar degeneration is also common among alcoholics and can lead to the ataxia and
oculomotor deficits seen in Wernicke-Korsakoff syndrome.
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Histopathology
The most common histologic findings for Wernicke-Korsakoff syndrome include gliosis and
microhemorrhages in the following areas: periaqueductal and paraventricular grey matter,
atrophy in the mamillary bodies and thalamus, volume deficits in the hippocampus, cerebellar
hemispheres, pons, and anterior superior vermis.
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History and Physical

As mentioned above, Wernicke encephalopathy and Korsakoff syndrome are often thought to
be on a spectrum with one another as they are both due to thiamine deficiency. Thus,
clinicians should screen for them together. Wernicke encephalopathy classically presents
with the triad of altered mental status, ophthalmoplegia, and ataxia. In reality, less than 20%
of patients will present with all three of these findings.[3] The following signs and symptoms
should cause suspicion for Wernicke-Korsakoff syndrome[3]:
 Altered mental status (up to 82% of patients) - amnesia, disorientation, confabulations
 Oculomotor findings - most often horizontal nystagmus, retinal hemorrhage,
ophthalmoplegia, cranial nerve IV palsy, conjugate gaze
 Ataxia - wide-based gait

The cognitive impairments specific to Korsakoff syndrome vs. Wernicke encephalopathy

include anterograde amnesia, profoundly limiting one's learning capacity, retrograde amnesia,
as well as executive deficits, resulting in decreased inhibition and difficulties with judgment,
planning and problem-solving.[7] Anterograde amnesia can result in the classic symptom of
confabulations, replacing one's gap in memory with untrue information.[9]
The Caine criteria have been described to have a sensitivity or 85% and specificity of 100%
for Wernicke encephalopathy, in the alcoholic population.[3] Because of the strong overlap,
this can be used to help screen for Korsakoff syndrome as well.
Caine criteria for the diagnosis of Wernicke encephalopathy in chronic alcoholics. Two of the
following four signs are necessary to diagnose Wernicke encephalopathy[3] clinically[3]:
 Dietary deficiency
 Oculomotor abnormalities
 Cerebellar dysfunction
  Either altered mental status or mild memory impairment
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Evaluation
Korsakoff syndrome is, for the most part, a clinical diagnosis. It should be diagnosed when
the signs and symptoms described above are present in a patient with risk factors for thiamine
deficiency. Thiamine blood tests often take days to result and should not delay empiric
treatment. Regarding neuroimaging, CT and MRI of the brain are not often indicated for
emergent diagnosis of Korsakoff syndrome, although they may be warranted to rule out other
causes of the patient’s symptoms. Non-emergent MRI can reveal specific findings of
Wernicke-Korsakoff syndrome including changes in the mamillary bodies, thalami, tectal
plate, and periaqueductal areas but sensitivity is only 53%.
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Treatment / Management
The mainstay of treatment in an acute presentation is thiamine replacement. There is little
evidence on the amount of thiamine to replace, but typical regimens include high dose
thiamine at 500 mg- 1500 mg, IV, three times daily for at least 3 days.[3] Electrolyte
abnormalities should be corrected and fluids replaced. In particular, magnesium requires
replacement, as thiamine-dependent enzymes cannot operate in a magnesium-deficient state.
Many patients will present needing glucose replacement as well, and traditionally it was
thought that replacing glucose before thiamine could exacerbate the patient’s symptoms.
Following a review of 19 papers, it has been recommended not to delay in correcting
hypoglycemia.[10] There are suggestions that prolonged and not acute replacement of
glucose without thiamine supplementation increased the risk of Wernicke encephalopathy.
After the acute phase of vitamin and electrolyte replacement, there is mounting evidence that
memory rehabilitation is beneficial in Korsakoff syndrome. Declarative memory ("knowing
what") seems to be most affected in Korsakoff syndrome, leading to many patients requiring
lifelong care. Because procedural learning ("knowing how") seems to remain somewhat
maintained in Korsakoff syndrome, memory rehabilitation focussed in this area has shown
promising outcomes. There has been some success in small Korsakoff syndrome patient
populations in learning procedures and improving their autonomy.[7]
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Differential Diagnosis
Differential diagnosis will vary based on the patient’s presentation but may include infection,
seizure, intoxication, metabolic disorders, medications, stroke, head trauma, brain mass,
multiple sclerosis, migraines, vertigo, ethanol neurotoxicity, schizophrenia.[3]
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Prognosis
High suspicion for Wernicke’s encephalopathy is key to improving patient prognosis.
Classically, the thinking was that once Korsakoff syndrome has set in, amnesia was generally
irreversible. As noted above, more recent research has shown promise in memory
rehabilitation including memory compensation techniques and error-less learning strategies.
[1]
Regarding neuroimaging, associations with cortical lesions have shown to correlate with a
worse prognosis.[3]
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Consultations
Consultations with dietary, social work, neurology, and neuropsychiatry can be beneficial in
the treatment of Wernicke-Korsakoff syndrome.
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Deterrence and Patient Education

Wernicke-Korsakoff syndrome is vastly underdiagnosed. [3] Patient often do not present
themselves due to substance abuse, and it is not until they are brought in by family members
that there is an evaluation. Alcohol withdrawal and intoxication can interfere with diagnosis
as well. Even once presenting to the physician, it is often misdiagnosed, with one study
estimating Wernicke encephalopathy is missed in 68% of alcoholic patients and 94% of
nonalcoholic patients.[3] There are also gaps in research of Wernicke-Korsakoff syndrome
due to a lack of a formal definition for Korsakoff syndrome, which makes it difficult to
accumulate data, especially regarding epidemiology, diagnosis, and prognosis.
Patients who are unable or unwilling to quit alcohol may benefit from proper nutrition and
thiamine supplementation.
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Pearls and Other Issues

Korsakoff syndrome is a neuropsychiatric condition causing damage to multiple areas of the
brain that results in cognitive impairment and amnesia.
Korsakoff syndrome can result from any condition leading to thiamine deficiency but most
often seen in chronic alcohol abuse.
Wernicke-Korsakoff syndrome is a clinical diagnosis, and Wernicke encephalopathy should
be suspected in anyone at risk for thiamine deficiency who presents with oculomotor
findings, ataxia or confusion. Once amnesia and executive deficits are present, Korsakoff
syndrome should be suspected.
The key to good outcomes is catching Wernicke encephalopathy early and treating with
thiamine.
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Enhancing Healthcare Team Outcomes

Providing quality care for patient’s with Korsakoff syndrome requires a large number of
resources and coordination between a variety of healthcare professionals. In the early stages,
triage nurses, visiting nurses and EMS providers can help identify patients who may be
presenting for other complaints or would otherwise not seek care. Effective screening tools in
the emergency department or outpatient clinic could help identify alcohol abuse, the major
risk factor for Wernicke-Korsakoff syndrome. In the acute setting, identifying the disease
(preferably early on or before the onset of Korsakoff Syndrome) and treating requires
interdisciplinary work between the emergency physicians, neurologists, and dieticians to rule
out other causes and treat. Long term care of these patients may require the attention of
neuropsychiatrists, neurologists, psychiatrists, dieticians, social workers, and the patient’s
primary care provider to ensure sobriety, continued nutrition, and memory rehabilitation.
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Questions
To access free multiple choice questions on this topic, click here.
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References
1.

Segal JB, Bouffard MA, Schlaug G. Characteristic Neuroimaging Abnormalities of Korsakoff

Syndrome. JAMA Neurol. 2016 Oct 01;73(10):1248-1249. [PubMed]

2.

Sharp CS, Wilson MP, Nordstrom K. Psychiatric Emergencies for Clinicians: Emergency
Department Management of Wernicke-Korsakoff Syndrome. J Emerg Med. 2016
Oct;51(4):401-404. [PubMed]

3.

Arts NJ, Walvoort SJ, Kessels RP. Korsakoff's syndrome: a critical review. Neuropsychiatr Dis
Treat. 2017;13:2875-2890. [PMC free article] [PubMed]

4.

Oudman E, Nijboer TC, Postma A, Wijnia JW, Van der Stigchel S. Procedural Learning and
Memory Rehabilitation in Korsakoff's Syndrome - a Review of the Literature. Neuropsychol
Rev. 2015 Jun;25(2):134-48. [PMC free article] [PubMed]

5.

Isenberg-Grzeda E, Rahane S, DeRosa AP, Ellis J, Nicolson SE. Wernicke-Korsakoff syndrome

in patients with cancer: a systematic review. Lancet Oncol. 2016 Apr;17(4):e142-
e148. [PubMed]

6.

Nikolakaros G, Ilonen T, Kurki T, Paju J, Papageorgiou SG, Vataja R. Non-alcoholic Korsakoff

syndrome in psychiatric patients with a history of undiagnosed Wernicke's
encephalopathy. J. Neurol. Sci. 2016 Nov 15;370:296-302. [PubMed]
 7.

Johnson JM, Fox V. Beyond Thiamine: Treatment for Cognitive Impairment in Korsakoff's
Syndrome. Psychosomatics. 2018 Jul - Aug;59(4):311-317. [PubMed]

8.

Isenberg-Grzeda E, Kutner HE, Nicolson SE. Wernicke-Korsakoff-syndrome: under-recognized

and under-treated. Psychosomatics. 2012 Nov-Dec;53(6):507-16. [PubMed]

9.

Paller KA, Acharya A, Richardson BC, Plaisant O, Shimamura AP, Reed BR, Jagust WJ.
Functional Neuroimaging of Cortical Dysfunction in Alcoholic Korsakoff's Syndrome. J Cogn
Neurosci. 1997 Mar;9(2):277-93. [PubMed]

10.

Schabelman E, Kuo D. Glucose before thiamine for Wernicke encephalopathy: a literature

review. J Emerg Med. 2012 Apr;42(4):488-94. [PubMed]

Eur Addict Res. 2019;25(3):103-110. doi: 10.1159/000499039. Epub 2019 Mar 21.

Thiamine Substitution in Alcohol Use Disorder: A

Narrative Review of Medical Guidelines.
Pruckner N1, Baumgartner J2, Hinterbuchinger B2, Glahn A3, Vyssoki S4, Vyssoki B2.

Author information
1
 Clinical Division of Social Psychiatry, Department of Psychiatry and Psychotherapy, Medical
University of Vienna, Vienna, Austria, nathalie.pruckner@meduniwien.ac.at.

Clinical Division of Social Psychiatry, Department of Psychiatry and Psychotherapy, Medical

University of Vienna, Vienna, Austria.

Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School,

Hannover, Germany.

Department of Health Sciences, St. Pölten University of Applied Sciences, Sankt Pölten,
Austria.

Abstract
AIMS:
Patients with alcohol use disorder (AUD) frequently suffer from cognitive deficits ranging from
mild symptoms to most severe forms. Wernicke encephalopathy (WE), caused
by thiamine deficiency, is a potentially fatal syndrome characterized by the clinical triad of
ophthalmoplegia, ataxia, and confusion. WE frequently presents in patients with AUD and, if left
untreated, can progress to Wernicke-Korsakoff syndrome, which constitutes severe anterograde
amnesia, confabulation, and behavioral abnormalities. Due to oftentimes indistinct clinical
presentation, WE remains undiagnosed in up to 80% of cases. We conducted a review of current
treatment guidelines for AUD in order to identify recommendations for the use of thiamine.

METHODS:
Three different keyword combinations ("alcohol treatment guideline," "alcohol withdrawal
guideline," and "alcohol treatment recommendation") were entered in PubMed and Scopus,
additional guidelines were searched screening the online sites of the respective agencies or
societies. In total, 14 guidelines were included.

RESULTS:
Thiamine was mentioned in all but one of the reviewed publications. Specifications on application
modalities and indications varied considerably. While the majority of reviewed guidelines
recommended parenteral thiamine only for patients at high risk for WE, some gave no
information regarding the application form or dosage.

CONCLUSION:
Substitution of parenteral thiamine in individuals with suspected WE is a well-established
treatment regimen. However, suggestions according to guidelines vary widely. Furthermore,
hardly any evidence-based recommendations exist on a more general use of thiamine as a
preventative intervention in individuals with AUD. Further research is of utmost importance to
raise awareness for this potentially undervalued problem.

© 2019 S. Karger AG, Basel.

KEYWORDS:
Alcohol use disorder; Thiamine; Wernicke encepalopathy ;  Guidelines

Am J Case Rep. 2019 Mar 13;20:330-334. doi: 10.12659/AJCR.914051.

Dry Beriberi Due to Thiamine Deficiency Associated

with Peripheral Neuropathy and Wernicke's
Encephalopathy Mimicking Guillain-Barré syndrome: A
Case Report and Review of the Literature.
Shible AA1,2, Ramadurai D3, Gergen D3, Reynolds PM1.

Author information
1

Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and

Pharmaceutical Sciences, Aurora, CO, USA.

Department of Pharmacy, Hamad General Hospital, Hamad Medical Corporation, Doha,

Qatar.

University of Colorado Internal Medicine Residency Training Program, University of Colorado,

Aurora, CO, USA.

Abstract
BACKGROUND Beriberi due to thiamine (vitamin B1) deficiency has two clinical presentations.
Patients with dry beriberi present with neuropathy, and patients with wet beriberi present with
heart failure, with or without neuropathy. Dry beriberi can mimic the most common form of
Guillain-Barre syndrome (GBS), an acute inflammatory demyelinating polyradiculoneuropathy
(AIDP). Severe thiamine deficiency results in Wernicke's encephalopathy. This report of a case
of dry beriberi and Wernicke's encephalopathy due to thiamine deficiency includes a review of
the literature. CASE REPORT A 56-year old woman with a history of gallstone pancreatitis and
protein-calorie malnutrition was treated six months previously with total parenteral nutrition
(TPN). She initially presented at another hospital with paresthesia of the lower limbs, arms, and
neck, and symptoms of encephalopathy. Initial diagnosis of GBS was made, based on magnetic
resonance imaging (MRI) and cerebrospinal fluid (CSF) findings. Despite five days of intravenous
immunoglobulin (IVIG) treatment, her encephalopathy worsened, requiring transfer to our
hospital, where she required intubation and treatment with vasopressors. A repeat MRI of her
brain showed changes consistent with Wernicke's encephalopathy. Following treatment with
high-dose intravenous thiamine, her mental status improved within 48 hours, and by the third
hospital day, she no longer required intubation. CONCLUSIONS Symptoms and signs of dry
beriberi due to thiamine deficiency can mimic those of acute or chronic GBS.
However, thiamine repletion leads to rapid clinical improvement and can prevent irreversible
neurologic sequelae, including Korsakoff syndrome. Clinicians should
consider thiamine deficiency in malnourished patients presenting with symptoms and signs of
GBS.