564 Psychosomatics

564 PSYCHOSOMATICS Case Report Wernicke-Korsakoff Syndrome DIMARTINI, M.D.

in

aLiver

Transplant

Recipient

ANDREA 

T hough commonly believed to be a manifestation of chronic alcoholism, WernickeKorsakoff syndrome may also occur in a large variety of nonalcoholic, nutritionally depleted states. In fact, the original report by Wernicke included a nonalcoholic woman with protracted vomiting. Any condition resulting in the depletion of thiamine (vitamin B,) either from diminished intake or absorption, including prolonged starvation, hyperemesis gravidarum, diarrhea, gastroplasty, chronic bowel disease, gastrointestinal carcinoma, AIDS, and thiamine-deficient total parenteral nutrition (TPN), can cause the Wernicke-Korsakoff syndrome. ‘ý Though not predisposed   by  transplantation alone, transplant patients may be at higher risk attributable to a variety of factors causing gastrointestinal disturbance, protracted vomiting, or nutritional depletion (i.e., cytomegalovirus gastritis, immunosuppression medication side effects, and nutritional depletion from end-stage organ disease).

Case Report Ms.   A.,   a   39­year­old,  married, African American woman, underwent orthotopic liver transplantation for fulminant hepatic failure of cryptogenic origin. Before emergency transplantation, she had been functioning normally without any mental or cognitive impairment. Shortly after discharge from her transplant hospitalization, she developed protracted nausea and vomiting. Neuropsychiatric symptoms developed insidiously 3 months after transplantation. Over several weeks, she became increasingly lethargic and fatigued, and later developed apathy, flat affect, tearfulness, and depressed mood. She had no prior history of depression and no family history of depression. So convincing were her depressive symptoms that she was first treated for a depressive disorder with nortriptyline, though her symptoms did not improve. Her 35-kg weight loss over this 4-month period posttransplant was not fully appreciated because of a lack of cachexia from an initially heavy weight (98 kg). Acute symptoms developed over a 2-week period, necessitating rehospitalization. On admission her mental status changes included confusion, disorientation, poor memory, and diminished concentration. For this delirious, immunosuppressed transplant recipient, possibilities of rejection, infection, metabolic/hematologic abnormalities, or drug reactions were investigated. Laboratory data was unremarkable, including electrolytes, white blood cell count, and differential, liver functions, glucose, calcium, magnesium, phosphorous, blood gases, thyroid functions, ANA, folate, iron, and ferritin. Abnormal labs included albumin (2.9 gm/dL), total protein (5.6 gmldL), hematocrit (24.7%), hemoglobin (8.5 gmldL), platelet (84 KJUL), and creatinine kinase (32 UIL). Cholesterol (215 mg/dL) and triglycerides (233 mg/dL) were elevated, and B,2 was normal, though these were checked after several days on TPN. Cerebrospinal fluid was unremarkable, including protein and glucose and bacterial, fungal, viral, and tuberculosis cultures. Blood cultures were sterile, and liver and gastric biopsies were negative for Received   June   21,   1995;  revised August 10, 1995; accepted October 13, 1995. From the Western Psychiatric

Institute and Clinic, the University of Pittsburgh, Department of Psychiatry, Pennsylvania. Address reprint requests to Dr. DiMartini, Western Psychiatric Institute and Clinic, 3811 O’Hara St., Pittsburgh, PA 15213. Copyright © 1996 The Academy of Psychosomatic Medicine. VOLUME 37 #{149} NUMBER 6 #{149} NOVEMBER - DECEMBER 1996 565 viral, fungal, and TB. HIV test and test for syphillis (VDRL) were also negative. A drug screen, including ethanol, was negative.Trough plasma levels of her immunosuppressive drug, FK-506, were subtherapeutic at 0. 1 ng/mL(normal range: 0.5-1 .0 ng/mL). Nevertheless, to eliminate the possibility that she was experiencing an idiosyncratic toxic reaction to FK-506, she was switched to cyclosporme (CYA). CYA levels were 800-900 ng/m/L (normal range: 500-1000 ng/mlL, with no improvement in her symptoms. Her nortriptyline level was 75 mg/dL (therapeutic range: 50-150 mg/dL); however, it was discontinued because of concerns over anticholinergic side effects. An electroencephalogram showed mild generalized slowing of the dominant rhythm consistent with the diagnosis of delirium. A computed tomography (CT) of the head with iodine contrast showed a low-attenuation area in the ventral posterolateral nuclei of the left thalamus described as a possible small lacunar infarct. There was no evidence of mammillary body necrosis. A magnetic resonance imaging (MRI) with gadolinium enhancement was normal. Within a week, her speech and thoughts were disorganized, and she developed paranoid delusions that her family was in danger and that the staff was trying to harm her. It was not until clear evidence of lateral gaze weakness, severe nystagmus, and ataxia developed 5 days after admission that Wernicke-Korsakoff syndrome was suspected. Her nystagmus occurred in all directions at rest and significantly worsened after she attempted to walk. She had a widebased shuffling gait requiring support to maintain her balance. The rest of her neurologic examination was normal, except for a fine, rapid tremor and cerebellar discoordination. A vitamin B, (thiamine) serum level was subnormal at 4 ng/mL (normal range: 10-60 ng/mL), even after several days of TPN (at our institution TPN has only 10 mg of thiamine per administration). A transketolase level was normal at 1.24 IU/g (normal range: 0.75-1.3 IU/g); however, this was checked after intravenous (IV) thiamine

was given. She was treated with thiamine (100 mg IV) for several days, which was later switched to oral. Her diet was changed to a low-carbohydrate diet, with no dextrose by IV solution. Ocular palsies and nystagmus resolved after 10 days of thiamine treatment, though the ataxia and discoordination persisted. Initially, she had periods of temporary improvement in her mental status and nystagmus lasting several hours following IV thiamine; however, the psychotic symptoms (paranoid delusions and feelings of being controlled by outside forces), gross confusion, and depressed affect took weeks to fully resolve, followed by an incomplete return of her long- and short-term memory. One year later, her affective and psychotic symptoms had completely remitted, but she continued to have significant short- and long-term memory loss and minimal gait and coordination problems. She has since been on disability. Discussion Though this patient eventually presented with classic symptoms, in a study of 131 cases of Wernicke-Korsakoff complex diagnosed at necropsy, only 16% had the classic clinical triad of ophthalmoplegia, gait ataxia, and abnormal mental state, and 19% had no documented clinical signs.4 However, a derangement in mental function, most commonly a global confusionalapathetic state is present in all but 10 % of patients.5 The etiology of our patient’s protracted nausea and vomiting are unknown. However, FK-506 can commonly cause nausea and vomiting,6 and these symptoms subsided when our patient’s FK-506 was switched to CYA. Some patients may have a genetic predisposition to the development of symptomatic thiamine deficiency on a diet marginal in thiamine.7 A low-blood thiamine level, lactic acidosis, elevated blood pyruvate, or low-transketolase activity can help diagnose thiamine deficiency, though thiamine blood levels may not reflect tissue stores, which can be lower. A transketolase level can help ascertain whether the patient

has a primary thiamine deficit or an inability to metabolize/use thiamine. However, an isolated transketolase level may not reflect diminished activity, which may only be proven by measuring the percentage of transketolase enzymatic activity given an excess of thiamine pyrophosphate (i.e., the TPP effect).8 In the context of liver disease, food consumption may not play the definitive role in the pathogenesis of thiamine deficiency but rather thiamine malabsorption. 9 Thiamine absorption occurs by active transport in the small intestine and requires adequate Naý-Ký ATPase activity in the enterocytes. FK-506 can cause derangements in potassium,’#{176} though the effect on Naý-Ký ATPase activity and thiamine transport is unknown. In Wernicke-Korsakoff, the quality of reversibility in the ocular dysfunction and the slower and frequently incomplete recovery of memory function suggests that the first is caused by a correctable biochemical derangement and the second caused by irreversible structural damage in the diencephalon, most specifically in the medial dorsal nuclei of the thalamus.5 Our patient had CT scan evidence of a thalamic lesion. However, since not all structural damage can be seen on CT/MRI scans, it is impossible to predict the reversibility of symptoms based on brain imaging. Alterations in mental status posttransplantation can occur for innumerable reasons, as investigated by our laboratory analysis in this patient. Specific neurotoxic side effects of FK506 usually occur in plasma, though at levels greater than 3 ng/mL, and can involve both central and peripheral nervous systems with akinetic mutism, aphasia, dysarthria, seizures, hemiplegia, encephalopathy, and peripheral neuropathy.”2 Lesions may be identifiable by MRI1ý2 Neurologic function usually improves often with a delay of several days after the FK-506 levels are decreased. Our patient’s status did not improve even when she was taken off FK-506. The initial treatment of WernickeKorsakoff requires rapid parenteral repletion. Thiamine (100 mg) can be administered safely

as an IV bolus.’3 At our institution, TPN contains 10 mg of thiamine per administration, which was not adequate replacement for this thiamine-depleted patient. High-carbohydrate diets increase thiamine requirements and may worsen symptoms. In fact, our patient developed the classic symptoms after TPN, which may have worsened her untreated thiamine deficiency. Therefore, low-carbohydrate diets should be maintained, and no dextrose by IV solutions should be given. The duration of available thiamine stores are unknown, but fatal deficiency can develop in as few as 3.5 weeks without thiamine intake.3 Because of the high percentage of missed clinical signs in Wernicke-Korsakoff and the wide variety of causes for diminished nutritional status, clinicians should maintain a high index of suspicion for thiamine deficiency in nutritionally depleted patients and in patients with mental status changes. Consideration of thiamine deficiency in the differential diagnosis can be an easy yet lifesaving course. The author thanks Siddharth Pantforassistance in the preparation this manuscript.