CASE IN POINT An Atypical Long-Term Treatment Regimen for Wernicke

Samra Shoaib, MD; Mehnaz Hyder, MD; and Margaret May, MD A patient with rapidly changing mental status responded to treatment with intramuscular or IV thiamine but not oral dosages, suggesting that presentation of can be highly variable, which can complicate the correct diagnosis and treatment.

ernicke- is a exhibited none of the classical triad symp- Samra Shoaib is a Clinical cluster of symptoms attributed to a toms prior to death.4 Hence, these conditions Extern; Mehnaz Hyder is a Staff Psychiatrist, Inpatient Wdisorder of B1 (thiamine) are surmised to be significantly underdiag- Psychiatry; and Margaret deficiency, manifesting as a combined pre- nosed and misdiagnosed. May is a Staff Psychiatrist, sentation of -induced Wernicke Though consensus regarding the appro- Inpatient Psychiatry and Mental Health Evaluation encephalopathy (WE) and Korsakoff syn- priate treatment regimen is lacking for WE, Clinic; all at the Veterans 1 drome (KS). While there is consensus on a common protocol consists of high-dose Affairs Palo Alto the characteristic presentation and symp- parenteral thiamine for 4 to 7 days.5 This Health Care System in toms of WE, there is a lack of agreement is usually followed by daily oral thiamine California. Margaret May also is a Clinical Instructor on the exact definition of KS. The classic repletion until the patient either achieves (Affiliate), Department of triad describing WE consists of , complete abstinence from alcohol (ideal) or Psychiatry and Behavioral ophthalmoplegia, and ; however, decreases consumption. The goal is to allow Sciences, Stanford reports now suggest that a majority of pa- thiamine stores to replete and maintain at University School of Medicine in California. tients exhibit only 1 or 2 of the elements minimum required body levels moving for- Correspondence: of the triad. KS is often seen as a condition ward. In this case report, we highlight the Margaret May of chronic thiamine deficiency manifesting utilization of a long-term, unconventional ([email protected]) as memory impairment alongside a cogni- intramuscular (IM) thiamine repletion reg- Fed Pract. 2020;37(8):405-409. tive and behavioral decline, with no clear imen to ensure maintenance of a patient’s doi:10.12788/fp.0029 consensus on the sequence of appearance mental status, highlighting discrepancies of symptoms. The typical relationship is in our understanding of the mechanisms at thought to be a progression of WE to KS if play in WE and its treatment. untreated. From a mental health perspective, CASE PRESENTATION WE presents with delirium and confusion A 65-year-old male patient with a more whereas KS manifests with irreversible de- than 3-decade history of daily hard li- mentia and a cognitive deterioration. Though quor intake, multiple psychiatric hospi- it is commonly taught that KS-induced mem- talizations for WE, and a prior suicide ory loss is permanent due to neuronal dam- attempt, presented to the emergency de- age (classically identified as damage to the partment (ED) with increased frequency mammillary bodies - though other structures of falls, poor oral intake, , have been implicated as well), more recent and diminished verbal communication. A research suggest otherwise.2 A review pub- chart review revealed memory impairment lished in 2018, for example, gathered sev- alongside the diagnoses of schizoaffec- eral case reports and case series that suggest tive disorder and WE, and confusion that significant improvement in memory and was responsive to thiamine administration cognition attributed to behavioral and phar- as well as a history of hypertension, hy- macologic interventions, indicating this as an perlipidemia, osteoarthritis, and urinary area deserving of further study.3 About 20% retention secondary to benign prostatic of patients diagnosed with WE by autopsy hyperplasia (BPH).

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FIGURE Patient Treatment Timeline First Hospitalization Day 1 Day 4 Day 15 Day 22 Day 27 Day 42 Day 80 Day 83 Day 96 Day 126

Admitted with Actively Lithium Fall, confusion, IM thiamine Improved IM thiamine Lethargic, Slight Discharged poor oral intake, suicidal, started, confabulation, started appetite tapered in nonverbal, improvement; to SNF mutism, self-injurious disorganized and decreased at 200 mg and preparation unsteady thiamine confusion, and behaviors thinking oral intake twice daily interaction; for gait; IM increased to gait issues; continued continued; lithium no falls/ discharge thiamine 3 times daily paliperidone stopped due to confusion returned to started; oral elevated creatinine twice daily thiamine initiated Second Hospitalization (within 24 h of discharge) Day 0 Day 1 Day 4 Day 12

Missed 2 doses of Admitted with AMS, ataxia, Patient activated, No AMS/mood symptoms IM thiamine disorganized speech, and fall; perseverating to go home; or gait disturbance; patient IV thiamine initiated thiamine therapy continued discharged

Abbreviations: AMS, altered mental status; IM, intramuscular; SNF, skilled nursing facility.

On examination the patient was found loss compared with the pattern typically to be disoriented with a clouded sensorium. seen in NPH. While the history of heavy daily alcohol In light of concern for WE and the pa- use was clear in the chart and confirmed by tient's history, treatment with IV thia- other sources, it appeared unlikely that the mine and IV fluids was initiated and the patient had been using alcohol in the pre- Liaison Psychiatry Service was consulted ceding month due to restricted access in his for cognitive disability and treatment of most recent living environment (a shared his mood. Administration of IV thiamine apartment with daily nursing assistance). rapidly restored his sensorium, but he He reported no lightheadedness, dizziness, became abruptly disorganized as the IV reg- palpitations, numbness, tingling, or any imen graduated to an oral thiamine dose of head trauma. He also negated the presence 200 mg 3 times daily. Simultaneously, as of active mood symptoms, auditory or vi- medical stabilization was achieved, the pa- sual hallucinations or suicidal ideation (SI). tient was transferred to the inpatient psychia- The patient was admitted to the Inter- try unit to address the nonresolving cognitive nal Medicine Service and received a workup impairment and behavioral disorganization. for the causes of delirium, including con- This specifically involved newly emerging, sideration of normal pressure hydrocepha- impulsive, self-harming behaviors like throw- lus (NPH) and other neurologic conditions. ing himself on the ground and banging his Laboratory tests including a comprehensive head on the floor. Such behaviors along with metabolic panel, thyroid stimulating hor- paucity of speech and decreased oral intake, mone, urinalysis, urine toxicology screen, ultimately warranted constant observation, and and levels were in which led to a decrease in self-harming activ- normal ranges. Although brain imaging re- ity. All this behavior was noted even though vealed enlarged ventricles, NPH was con- the patient was adherent to oral adminis- sidered unlikely because of the absence of tration of thiamine. Throughout this time, ophthalmologic abnormalities, like gaze the patient underwent several transfers back , and urinary incontinence; con- and forth between the Psychiatry and Inter- versely, there was some presence of urinary nal Medicine services due to ongoing con- retention attributed to BPH and required cern for the possibility of delirium or WE. an admission a few months prior. More- However, the and Internal Med- over, magnetic resonance images showed icine services did not feel that WE would that the ventricles were enlarged slightly explain the patient’s mental and behavioral out of proportion to the sulci, which can status, in part due to his ongoing adherence be seen with predominantly central volume with daily oral thiamine dosing that was

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not associated with improvement in mental versations. Some speech content remained status. disorganized particularly if engaged beyond Recollecting the patient’s improvement simple exchanges. with the parenteral thiamine regimen (IV The patient was discharged to a skilled and IM), the psychiatry unit tried a thia- nursing facility after a month of 3 times daily mine regimen of 200 mg IM and 100 mg oral IM administration of thiamine. Within the 2 times daily. After about 2 weeks on this reg- next 24 hours, the patient returned to the imen, the patient subsequently achieved re- ED with the originally reported symptoms markable improvement in his cognitive and of ataxia, agitation, and confusion. On in- behavioral status, with resolution of self- quiry, it was revealed that the ordered vials harming behaviors. The patient was noted of IM thiamine for injection had not arrived to be calmer, more linear, and more oriented, with him at the nursing facility and he had though he remained incompletely oriented missed 2 doses. The blood laboratory results, throughout his hospitalization. As improve- scans, and all other parameters were other- ment in sensorium was established and the wise found to be normal and the patient was patient’s hospital stay prolonged (Figure), adherent to his prescribed antipsychotics and his mood symptoms began manifesting as antidepressants. As anticipated, restoration guilt, low energy, decreased appetite, with- of the IM thiamine regimen revived his base- drawal, and passive SI. This was followed by line within hours. While confusion and de- a trial of lithium that was discontinued due lirium resolved completely with treatment, to elevated creatine levels. As the patient con- the memory impairments persisted. This pa- tinued to report depression, a multidrug regi- tient has been administered a 3 times daily men of divalproex, fluoxetine, and quetiapine IM dose of 200 mg thiamine for more than was administered, which lead to remarkable 2 years with a stable cognitive clinical improvement. picture. At this time, it was concluded that the stores of thiamine in the patient’s body may DISCUSSION have been replenished, the alcohol intake According to data from the 2016 National completely ceased and that he needed to be Survey on Drug Use and Health, 16 mil- weaned off of thiamine. The next step taken lion individuals in the US aged ≥ 12 years re- was reduction of the twice daily 200 mg IM ported heavy alcohol use, which is defined thiamine dose to a once daily regimen, and as binge drinking on ≥ 5 days in the past oral thiamine was put on hold. Over the next month.6,7 Thiamine deficiency is an alcohol- 48 hours, the patient became less verbal, related disorder that is frequently encoun- more withdrawn, incontinent of urine, and tered in hospital settings. This deficiency can delirious. The twice daily IM 200 mg thi- also occur in the context of malabsorption, amine was restarted, but this time the pa- , a prolonged course of vomit- tient demonstrated very slow improvement. ing, and .8,9 After 2 weeks, the IM thiamine 200 mg The deficiency in thiamine, which is was increased to 3 times daily, and the pa- sometimes known as WE, manifests rarely tient showed marked improvement in recall, with all 3 of the classic triad of gait dis- mood, and effect. turbances, abnormal eye movements, and Several attempts were made to reduce mental status changes, with only 16.5% of the IM thiamine burden on the patient and/ patients displaying all of the triad.4 Moreover, or transition to an exclusively oral regimen. there may be additional symptoms not listed However, he rapidly decompensated within in this triad, such as memory impairment, bi- hours of each attempt to taper the IM dose lateral sixth nerve palsy, ptosis, hypotension, and required immediate reinstation. On the and .10.11 This inconsistent pre- IM thiamine regimen, he eventually appeared sentation makes the diagnosis challenging to reach a stable cognitive and affective base- and therefore requires a higher threshold for line marked by incomplete orientation but suspicion. If undiagnosed and/or untreated, pleasant affect, he reported no mood com- WE can lead to chronic thiamine deficiency plaints, behavioral stability, and an ability to causing permanent brain damage in the guise comply with care needs and have simple con- of KS. This further increases the importance

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of timely diagnosis and treatment. gressively, the patient seemed to improve tre- Our case highlights the utilization of an mendously. Presence of memory problems unconventional thiamine regimen that ap- and confabulation, both of which this pa- peared to be temporally associated with tient exhibited, are suggestive of KS and are mental status improvement. The patient’s not expected to recover with treatment, yet clouded sensorium and confusion could not for this patient there did seem to be some be attributed to metabolic, encephalopathic, improvement—though not complete resolu- or infectious pathologies due to the absence tion. This is consistent with newer evidence of supportive laboratory evidence. He re- suggesting that some recovery from the defi- sponded to IV and IM doses of thiamine, cits seen in KS is possible.3 but repeated attempts to taper the IM doses Once diagnosed, the treatment objective with the objective of transitioning to oral is the replenishment of thiamine stores and thiamine supplementation were followed optimization of the metabolic scenario of by immediate decompensations in mental the body to prevent recurrence. For acute status. This was atypical of WE as the pa- WE symptoms, many regimens call for tient seemed adequately replete with thia- 250 to 500 mg of IV thiamine supplementa- mine, and missing a few doses should not be tion 2 to 3 times daily for 3 to 5 days. High enough to deplete his stores. Thus, reflecting dose IV thiamine (≥ 500 mg daily) has been a unique case of thiamine-dependent chroni- proposed to be efficacious and free of con- cally set WE when even a single missed dose siderable adverse effects.12 A study con- of thiamine adversely affected the patient’s ducted at the University of North Carolina cognitive baseline. Interesting to note is this described thiamine prescribing practices in a patient’s memory issue, as evident by clinical large academic hospital, analyzing data with examination and dating back at least 5 years the objective of assessing outcomes of order- as per chart review. This premature amnes- ing high-dose IV thiamine (HDIV, ≥ 200 mg tic component of his presentation indicates IV twice daily) to patients with encephalopa- a likely parallel running KS component of thy.13 The researchers concluded that HDIV, his presentation. Conversely, the patient’s even though rarely prescribed, was associ- long history of alcohol use disorder, prior ated with decreased inpatient mortality in bi- episodes of WE, and ideal response achieved variable models. However, in multivariable only on parenteral thiamine repletion further analyses this decrease was found to be clin- supported the diagnosis of WE and our im- ically insignificant. Our patient benefitted pression of the scenario. from both IV and IM delivery. Even though this patient had prior ep- Ideally, after the initial IV thiamine dose, isodes of WE, there remained diagnostic oral administration of thiamine 250 to uncertainty regarding his altered mental sta- 1,000 mg is continued until a reduc- tus for some time before the nonoral thia- tion, if not abstinence, from alcohol use is mine repletion treatment was implemented. achieved.5 Many patients are discharged Particularly in this admission, the patient’s on an oral maintenance dose of thiamine mental status frequently waxed and waned 100 mg. Oral thiamine is poorly absorbed and there was the additional confusion of and less effective in both prophylaxis and whether a potential psychiatric etiology con- treatment of newly diagnosed WE; there- tributed to some of the elements of his pre- fore, it is typically used only after IM or sentation, such as his impulsive self-harm IV replenishment. It remains unclear why behaviors. This behavior led to recurrent this patient required IM thiamine multiple transfers among the Psychiatry Service, In- times per day to maintain his mental sta- ternal Medicine Service, and the ED. tus, and why he would present with self- The patient’s presentation did not reflect injurious behaviors after missing doses. the classical triad of WE, and while this is The patient’s response can be attributed consistent with the majority of clinical man- to late-onset defects in oral thiamine ab- ifestations, various services were reluctant sorption at the carrier protein level of the to attribute his symptoms to WE. Once the brush border and basolateral membranes threshold of suspicion of thiamine deficiency of his jejunum; however, an invasive pro- was lowered and the deficit treated more ag- cedure like a jejunal biopsy to establish the

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definitive etiology was neither necessary nor Author disclosures The authors report no actual or potential conflicts of interest practical once treatment response was ob- with regard to this article. served.14 Other possible explanations in- clude rapid thiamine metabolism, poor Disclaimer gastrointestinal absorption and a late-on- The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline set deficit in the thiamine diffusion mech- Medical Communications Inc., the US Government, or any anisms, and active transport systems of its agencies. This article may discuss unlabeled or inves- tigational use of certain drugs. Please review the complete (thiamine utilization depends on active prescribing information for specific drugs or drug combina- transport in low availability states and pas- tions—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy sive transport when readily available). The to patients. nature of these mechanisms deserves further study. Less data have been reported on the References administration and utility of IM thiamine for 1. Lough ME. Wernicke’s encephalopathy: expanding the di- agnostic toolbox. Neuropsychol Rev. 2012;22(2):181-194. chronic WE; hence, our case report is one of doi:10.1007/s11065-012-9200-7 the first illustrating the role of this method 2. Arts NJ, Walvoort SJ, Kessels RP. Korsakoff’s syndrome: a critical review. Neuropsychiatr Dis Treat. 2017;13:2875- for sustained repletion. 2890. Published 2017 Nov 27. doi:10.2147/NDT.S130078 3. Johnson JM, Fox V. Beyond thiamine: treatment for cogni- CONCLUSIONS tive impairment in Korsakoff’s syndrome. Psychosomatics. 2018;59(4):311-317. doi:10.1016/j.psym.2018.03.011 This case presented a clinical dilemma be- 4. Harper CG, Giles M, Finlay-Jones R. Clinical signs in cause the conventional treatment regimen for the Wernicke-Korsakoff complex: a retrospective analy- sis of 131 cases diagnosed at necropsy. J Neurol Neu- WE didn’t yield the desired outcome until the rosurg Psychiatry. 1986;49(4):341-345. doi:10.1136/ mode and duration of thiamine administra- jnnp.49.4.341 tion were adjusted. It illustrates the utility of 5. Xiong GL, Kenedl, CA. Wernicke-Korsakoff syndrome. https://emedicine.medscape.com/article/288379-overview. a sustained intensive thiamine regimen irre- Updated May 16, 2018, Accessed July 24, 2020. spective of sobriety status, as opposed to the 6. Ahrnsbrak R, Bose J, Hedden SL, Lipari RN, Park-Lee E. Results from the 2016 National Survey on Drug Use and traditional regimen of parenteral (primarily Health. https://www.samhsa.gov/data/sites/default/files IV) thiamine for 3 to 7 days, followed by oral /NSDUH-FFR1-2016/NSDUH-FFR1-2016.htm. Accessed repletion until the patient achieves sustained July 22, 2020. 7. National Institute on and . abstinence. In this patient’s case, access to Drinking Levels Defined. https://www.niaaa.nih.gov nursing care postdischarge facilitated his con- /alcohol-health/overview-alcohol-consumption/moderate tinued adherence to IM thiamine therapy. -binge-drinking Accessed July 24, 2020. 8. Heye N, Terstegge K, Sirtl C, McMonagle U, Schreiber K, The longitudinal time course of this case Meyer-Gessner M. Wernicke’s encephalopathy--causes suggests a relationship between this route of to consider. Intensive Care Med. 1994;20(4):282-286. doi:10.1007/BF01708966 administration and improvement in symp- 9. Aasheim ET. Wernicke encephalopathy after bariatric sur- tom burden and indicates that this patient gery: a systematic review. Ann Surg. 2008;248(5):714-720. may have a long-term need for IM thiamine doi:10.1097/SLA.0b013e3181884308 10. Victor M, Adams RD, Collins GH. The Wernicke-Korsakoff to maintain his baseline mental status. Of Syndrome and Related Neurologic Disorders Due to Alco- great benefit in such patients would be the holism and Malnutrition. Philadelphia, PA: FA Davis; 1989. 11. Thomson AD, Cook CC, Touquet R, Henry JA; Royal availability of a long-acting IM thiamine ther- College of Physicians, London. The Royal College of apy. Risk of overdose is unlikely due to the Physicians report on alcohol: guidelines for managing water solubility of B group . Wernicke’s encephalopathy in the accident and Emer- gency Department [published correction appears in Al- This case report highlights the impor- cohol Alcohol. 2003 May-Jun;38(3):291]. Alcohol Alcohol. tance of setting a high clinical suspicion 2002;37(6):513-521. doi:10.1093/alcalc/37.6.513 12. Nishimoto A, Usery J, Winton JC, Twilla J. High-dose for WE due to its ever-increasing incidence parenteral thiamine in treatment of Wernicke’s encepha- in these times. We also wish to direct re- lopathy: case series and review of the literature. In Vivo. searchers to consider other out-of-the-box 2017;31(1):121-124. doi:10.21873/invivo.11034 13. Nakamura ZM, Tatreau JR, Rosenstein DL, Park EM. Clini- treatment options in case of failure of the cal characteristics and outcomes associated with high- conventional regime. In documenting this dose intravenous thiamine administration in patients with encephalopathy. Psychosomatics. 2018;59(4):379-387. patient report, we invite more medical pro- doi:10.1016/j.psym.2018.01.004 viders to investigate and explore other ther- 14. Subramanya SB, Subramanian VS, Said HM. Chronic apeutic options for WE treatment with the alcohol consumption and intestinal thiamin absorption: effects on physiological and molecular parameters of the aim of decreasing both morbidity and mor- uptake process. Am J Physiol Gastrointest Physiol. tality secondary to the condition. 2010;299(1):G23-G31. doi:10.1152/ajpgi.00132.2010

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