Neurologic complications of bariatric surgery.

Review Article Address correspondence to Dr Neeraj Kumar, Mayo Clinic, Department of Neurology, 200 1st St SW, Rochester, MN 55905-0001, [email protected]. Relationship Disclosure: Dr Kumar reports no disclosure. Unlabeled Use of Products/Investigational Use Disclosure: Dr Kumar reports no disclosure. * 2014, American Academy of Neurology.

Neurologic Complications of Bariatric Surgery Neeraj Kumar, MD ABSTRACT Purpose of Review: The increasing utilization of bariatric surgery has been accompanied by an increased incidence and awareness of related neurologic complications. The purpose of this review is to provide up-to-date information on the neurologic complications related to bariatric surgery. Recent Findings: Neurologic complications related to bariatric surgery are predominantly due to nutrient deficiencies. Common early complications include Wernicke encephalopathy due to thiamine deficiency, and late complications include myelopathy or myeloneuropathy due to vitamin B12 or copper deficiency. Summary: Early recognition and prompt institution of treatment is essential to prevent long-term disability. Often, life-long supplementation may be required. Continuum (Minneap Minn) 2014;20(3):580–597.

INTRODUCTION The epidemic of obesity and limited efficacy of available medical treatments have resulted in increasing utilization of bariatric surgical procedures for treatment of medically complicated obesity.1Y3 Weight loss following bariatric surgery results from caloric restriction, malabsorption, and modulation of the enteroencephalic endocrine axis. The earliest surgical treatments for obesity were malabsorptive procedures such as the jejunocolic and jejunoileal bypass. These operations were abandoned because of severe metabolic derangements. Restrictive procedures (eg, gastric partitioning, gastroplasty, vertical banded gastroplasty, gastric stapling) separate the stomach into a restricted upper pouch that empties into the rest of the stomach through a narrow channel, thus restricting the quantity and rate of food ingested. Weight loss following gastric restriction is frequently not sustained. Procedures

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that are restrictive and associated with dumping and some malabsorption (eg, Roux-en-Y gastric bypass, gastrojejunal bypass with gastric restriction) or those where partial gastric restriction is combined with procedures associated with significant malabsorption (eg, partial biliopancreatic bypass; biliopancreatic diversion with duodenal switch; distal gastric bypass; very, very long limb gastric bypass) typically have more durable benefits, although with a higher complication rate. The Roux-en-Y gastric bypass is increasingly done laparoscopically. Use of a laparoscopically placed adjustable gastric band had also gained some popularity in recent years and has almost completely replaced the vertical banded gastroplasty. This procedure differs from previously performed restrictive procedures in that there is adjustment of the band in response to rate of weight loss and absence of an enterotomy or permanent change to the anatomy. In recent years interest

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has been shown in laparoscopic and endoscopic vertical sleeve gastrectomy as a stand-alone restrictive procedure. Particularly important for functioning of the nervous system are the B-group vitamins (vitamin B12, thiamine, niacin, pyridoxine, folate), vitamin E, copper, and vitamin D. Increased utilization of bariatric surgery in the treatment of obesity has been accompanied by an increased incidence and awareness of neurologic complications resulting from bariatric surgery. These are often related to nutrient deficiencies. A number of reviews address the issue of neurologic complications of bariatric surgery.4Y11 The interested reader is directed to these for detailed bibliographies. The bibliography that accompanies this article is weighted toward recent review articles and case series rather than individual case reports. Laboratory evidence of a nutrient deficiency may not be accompanied by clinical manifestations associated with that particular nutrient deficiency. For many nutrients, the clinical manifestations associated with the deficiency state that have been discussed in this article have not been reported in the context of bariatric surgery. Furthermore, for many deficiencies the related clinical manifestations described here are from the gastrectomy literature rather than literature that deals with gastric bypass for obesity. Finally, it is important to note that recommendations regarding monitoring and replacement are based on expert opinion and observational research rather than prospectively controlled randomized trials. FREQUENCY, NATURE, AND TIMING OF NEUROLOGIC COMPLICATIONS FOLLOWING BARIATRIC SURGERY Complications related to the central or peripheral nervous system or both Continuum (Minneap Minn) 2014;20(3):580–597

may be seen in approximately 5% to 16% of patients after surgery for peptic ulcer disease or obesity.4Y8,12Y15 Neurologic complications following bariatric surgery can involve any level of the neuraxis. Commonly recognized neurologic complications related to bariatric surgery include encephalopathy, optic neuropathy, myelopathy or myeloneuropathy, radiculoplexus neuropathy, polyneuropathy, and mononeuropathy (resulting in carpal tunnel syndrome, meralgia paresthetica or footdrop). Patients undergoing bariatric surgery may also be prone to developing ulnar neuropathy or brachial plexus stretch injury.16 Frequently, more than one part of the nervous system is involved (eg, cooccurrence of encephalopathy and peripheral neuropathy). Encephalopathy, polyradiculopathy, and mononeuropathy are early complications; myelopathy and polyneuropathy are generally delayed complications.7,9 A review of 50 reports of neurologic complications related to bariatric surgery identified 96 patients.6 Peripheral neuropathy was noted in 60 patients and an encephalopathy in 30. Of the 60 patients with a peripheral neuropathy, polyneuropathy was noted in 40 and meralgia paresthetica in 17. There was one patient with a radiculopathy, one with a lumbar plexopathy, and one with footdrop. Eighteen of the 40 cases of polyneuropathy were attributed to thiamine deficiency. Of the 30 patients with an encephalopathy, Wernicke encephalopathy or Wernicke-Korsakoff syndrome was present in 27. Twelve of these patients had an accompanying peripheral neuropathy. Optic nerve involvement was noted in eight, a myelopathy in two, and muscle disease in seven. Some patients had more than one site of neurologic involvement. A prospective series noted neurologic complications in 23 of 500 patients

KEY POINTS

h The epidemic of obesity and limited efficacy of available medical treatments have resulted in increasing utilization of bariatric surgical procedures for treatment of medically complicated obesity.

h The Roux-en-Y gastric bypass is increasingly being done laparoscopically. A laparoscopically placed adjustable gastric band had also gained some popularity in recent years and has almost completely replaced the vertical banded gastroplasty.

h Increased utilization of bariatric surgery in the treatment of obesity has been accompanied by an increased incidence and awareness of neurologic complications resulting from bariatric surgery. Such complications are often related to nutrient deficiencies.

h Complications related to the central or peripheral nervous system or both may be seen in approximately 5% to 16% of patients after surgery for peptic ulcer disease or obesity.



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Bariatric Surgery KEY POINTS

h Commonly recognized neurologic complications related to bariatric surgery include encephalopathy, optic neuropathy, myelopathy or myeloneuropathy, radiculoplexus neuropathy, polyneuropathy, and mononeuropathy. Encephalopathy, polyradiculopathy, and mononeuropathy are early complications; myelopathy and polyneuropathy are generally delayed complications.

h Risk factors for neurologic complications after bariatric surgery include rate and amount of weight loss, prolonged gastrointestinal symptoms (eg, nausea, vomiting), postsurgical complications, subclinical preoperative deficiency, inadequate nutritional follow-up and failure to take recommended supplements, food avoidance, postoperative loss of appetite, and type of procedure.

h Commonly implicated nutrient deficiencies in patients with a history of bariatric surgery and neurologic complications include vitamin B12, thiamine, and copper.

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(4.6%) followed for 3 to 20 months.4 In a controlled retrospective study of peripheral neuropathy after bariatric surgery, peripheral neuropathy was noted to develop in 71 of 435 patients: sensory-predominant polyneuropathy in 27, mononeuropathy in 39 (median neuropathy at the wrist, ulnar neuropathy at the elbow, radial neuropathy, superficial radial sensory neuropathy, sciatic neuropathy, or peroneal neuropathy), and radiculoplexopathy in 5.12 A series of 26 patients with bariatric surgeryYrelated neurologic complications identified a delayed-onset posterolateral myelopathy, often related to vitamin B12 (cobalamin) or copper deficiency, to be the most frequent and disabling complication.7 RISK FACTORS AND MECHANISMS OF NEUROLOGIC COMPLICATIONS RELATED TO BARIATRIC SURGERY Risk factors for neurologic complications after bariatric surgery include rate and amount of weight loss, prolonged gastrointestinal symptoms (eg, nausea, vomiting, diarrhea, dumping syndrome), postsurgical complications, subclinical preoperative deficiency, inadequate nutritional follow-up and failure to take recommended supplements, food avoidance, postoperative loss of appetite, reduced serum albumin and transferrin, presence of additional causes of specific nutrient deficiencies, and type of procedure.4,6Y9,12,17 In particular, the biliopancreatic diversion with or without a duodenal switch is associated with iron deficiency, metabolic bone disease, hypoalbuminemia, and malabsorption of fat-soluble vitamins.3,18 Neurologic complications following bariatric surgery are commonly related to nutrient deficiencies.19,20 Despite their obesity, patients may have nutritional deficiencies prior to bariatric

surgery.18,21 Following surgery, factors implicated in malabsorption of nutrients include decreased gastric acidity, bypassed proximal intestines resulting in limited absorption due to shorter food contact time, increased frequency of bowel movements and diarrhea associated with a dumping syndrome, blind loop syndrome, and functional exocrine insufficiency.9 Commonly implicated nutrient deficiencies in patients with a history of bariatric surgery and neurologic complications include vitamin B12, thiamine, and copper. 7,8 The precise neurologic significance related to biochemically detected deficiencies of other vitamins like pyridoxine, folate, niacin, riboflavin, vitamin E, and vitamin D is unclear. Minerals (eg, calcium, phosphorus, magnesium) and trace elements (eg, zinc, iodine, selenium) have not been well studied in patients after bariatric surgery. While iron deficiency is particularly common after bariatric surgery, it does not have direct neurologic consequences. Multiple nutrient deficiencies may coexist. Often a specific nutrient deficiency as a cause for neurologic manifestations is not identified.4 A review of 957 patients in eight reports of nutrient deficiencies following bariatric surgery noted vitamin B12 deficiency in 236, folate deficiency in 195, and thiamine deficiency in 11.6 Thaisetthawatkul and colleagues12 have suggested a possible immunemediated or inflammatory basis for bariatric surgeryYrelated neurologic complications. In one study, some patients with neurologic complications following bariatric surgery were noted to have increased intrathecal immunoglobulin G synthesis.7 Additionally, weight loss may predispose to compression mononeuropathies like common peroneal nerve involvement at the fibular head.22 The presence of a widespread polyneuropathy is an additional



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TABLE 4-1 Neurologic Complications Associated with Bariatric Surgery and Implicated Nutrient Deficiency Neurologic Complication

Implicated Nutrient Deficiency

Encephalopathy

Thiamine, vitamin B12 (rarely folate, niacin)

Myelopathy

Vitamin B12, copper (rarely folate, vitamin E)

Optic neuropathy

Vitamin B12, thiamine, copper (rarely folate)

Polyradiculopathy

Thiamine

Neuropathy

Vitamin B12, thiamine,a copper (rarely pyridoxine, folate, niacin, vitamin E)

Myopathy (rare)

Vitamin D, vitamin E

a

Thiamine deficiency can be associated with a polyradiculoneuropathy that mimics Guillain-Barre´ syndrome.

risk factor for development of a superimposed peroneal neuropathy.22 Table 4-1 summarizes the neurologic manifestations seen after bariatric surgery and the implicated nutrient

deficiency. Table 4-2, Table 4-3, and Table 4-4 summarize salient points regarding bariatric surgery and thiamine (vitamin B1), vitamin B12, and copper deficiency, respectively.

TABLE 4-2 Thiamine (Vitamin B1) Deficiency and Bariatric Surgery Pathophysiology

Intractable vomiting, rapid weight loss, inadequate vitamin supplementation, glucose administration without thiamine, parenteral feeding, bacterial overgrowth

Clinical manifestations

Wernicke encephalopathy (ocular abnormalities, gait ataxia, mental status changes [classic triad rarely seen]) Korsakoff syndrome (amnestic-confabulatory syndrome) Peripheral neuropathy, dry beriberi, wet beriberi (peripheral neuropathy with congestive heart failure) Polyradiculopathy (may mimic Guillain-Barre´ syndrome)

Diagnosis

Largely clinical diagnosis Erythrocyte transketolase activation assay or red blood cell thiamine diphosphate MRI may show abnormal signal in paraventricular regions

Management

For Wernicke encephalopathy: 500 mg of thiamine IV 3 times a day for 2Y3 days, followed by 250 mg/d IV or IM for 3Y5 days, followed by long-term oral maintenance of 50Y100 mg/d

Additional comments

Manifestations seen within weeks of bariatric surgery Body thiamine stores can be depleted in 4Y6 weeks

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TABLE 4-3 Vitamin B12 Deficiency and Bariatric Surgery Pathophysiology

Inadequate intake, impaired hydrolysis of vitamin B12 from dietary protein because of reduction in gastric acid and pepsin, intrinsic factor loss, decreased contact time in the ileum, duodenal bypass, bacterial overgrowth Other causes of vitamin B12 deficiency such as pernicious anemia may coexist


Myelopathy with involvement of dorsal column and corticospinal tract Peripheral neuropathy Myeloneuropathy Optic neuropathy Neuropsychiatric manifestations

Diagnosis

Serum vitamin B12, serum methylmalonic and plasma homocysteine, hematologic abnormalities (anemia, macrocytosis, hypersegmented neutrophils, megaloblastic marrow) MRI may show abnormal signal in the dorsal column and/or lateral corticospinal tract

Management

A common regimen is daily 1000 2g IM injections for 5Y7 days followed by weekly and then monthly 1000 2g IM injections

Additional comments

Manifestations seen years after bariatric surgery Body stores depleted in 2Y5 years in the absence of supplementation

TABLE 4-4 Copper Deficiency and Bariatric Surgery Pathophysiology

Copper is absorbed from the proximal intestines and stomach The acidic environment in the stomach facilitates solubilization of copper by dissociating it from copper-containing dietary macromolecules Other causes of copper deficiency such as zinc ingestion or bacterial overgrowth may coexist


Myelopathy with involvement of dorsal column and corticospinal tract Peripheral neuropathy Myeloneuropathy Optic neuropathy

Diagnosis

Serum and urinary copper, serum ceruloplasmin, hematologic abnormalities MRI shows increased signal involving the dorsal column

Management

Oral regimen: 8 mg/d of elemental copper taken orally for 1 week, 6 mg/d for the second week, 4 mg/d for the third week and 2 mg/d thereafter Parenteral regimen: 2 mg/d of elemental copper IV for 5 days

Additional comments

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Manifestations seen years after bariatric surgery Copper and vitamin B12 deficiency may coexist



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NUTRIENT DEFICIENCY AND RELATED NEUROLOGIC MANIFESTATIONS Thiamine (Vitamin B1) Thiamine deficiency and bariatric surgery. Thiamine deficiency is frequently seen following bariatric surgery (Case 4-1).8,13,17,19,23 In one study, the incidence of thiamine deficiency 2 years following bariatric surgery was approximately 18%.19 Most cases of thiamine deficiencyYrelated neurologic manifestations are seen 4 to 12 weeks after bariatric surgery.13 It takes approximately 4 to 6 weeks for body stores of thiamine to be depleted.24 Because of its short half-life and absence of significant storage amounts, a continuous dietary supply of thiamine is necessary. Thiamine deficiency can result from any of the following conditions: decreased intake, decreased absorption, defective transport, increased losses, and

enhanced requirements.25 Thiamine deficiency following bariatric surgery may be due to intractable vomiting, rapid weight loss, inadequate vitamin repletion, glucose administration without thiamine, parenteral feeding, and bacterial overgrowth (Case 4-1).17 A high caloric and high carbohydrate diet increases the demand for thiamine. In patients with a marginal nutritional status, the increased metabolic demand associated with various diseases can precipitate symptoms of thiamine deficiency. Physiologic role of thiamine. Thiamine is a coenzyme in the metabolism of carbohydrates, lipids, and amino acids.25 It has a role in adenosine triphosphate synthesis, myelin sheath maintenance, and neurotransmitter production. Thiamine diphosphate is a cofactor for the pyruvate dehydrogenase complex, !-ketoglutarate dehydrogenase, and transketolase. Pyruvate dehydrogenase and !-ketoglutarate dehydrogenase are involved in the tricarboxylic acid cycle

KEY POINT

h Most cases of thiamine deficiencyYrelated neurologic manifestations are seen 4 to 12 weeks after bariatric surgery.

Case 4-1 A 33-year-old woman presented with a 5-day history of subacute-onset confusion and gait ataxia. Ten weeks earlier she had undergone gastric bypass surgery for obesity. The postoperative period was complicated by prolonged anorexia, nausea, and vomiting. She lost over 13.6 kg (30 lb) in the first 3 weeks. Her examination was remarkable for inattention, a wide-based ataxic gait, and absent lower limb reflexes. Whole blood thiamine diphosphate levels were normal. Brain MRI showed hyperintense signal involving the periaqueductal gray matter and medial thalami. Comment. Wernicke encephalopathy is a well-recognized early complication of bariatric surgery. Intractable vomiting and rapid weight loss are well-recognized risk factors. The classic triad of ocular abnormalities, gait ataxia, and mental status changes may not be present. The gait difficulty may be due to cerebellar dysfunction or vestibular involvement. A coexisting polyneuropathy or polyradiculoneuropathy may be present. Blood thiamine levels may not be reduced. Typical brain MRI findings of thiamine deficiency may be a clue to the diagnosis, but a normal brain MRI does not rule out the diagnosis. Neurologic manifestations of thiamine deficiency are a well-recognized early complication of bariatric surgery. High-risk patients should receive parenteral thiamine prior to glucose or parenteral nutrition administration. Wernicke encephalopathy is a clinical diagnosis. When suspected, thiamine should be administered emergently without waiting for results of imaging or laboratory determination of thiamine levels. Continuum (Minneap Minn) 2014;20(3):580–597



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Bariatric Surgery KEY POINT

h The clinical features of Wernicke encephalopathy include a subacute onset of the classic triad of ocular abnormalities, gait ataxia, and mental status changes. The onset may be gradual, and frequently not all of the elements of the classic triad are present.

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and transketolase in the hexose monophosphate shunt (pentose phosphate pathway). Neurologic manifestations of thiamine deficiency. Thiamine deficiency variably affects the CNS, peripheral nervous system, and cardiovascular system.25Y27 Cardiac involvement may manifest as high-output or low-output cardiac failure. The peripheral neuropathy associated with thiamine deficiency is called beriberi and is a sensorimotor distal axonopathy often associated with calf cramps, muscle tenderness, burning feet, and autonomic features. A rapid progression of the neuropathy mimick´ syndrome has also ing Guillain-Barre been described.28 The symptoms of subclinical thiamine deficiency are often vague and nonspecific and include fatigue, lethargy, irritability, restlessness, and headaches.25 The best-characterized neurologic disorders due to thiamine deficiency are Wernicke encephalopathy and Korsakoff syndrome (also referred to as Korsakoff psychosis).25,27 The term Wernicke-Korsakoff syndrome is commonly used. Wernicke encephalopathy is a consequence of severe, short-term thiamine deficiency whereas peripheral neuropathy more often is a result of prolonged mild to moderate thiamine deficiency.25 Wernicke encephalopathy related to bariatric surgery has been more commonly reported in women. It is unclear if this relates to a female predisposition for Wernicke encephalopathy or is a reflection of the higher rates of bariatric surgery in women.13 Wernicke encephalopathy is characterized by a subacute onset of the classic triad of ocular abnormalities, gait ataxia, and mental status changes.25Y27 The onset may be gradual, and frequently not all of the elements of the classic triad are present. Ocular abnormalities include nystagmus, ophthalmoparesis, and conjugate gaze palsies. The gait

and trunk ataxia is a consequence of cerebellar and vestibular dysfunction. A coexisting chronic peripheral neuropathy may also contribute to the gait difficulty. Mental status changes include inability to concentrate, apathy, spatial disorientation, delirium, and psychosis. If untreated, Wernicke encephalopathy can progress to coma (which, rarely, may be the sole manifestation of Wernicke encephalopathy) and death. Also, Wernicke encephalopathy following bariatric surgery has been associated with atypical features including optic neuropathy, papilledema, deafness, paresis, seizures, myoclonus, and asterixis.13,23 About 80% of patients with Wernicke encephalopathy who survive develop Korsakoff syndrome, which is an amnestic-confabulatory condition characterized by severe anterograde and retrograde amnesia that emerges as ocular manifestations and acute encephalopathy subside. Korsakoff syndrome is probably more likely to manifest when Wernicke encephalopathy results from a history of alcohol abuse.29 With Korsakoff syndrome, memory is disproportionately impaired relative to other aspects of cognitive function like alertness and attention. Investigations. Wernicke encephalopathy is primarily a clinical diagnosis.13 Urinary thiamine excretion and serum thiamine levels may be decreased in patients with Wernicke encephalopathy, but these levels do not accurately indicate tissue concentrations. A normal serum thiamine level does not exclude Wernicke encephalopathy. Whole blood thiamine levels are more sensitive than plasma thiamine levels. The preferred tests are the erythrocyte transketolase activation assay or measurement of thiamine diphosphate in red blood cell hemolysates using high-performance liquid chromatography. Since these laboratory abnormalities normalize



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quickly, a blood sample should be drawn before initiation of treatment. Pyruvate accumulates in patients with thiamine deficiency, and serum lactate may therefore be elevated. MRI is the imaging modality of choice.23,25Y27 Not infrequently, no radiographic abnormalities are present.13 Typical MRI findings include increased T2, proton density, or fluid-attenuated inversion recovery (FLAIR) signal in the periventricular regions (Figure 4-1). Involved areas include the thalamus, hypothalamus, mammillary body, periaqueductal midbrain, tectal plate, red nucleus, pons, floor of the fourth ventricle, medulla, midline cerebellum, dentate, and, rarely, the splenium of the corpus callosum or basal ganglia structures.23 Increased signal may involve the hypoglossal, medial vestibular, facial, and dentate nuclei.30 Involvement of cortical regions on MRI has also been reported and may indicate irreversible lesions. Contrast enhancement may be present in the early stages. Hemorrhagic lesions are rare. The signal abnormalities typically resolve with treatment, but shrunken mamillary bodies may persist as sequelae. Management. Patients with a history of bariatric surgery who present with signs of gastrointestinal distress should receive thiamine preventively.17 At-risk patients should receive parenteral thiamine prior to administration of glucose or parenteral nutrition. Patients suspected of having beriberi or Wernicke encephalopathy should promptly receive parenteral thiamine. A commonly used thiamine replacement regimen is 100 mg IV every 8 hours.23 Higher doses may be required in patients with Wernicke encephalopathy.25,31 It has been suggested that patients with signs of Wernicke encephalopathy receive 500 mg of thiamine hydrochloride by infusion over 30 minutes, 3 times a day for 3 days.24,25,31,32 Thereafter, the dose may be reduced to 250 mg/d of IV or IM thiamine for 5 days. Long-term oral Continuum (Minneap Minn) 2014;20(3):580–597

maintenance with 50 mg to 100 mg of thiamine daily is commonly employed. In wet beriberi, cardiac symptoms may clear within days, although improvement in motor and sensory symptoms takes months. Response in Wernicke encephalopathy is variable. Ocular signs improve in a few hours. A fine horizontal nystagmus may persist. Improvement in gait ataxia and memory is often delayed. Prompt treatment of Wernicke encephalopathy prevents the development of Korsakoff syndrome. Korsakoff syndrome often does not respond to thiamine therapy. Recovery of consciousness may be seen even in patients in deep coma.

KEY POINT

h Typical MRI findings in Wernicke encephalopathy include increased T2, proton density, or fluid-attenuated inversion recovery signal in the periventricular regions.

Vitamin B12 (Cobalamin) Vitamin B12 deficiency and bariatric surgery. Vitamin B12 deficiency is commonly seen following gastric surgery

Axial fluid-attenuated inversion recovery (FLAIR) brain MRI of a patient with Wernicke encephalopathy showing bilateral, symmetric, hyperintense signal involving the medial thalami (arrows). This patient also had signal change in the periaqueductal gray matter (not shown). This patient’s Wernicke encephalopathy occurred weeks after bariatric surgery.

FIGURE 4-1

Reprinted with permission from Foster D, et al, Neurology.23 B 2005, American Academy of Neurology. www.neurology.org/content/65/12/ 1987.short?sid=3f566b80-7408-416b-988e-edef3b1bf70d.



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h Deficient vitamin B12 levels and neurologic complications related to vitamin B12 deficiency are generally not seen until months to years after bariatric surgery.

(gastrectomy and bariatric surgery) (Case 4-2).6,7,19 The estimated daily losses of vitamin B12 are minute compared with body stores. Hence, even in the presence of severe malabsorption, 2 to 5 years may pass before clinically evident vitamin B12 deficiency develops.33 Deficient vitamin B12 levels and neurologic complications related to vitamin B12 deficiency are generally not seen until months to years after bariatric surgery. Vitamin B12 deficiency following gastric surgery may result from inadequate intake, impaired hydrolysis of

vitamin B12 from dietary protein due to reduction in gastric acid and pepsin, intrinsic factor loss, abnormal intrinsic factor and vitamin B12 interaction, decreased contact time in the ileum, duodenal bypass, or bacterial overgrowth.6,8 Other causes of vitamin B12 deficiency may coexist. These include pernicious anemia, atrophic gastritis, Helicobacter pylori infection, antacid therapy, gastrointestinal diseases associated with malabsorption, pancreatic disease, and vegetarianism. Physiologic role of vitamin B12. Methylcobalamin is a cofactor for a

Case 4-2 A 36-year-old woman was evaluated for a 3-year history of imbalance and distal lower limb paresthesia. She had undergone gastric bypass surgery 11 years ago for obesity, and until 7 years ago she had been on vitamin B12 replacement. Her neurologic examination was remarkable for a spastic ataxic gait with impaired perception of position at the toes and decreased perception of vibration up to the tibial tuberosities. Her ankle jerks were absent, knee jerks were brisk, and plantar responses were extensor. Her nerve conduction studies were consistent with a mild peripheral neuropathy. Somatosensory evoked potential studies demonstrated a central conduction delay that localized to the cervical cord. Her cervical and thoracic spine MRI was unremarkable. Laboratory investigations were remarkable for a mild normocytic anemia and neutropenia and vitamin B12 levels that were on the lower side of the normal range. Comment. Her clinical presentation was suggestive of a myeloneuropathy. A common cause of a myeloneuropathy is vitamin B12 deficiency. Vitamin B12 deficiency is commonly seen after gastric bypass surgery, and vitamin B12 supplementation is routinely recommended. It takes 2 to 5 years for body vitamin B12 stores to be depleted. A low-normal vitamin B12 level, if associated with an elevated methylmalonic acid level, may be due to a clinically significant vitamin B12 deficiency. A similar clinical presentation can also result from copper deficiency. It is imperative to look for copper deficiency in patients with a myeloneuropathy. Copper and vitamin B12 deficiency can coexist, and a prior history of gastric surgery is a risk factor for both. Either condition can be associated with hematologic manifestations. In both conditions neurologic manifestations may be seen in the absence of hematologic derangement. Even in patients with subacute combined degeneration due to vitamin B12 deficiency, deterioration despite adequate vitamin B12 supplementation should prompt a search for copper deficiency as a likely cause. The spinal cord MRI may be normal or show increased signal involving the dorsal column on T2-weighted images. A myelopathy or myeloneuropathy due to vitamin B12 or copper deficiency is a delayed and preventable complication of bariatric surgery.

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cytosolic enzyme, methionine synthase, in a methyl-transfer reaction, which converts homocysteine to methionine. Methionine is adenosylated to S-adenosyl-L-methionine, a methyl group donor required for neuronal methylation reactions. Adenosylcobalamin is a cofactor for mitochondrial L-methylmalonyl coenzyme A mutase, which catalyzes the conversion of L-methylmalonyl coenzyme A to succinyl coenzyme A. Accumulation of methylmalonate and propionate may provide abnormal substrates for fatty acid synthesis. Neurologic manifestations of vitamin B12 deficiency. Neurologic manifestations may be the earliest and often the only manifestation of vitamin B12 deficiency.26,27,34Y36 The commonly recognized neurologic manifestations include a myelopathy with or without an associated neuropathy, optic neuropathy, and paresthesia without abnormal signs (Case 4-2). Neuropsychiatric manifestations of vitamin B12 deficiency include impaired memory, personality change, psychosis, emotional lability, and, rarely, delirium or coma. Encephalopathy may obscure a coexisting myelopathy. Investigations. Although a widely used screening test, serum vitamin B12 measurement has technical and interpretive problems and lacks sensitivity and specificity for the diagnosis of vitamin B12 deficiency.33Y36 A proportion of vitamin B12Ydeficient patients may have vitamin B12 levels that are on the lower side of the normal range. Levels of serum methylmalonic acid and plasma total homocysteine are useful as ancillary tests. The specificity of methylmalonic acid is superior to that of homocysteine. Hematologic manifestations of vitamin B12 deficiency including macrocytosis, anemia, neutrophil hypersegmentation, and megaloblastic bone marrow changes may be seen. Electrophysiologic abnormalities include nerve conduction studies sugContinuum (Minneap Minn) 2014;20(3):580–597

gestive of a sensorimotor axonopathy and abnormalities on evoked potential studies. MRI abnormalities in vitamin B12 deficiency include signal change in the posterior and lateral columns of the spinal cord and less commonly the subcortical white matter.26 Management. The goals of treatment are to reverse the signs and symptoms of deficiency, replete body stores, and monitor response to therapy. A short course of daily therapy is often followed by weekly administration for 1 month and then monthly maintenance therapy. A commonly used IM dose is 1000 Hg. The role of oral therapy in patients with severe neurologic disease has not been well studied. In the absence of controlled studies, most recommend routine initiation of vitamin B12 supplementation following bariatric surgery. Monthly IM administration of 1000 Hg or oral crystalline vitamin B12 in a dose of at least 350 Hg/d should suffice.1 Response to treatment may relate to extent of involvement and delay in starting treatment. Response of the neurologic manifestations is variable, may be incomplete, and often starts in the first week. Response of the hematologic derangements is prompt and complete. Methylmalonic acid and plasma total homocysteine levels may normalize by 10 to 14 days.

KEY POINTS

h The commonly recognized neurologic manifestations due to vitamin B12 deficiency include a myelopathy with or without an associated neuropathy, optic neuropathy, and paresthesia without abnormal signs.

h Although a widely used screening test, serum vitamin B12 measurement has technical and interpretive problems and lacks sensitivity and specificity for the diagnosis of vitamin B12 deficiency. Levels of serum methylmalonic acid and plasma total homocysteine are useful as ancillary diagnostic tests.

Copper Copper deficiency and bariatric surgery. The most common cause of acquired copper deficiency is a prior history of gastric surgery (for peptic ulcer disease or bariatric surgery).7,8,37Y42 In a review of reported cases of copper deficiency myelopathy, a prior history of gastric surgery was present in nearly half the cases.42 The duration between gastric surgery and onset of neurologic symptoms may range from less than a year to over 2 decades.39,40 www.ContinuumJournal.com


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h Continued neurologic deterioration in patients with a history of vitamin B12Yrelated myelopathy who have a normal vitamin B12 level while on replacement should be evaluated for copper deficiency.

h The best-characterized neurologic manifestation of acquired copper deficiency is a myelopathy or myeloneuropathy that resembles the subacute combined degeneration seen with vitamin B12 deficiency.

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Copper is absorbed from the proximal intestines and stomach. The acidic environment in the stomach facilitates solubilization of copper by dissociating it from copper-containing dietary macromolecules. Gastric bypass leads to copper malabsorption and resulting deficiency. Also, bacterial overgrowth was implicated as a cause of copper deficiency in a patient with a prior history of gastric surgery.41 Other causes of copper deficiency include excessive zinc supplementation, gastrointestinal diseases associated with malabsorption like celiac disease or inflammatory bowel disease, and prolonged parenteral nutrition.26 The coexistence of multiple causes of copper deficiency increases the chances of development of a clinically significant deficiency state.41 Other nutrient deficiencies, such as in vitamin B12 or vitamin E, can coexist with copper deficiency.41,43 Continued neurologic deterioration in patients with a history of vitamin B12Y related myelopathy who have a normal vitamin B12 level while on replacement should be evaluated for copper deficiency. Physiologic role of copper. Copper is a component of enzymes that have a critical role in the structure and function of the nervous system.26 Copper permits electron transfer in key enzymatic pathways. These copper-associated enzymes include cytochrome c oxidase, copper/ zinc superoxide dismutase, tyrosinase, dopamine "-hydroxylase, lysyl oxidase, peptidylglycine !-amidating monooxygenase, monoamine oxidase, and ceruloplasmin. Neurologic manifestations of copper deficiency. The best-characterized neurologic manifestation of acquired copper deficiency is a myelopathy or myeloneuropathy that resembles the subacute combined degeneration seen with vitamin B12 deficiency.38,39 Investigations. Laboratory indicators of copper deficiency include decrease in serum copper or cerulo-

plasmin, and decrease in 24-hour urinary copper excretion. These parameters are not sensitive to marginal copper status and are inadequate for assessing body copper stores. Urinary copper declines only when dietary copper is very low. Changes in serum copper usually parallel the ceruloplasmin concentration. Ceruloplasmin is an acute-phase reactant, and the rise in ceruloplasmin is probably responsible for the increase in serum copper seen in conditions like pregnancy; oral contraceptive use; and various inflammatory, infectious, and systemic diseases. Such conditions could mask copper deficiency. Serum zinc and 24-hour urinary zinc excretion levels should be obtained; elevation in these levels should prompt a thorough search for an exogenous source of zinc. Hematologic manifestations of copper deficiency may be present and include anemia, neutropenia, and bone marrow evidence of left shift in granulocytic and erythroid maturation with cytoplasmic vacuolization in erythroid and myeloid precursors.38,39,44 Evoked potential studies may provide electrophysiologic evidence of posterior column or visual pathway dysfunction.38,39 Axonal loss predominates on nerve conduction studies. Spinal cord MRI may show increased T2 signal involving the dorsal column (Figure 4-2).38,39,45 This is similar to the spinal cord MRI changes seen in patients with vitamin B12 deficiency. The cervical cord is most commonly involved, and contrast enhancement is not present. Management. No studies that address the most appropriate dose, duration, route, and form of copper supplementation have been conducted. Despite a suspected absorption defect, oral copper supplementation is generally the preferred route of supplementation. In this author’s current practice, 8 mg/d of elemental copper is given



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FIGURE 4-2

Sagittal (A) and axial (B) cervical spine MRI from a patient with copper deficiency myelopathy showing a diffuse cord signal abnormality (arrows) involving the posterior aspect of the cord (dorsal column). Similar MRI findings are seen in vitamin B12 deficiencyYassociated myelopathy.

orally for 1 week, 6 mg/d for the second week, 4 mg/d for the third week, and 2 mg/d thereafter. Periodic assessment of serum copper is essential to determine adequacy of replacement. Because of the need for long-term replacement, parenteral therapy is not preferred and is generally not required. A commonly used initial parenteral regimen is 2 mg of elemental copper administered intravenously (over 2 hours) daily for 5 days. Response of the hematologic parameters (including bone marrow findings) is prompt and often complete.26,38,39 Recovery of neurologic signs and symptoms is variable. Normalization of serum copper with improvement in neurologic symptoms, electrophysiology, and imaging has been reported, but the more common outcome is cessation of progression. Improvement is often subjective and involves sensory symptoms. Periodic monitoring of copper status Continuum (Minneap Minn) 2014;20(3):580–597

should be considered in high-risk patients after bariatric surgery.3 Vitamin B6 (Pyridoxine) Vitamin B6 deficiency and bariatric surgery. Laboratory evidence of vitamin B6 deficiency has been recognized after bariatric surgery.19 Additional causes of vitamin B6 deficiency include gastrointestinal diseases associated with malabsorption and alcoholism. Individuals at risk of developing vitamin B6 deficiency include pregnant and lactating women and elderly individuals. Physiologic role of vitamin B6. Pyridoxal phosphate serves as a coenzyme in many reactions involved in the metabolism of amino acids, lipids, nucleic acid, and one-carbon units, in the pathways of gluconeogenesis, and neurotransmitter and heme biosynthesis. Neurologic manifestations of vitamin B6 deficiency. Adults are much more tolerant of pyridoxine deficiency www.ContinuumJournal.com


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h Folate deficiency following gastric bypass is a relatively rare occurrence, particularly so with routine vitamin supplementation.

than infants. In adults, even with low levels, symptoms are rare. Chronic vitamin B6 deficiency may result in a peripheral neuropathy. Other manifestations of vitamin B6 deficiency include microcytic hypochromic anemia, secondary hyperoxaluria and nephrolithiasis, glossitis, stomatitis, cheilosis, and dermatitis. Investigations. Vitamin B6 status can be assessed by measuring its levels in the blood or urine. The most commonly used measure is plasma pyridoxal phosphate. Functional indicators of vitamin B6 status are based on pyridoxal phosphateYdependent reactions. Management. Vitamin B6 may be supplemented in a dose of 50 mg/d to 100 mg/d to prevent development of the neuropathy. Higher doses of vitamin B6 have been associated with a sensory neuronopathy. Folate Folate deficiency and bariatric surgery. Folate deficiency following gastric bypass is a relatively rare occurrence, particularly so with routine vitamin supplementation.46,47 Clinical features of folate deficiency may occur more rapidly with low stores or coexisting alcoholism. Folate deficiency rarely exists in the pure state. It may coexist with other nutrient deficiencies. Hence, attribution of neurologic manifestations to folate deficiency requires exclusion of other potential causes. Serum folate falls within 3 weeks after decrease in folate intake or absorption, red blood cell folate declines weeks later, and clinically significant depletion of folate stores may be seen within months. Physiologic role of folate. Folate functions as a coenzyme or cosubstrate by modifying, accepting, or transferring one-carbon moieties in single-carbon reactions involved in the metabolism of nucleic and amino acids. The biologically active folates are in the tetrahydrofolate form. Methyl tetrahydrofolate is the

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predominant folate and is required for the cobalamin-dependent remethylation of homocysteine to methionine. Methylation of deoxyuridylate to thymidylate is mediated by methylene tetrahydrofolate. Impairment of this reaction results in accumulation of uracil that replaces the decreased thymine in nucleoprotein synthesis and initiates the process that leads to megaloblastic anemia. Neurologic manifestations of folate deficiency. Theoretically, folate deficiency could cause the same deficits as those seen with vitamin B12 deficiency because of its importance in the production of methionine, S-adenosyl-L-methionine, and tetrahydrofolate. For unclear reasons, neurologic manifestations like those seen in vitamin B12 deficiency are rare in folate deficiency. The myeloneuropathy, neuropathy, or megaloblastic anemia seen in association with folate deficiency is indistinguishable from vitamin B12 deficiency.26 The relationship between folate deficiency in pregnancy and neural tube defects is well established. Folate deficiency has been associated with affective disorders, cognitive impairment, and vascular disease, but the precise significance of these observations awaits further studies.26 Investigations. Plasma homocysteine levels have been shown to be elevated in patients with clinically significant folate deficiency. Serum folate fluctuates daily and does not correlate with tissue stores. Red blood cell folate is more reliable than plasma folate because its levels are less affected by short-term fluctuations in intake.26 However, red blood cell folate assay is subject to greater variation depending on the method and laboratory. Management. With documented folate deficiency, an oral dose of 1 mg three times a day may be followed by a maintenance dose of 1 mg/d. Acutely ill patients may need parenteral administration in a dose of 1 mg to 5 mg. A



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reasonable maintenance dose is 400 Hg/d. Coexisting vitamin B12 deficiency should be ruled out before instituting folate therapy. Plasma homocysteine is likely the best biochemical tool for monitoring response to therapy; it decreases within a few days of instituting folate therapy. Since folate deficiency is generally seen in association with a broader dietary inadequacy, the associated comorbidities need to be addressed. Vitamin E Vitamin E deficiency and bariatric surgery. Low vitamin E levels have been recognized following biliopancreatic diversion.48 Many years of malabsorption are required to deplete vitamin E stores. Additional causes of vitamin E deficiency include chronic cholestasis, pancreatic insufficiency, intestinal diseases associated with malabsorption, and inadequate supplementation in patients on total parenteral nutrition. Physiologic role of vitamin E. In humans, "-tocopherol is the active and most important biological form of vitamin E. Vitamin E serves as an antioxidant and prevents the formation of toxic free-radical products. Neurologic manifestations of vitamin E deficiency. The neurologic manifestations of vitamin E deficiency include a spinocerebellar syndrome with variable peripheral nerve involvement.26 The phenotype is similar to that of Friedreich ataxia. Investigations. Serum vitamin E levels are dependent on the concentrations of serum lipids, cholesterol, and very-lowdensity lipoprotein (VLDL). Hyperlipidemia or hypolipidemia can independently increase or decrease serum vitamin E without reflecting similar alterations in tissue levels of the vitamin.26 In patients with neurologic manifestations due to vitamin E deficiency, the serum vitamin E levels are often undetectable. Additional Continuum (Minneap Minn) 2014;20(3):580–597

markers of fat malabsorption, such as increased stool fat and decreased serum carotene levels, may be present. Spinal cord MRI of patients with vitamin E deficiencyYrelated myeloneuropathy may show increased signal in the cervical cord dorsal column.26 Management. The suggested supplementation in an asymptomatic postsurgical patient is a standard vitamin EYcontaining multivitaminmineral preparation. Higher doses are required in the presence of overt deficiency. Vitamin D Vitamin D and calcium deficiency and bariatric surgery. Laboratory evidence of vitamin D deficiency has been recognized after Roux-en-Y gastric bypass surgery.19 Obesity itself is associated with low levels of serum 25-hydroxyvitamin D (25[OH]D).18 Osteoporosis and osteomalacia have been reported as late effects of bariatric surgery.49 Aches and pains occurring 1 year after bypass surgery have been called ‘‘bypass bone disease.’’ Bone mineral density may be significantly decreased 3 to 9 months after Roux-en-Y gastric bypass.50 Physiologic role of vitamin D. Vitamin D exists in two forms: vitamin D2 (ergocalciferol, produced by plants) and vitamin D3 (cholecalciferol, derived from 7-dehydrocholesterol when exposed to ultraviolet light in the skin). Vitamin D functions more like a hormone than a vitamin. Sun-stimulated skin synthesis can provide 100% of the daily requirement from 7-dehydrocholesterol in the absence of oral intake. In the liver, vitamin D is hydroxylated to 25(OH)D. Further hydroxylation occurs in the kidney to 1,25(OH)D, the active form. With replete stores, 25(OH)D is hydroxylated to 24,25(OH)D and is excreted in the bile and urine.

KEY POINTS

h Low vitamin E levels have been recognized following biliopancreatic diversion.

h The neurologic manifestations of vitamin E deficiency include a spinocerebellar syndrome with variable peripheral nerve involvement.

h Laboratory evidence of vitamin D deficiency has been recognized after Roux-en-Y gastric bypass surgery. Obesity itself is associated with vitamin D deficiency.



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h Vitamin D deficiency can cause a proximal myopathy that often exists in association with osteomalacia, pathologic fractures, and bone pain.

h Vitamin D status is best assessed by serum 25-hydroxyvitamin D levels.

h Preoperative nutritional deficiencies in patients being worked up for bariatric surgery need to be identified and treated. After surgery, long-term follow-up with dietary counseling is important. Nutritional deficiencies may develop despite vitamin supplementation.

h The need for biochemical surveillance of nutritional status after surgery is particularly important in those who have had malabsorptive bariatric surgical procedures such as Roux-en-Y gastric bypass or biliopancreatic diversion.

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Clinical manifestations of vitamin D deficiency. Vitamin D deficiency results in defective mineralization of newly formed bone. Vitamin D deficiency results in hypocalcemia with secondary hyperparathyroidism that further impairs normal bone mineralization; this causes rickets in children and osteomalacia in adults. Vitamin D deficiency can cause a proximal myopathy that often exists in association with osteomalacia, pathologic fractures, and bone pain.26 The pelvic and thigh musculature is involved more than the arms. A waddling gait may be present. Neck muscles may be involved; bulbar and ocular muscles are spared. Hypovitaminosis D has been associated with persistent, nonspecific musculoskeletal pain in some studies but not in others. Severe hypocalcemia may result in tetany and may be associated with hypomagnesemia. Investigations. Vitamin D deficiency may be accompanied by decreased serum calcium and increased parathormone levels. Since 25(OH)D is hydroxylated to the active form, the level of 1,25(OH)D may be normal, whereas its immediate precursor may be very low. Hence, vitamin D status is best assessed by 25(OH)D levels. Other laboratory abnormalities may include raised alkaline phosphatase of bone origin, hypocalcemia, hypophosphatemia, raised parathormone, reduced urinary calcium excretion, and raised urinary hydroxyproline. Management. Vitamin D can be given orally as vitamin D2 or vitamin D3. In individuals with minimal sun exposure, 400 IU/d of vitamin D is adequate to prevent deficiency. With clinical deficiency, 50,000 IU weekly of vitamin D2 or vitamin D3 may be required for 6 to 8 weeks. This may be followed by 800 IU/d to 1000 IU/d. Larger oral doses (or even parenteral administration) may also be required

in the presence of malabsorption. Associated secondary hyperparathyroidism can cause hypercalcemia, hypercalciuria, and nephrolithiasis. This can be prevented by ensuring that calcium repletion is adequate, thus avoiding parathyroid stimulation. MANAGEMENT Prevention, diagnosis, and treatment of neurologic disorders related to bariatric surgery are necessary elements of lifelong care after bariatric surgery.1,3,15 Preoperative nutritional deficiencies need to be identified and treated. Patients who have been dieting may be at higher risk for postoperative deficiencies because of lower reserves.15 Long-term follow-up with dietary counseling is important. Nutritional deficiencies may develop despite vitamin supplementation. The need for biochemical surveillance of nutritional status after surgery is particularly important in those who have had malabsorptive bariatric surgical procedures like Roux-en-Y gastric bypass or biliopancreatic diversion.1,3 Patients who have undergone Roux-en-Y gastric bypass need surveillance every 3 to 6 months for the first year and annually thereafter. For patients who have undergone biliopancreatic diversion, the suggested monitoring frequency is every 3 months for the first year and every 3 to 6 months thereafter. Laboratory studies should include complete blood count, platelets, electrolytes, glucose, iron, vitamin B12, vitamin D, parathyroid hormone, liver function, and lipid profile. Additional laboratory testing may include vitamin A, thiamine, copper, zinc, and selenium. Oral supplementation containing the recommended daily allowance for micronutrients can prevent abnormal blood indicators of most vitamins and minerals but are insufficient to maintain



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Mineral Supplementation Following TABLE 4-5 Daily Vitamin and Bariatric Surgerya Vitamin/Mineral

Dose

Vitamin B12

350Y500 2g of the oral crystalline form; some patients may need monthly IM injections of 1000 2g

Folic acid

400Y800 2g

Vitamin D

800Y1200 IU

Iron

65Y130 mg

Calcium citrate

1200Y2000 mg

Thiamine

50Y100 mg

Copper

2 mg

Vitamin A

5000Y10,000 IU

Vitamin E

400 IU

Vitamin K

300 2gY1 mg

a

Indefinite use of vitamin and mineral supplements is required after malabsorptive procedures like Roux-en-Y gastric bypass. Standard multivitamin and mineral preparations may be inadequate sources of iron and vitamin B12. Supplementation with vitamins A, E, and K is required in patients who have undergone biliopancreatic diversion with duodenal switch. No formal recommendations exist regarding copper supplementation. Zinc supplementation may increase the risk of copper deficiency.

normal plasma vitamin B12 levels in approximately 30% of gastric bypass patients. Indefinite use of the daily supplements noted in Table 4-5 has been suggested.1,10 Much of this vitamin and mineral supplementation can be obtained from a multivitaminmineral preparation. Supplements should not be time-release or entericcoated formulations since most bariatric surgery patients have impaired gastric phase digestion.18 Liquid, suspensions, or chewable preparations are ideal. Patients who have had a biliopancreatic diversion with or without the duodenal switch should also take daily doses of fat-soluble vitamins (vitamin A, vitamin E, and vitamin K) as indicated in Table 4-5. Most multivitamins have 2 mg of copper. Correction of a particular deficiency may not result in reversal of the neurologic manifestation. Gradual clinical improvement or stabilization may be seen. In some cases, improveContinuum (Minneap Minn) 2014;20(3):580–597

ment may be seen only following surgical revision. REFERENCES 1. Mechanick JI, Kushner RF, Sugerman HJ, et al. American Association of Clinical Endocrinologists, The Obesity Society, and American Society for Metabolic & Bariatric Surgery Medical guidelines for clinical practice for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient. Endocr Pract 2008;14(suppl 1):1Y83. 2. Buchwald H. Metabolic surgery: a brief history and perspective. Surg Obes Relat Dis 2010;6(2):221Y222. 3. Mechanick JI, Youdim A, Jones DB, et al. Clinical practice guidelines for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patientV2013 update: cosponsored by American Association of Clinical Endocrinologists, The Obesity Society, and American Society for Metabolic & Bariatric Surgery. Obesity (Silver Spring) 2013;21 (suppl 1):S1YS27. 4. Abarbanel JM, Berginer VM, Osimani A, et al. Neurologic complications after gastric restriction surgery for morbid obesity. Neurology 1987;37(2):196Y200. www.ContinuumJournal.com


595

Bariatric Surgery

5. Berger JR. The neurological complications of bariatric surgery. Arch Neurol 2004;61(8): 1185Y1189. 6. Koffman BM, Greenfield LJ, Ali II, Pirzada NA. Neurologic complications after surgery for obesity. Muscle Nerve 2006;33(2):166Y176. 7. Juhasz-Pocsine K, Rudnicki SA, Archer RL, Harik SI. Neurologic complications of gastric bypass surgery for morbid obesity. Neurology 2007;68(21):1843Y1850. 8. Kazemi A, Frazier T, Cave M. Micronutrientrelated neurologic complications following bariatric surgery. Curr Gastroenterol Rep 2010;12(4):288Y295. 9. Ba F, Siddiqi ZA. Neurologic complications of bariatric surgery. Rev Neurol Dis 2010;7(4): 119Y124. 10. Becker DA, Balcer LJ, Galetta SL. The neurological complications of nutritional deficiency following bariatric surgery. J Obes 2012;2012:608534. 11. Frantz DJ. Neurologic complications of bariatric surgery: involvement of central, peripheral, and enteric nervous systems. Curr Gastroenterol Rep 2012;14(4):367Y372. 12. Thaisetthawatkul P, Collazo-Clavell ML, Sarr MG, et al. A controlled study of peripheral neuropathy after bariatric surgery. Neurology 2004;63(8):1462Y1470. 13. Singh S, Kumar A. Wernicke encephalopathy after obesity surgery. Neurology 2007;68(11): 807Y811. 14. Clark N. Neuropathy following bariatric surgery. Semin Neurol 2010;30(4):433Y435. 15. Rudnicki SA. Prevention and treatment of peripheral neuropathy after bariatric surgery. Curr Treat Options Neurol 2010;12(1):29Y36. 16. McGlinch BP, Que FG, Nelson JL, et al. Perioperative care of patients undergoing bariatric surgery. Mayo Clin Proc 2006;81 (10 suppl):S25YS33.

22. Elias WJ, Pouratian N, Oskouian RJ, et al. Peroneal neuropathy following successful bariatric surgery. Case report and review of the literature. J Neurosurg 2006;105(4): 631Y635. 23. Foster D, Falah M, Kadom N, Mandler R. Wernicke encephalopathy after bariatric surgery: losing more than just weight. Neurology 2005;65(12):1987; discussion 1847. 24. Thomson AD, Marshall EJ. The natural history and pathophysiology of Wernicke’s Encephalopathy and Korsakoff’s Psychosis. Alcohol Alcohol 2006;41(2):151Y158. 25. Sechi G, Serra A. Wernicke’s encephalopathy: new clinical settings and recent advances in diagnosis and management. Lancet Neurol 2007;6(5):442Y455. 26. Kumar N. Neurologic presentations of nutritional deficiencies. Neurol Clin 2010; 28(1):107Y170. 27. Kumar N. Acute and subacute encephalopathies: deficiency states (nutritional). Semin Neurol 2011;31(2): 169Y183. 28. Koike H, Ito S, Morozumi S, et al. Rapidly developing weakness mimicking Guillain-Barre´ syndrome in beriberi neuropathy: two case reports. Nutrition 2008;24(7Y8):776Y780. 29. Homewood J, Bond NW. Thiamin deficiency and Korsakoff’s syndrome: failure to find memory impairments following nonalcoholic Wernicke’s encephalopathy. Alcohol 1999;19(1):75Y84. 30. Zuccoli G, Motti L. Atypical Wernicke’s encephalopathy showing lesions in the cranial nerve nuclei and cerebellum. J Neuroimaging 2008;18(2):194Y197.

17. Aasheim ET. Wernicke encephalopathy after bariatric surgery: a systematic review. Ann Surg 2008;248(5):714Y720.

31. Thomson AD, Marshall EJ. The treatment of patients at risk of developing Wernicke’s encephalopathy in the community. Alcohol Alcohol 2006;41(2):159Y167.

18. Xanthakos SA. Nutritional deficiencies in obesity and after bariatric surgery. Pediatr Clin North Am 2009;56(5):1105Y1121.

32. Sechi G. Prognosis and therapy of Wernicke’s encephalopathy after obesity surgery. Am J Gastroenterol 2008;103(12):3219.

19. Clements RH, Katasani VG, Palepu R, et al. Incidence of vitamin deficiency after laparoscopic Roux-en-Y gastric bypass in a university hospital setting. Am Surg 2006; 72(12):1196Y1202; discussion 1203Y1194.

33. Green R, Kinsella LJ. Current concepts in the diagnosis of cobalamin deficiency. Neurology 1995;45(8):1435Y1440.

20. Malinowski SS. Nutritional and metabolic complications of bariatric surgery. Am J Med Sci 2006;331(4):219Y225.

596

21. Ernst B, Thurnheer M, Schmid SM, Schultes B. Evidence for the necessity to systematically assess micronutrient status prior to bariatric surgery. Obes Surg 2009;19(1):66Y73.

34. Carmel R. Current concepts in cobalamin deficiency. Annu Rev Med 2000;51:357Y375. 35. Carmel R, Green R, Rosenblatt DS, Watkins D. Update on cobalamin, folate, and



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homocysteine. Hematology Am Soc Hematol Educ Program 2003:62Y81. 36. Stabler SP. Vitamin B12 deficiency. N Engl J Med 2013;368(21):2041Y2042. 37. Kumar N, Ahlskog JE, Gross JB Jr. Acquired hypocupremia after gastric surgery. Clin Gastroenterol Hepatol 2004;2(12): 1074Y1079. 38. Kumar N, Gross JB Jr, Ahlskog JE. Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration. Neurology 2004;63(1):33Y39. 39. Kumar N. Copper deficiency myelopathy (human swayback). Mayo Clin Proc 2006;81(10):1371Y1384. 40. Prodan CI, Bottomley SS, Holland NR, Lind SE. Relapsing hypocupraemic myelopathy requiring high-dose oral copper replacement. J Neurol Neurosurg Psychiatry 2006;77(9): 1092Y1093. 41. Spinazzi M, De Lazzari F, Tavolato B, et al. Myelo-optico-neuropathy in copper deficiency occurring after partial gastrectomy. Do small bowel bacterial overgrowth syndrome and occult zinc ingestion tip the balance? J Neurol 2007;254(8):1012Y1017. 42. Jaiser SR, Winston GP. Copper deficiency myelopathy. J Neurol 2010;257(6):869Y881. 43. Henri-Bhargava A, Melmed C, Glikstein R, Schipper HM. Neurologic impairment due to vitamin E and copper deficiencies in celiac

Continuum (Minneap Minn) 2014;20(3):580–597

disease. Neurology 2008;71(11):860Y861. 44. Kumar N, Elliott MA, Hoyer JD, et al. ‘‘Myelodysplasia,’’ myeloneuropathy, and copper deficiency. Mayo Clin Proc 2005;80(7):943Y946. 45. Kumar N, Ahlskog JE, Klein CJ, Port JD. Imaging features of copper deficiency myelopathy: a study of 25 cases. Neuroradiology 2006;48(2):78Y83. 46. Mallory GN, Macgregor AM. Folate status following gastric bypass surgery (the Great Folate Mystery). Obes Surg 1991;1(1): 69Y72. 47. Vargas-Ruiz AG, Hernandez-Rivera G, Herrera MF. Prevalence of iron, folate, and vitamin B12 deficiency anemia after laparoscopic Roux-en-Y gastric bypass. Obes Surg 2008;18(3):288Y293. 48. de Luis DA, Pacheco D, Izaola O, et al. Clinical results and nutritional consequences of biliopancreatic diversion: three years of follow-up. Ann Nutr Metab 2008;53(3Y4): 234Y239. 49. Crowley LV, Seay J, Mullin G. Late effects of gastric bypass for obesity. Am J Gastroenterol 1984;79(11):850Y860. 50. Coates PS, Fernstrom JD, Fernstrom MH, et al. Gastric bypass surgery for morbid obesity leads to an increase in bone turnover and a decrease in bone mass. J Clin Endocrinol Metab 2004;89(3):1061Y1065.



597

The neurologic complications of bariatric surgery.

Neurological Complications of Bariatric Surgery.

Neurological complications of bariatric surgery.

Neurological complications of bariatric surgery.

Gastrointestinal Complications After Bariatric Surgery.

Management of complications following bariatric surgery: summary.

[Management of complications in bariatric surgery].

Autopsy following complications of bariatric surgery.

Endoscopic management of post-bariatric surgery complications.

Critical Care Management of Bariatric Surgery Complications.

Complications from micronutrient deficiency following bariatric surgery.

COMPLICATIONS REQUIRING HOSPITAL MANAGEMENT AFTER BARIATRIC SURGERY.

Neurologic complications of aortic diseases and aortic surgery.

[Neurologic complications of coronary bypass surgery--a prospective study].

Neurologic complications of surgery for cervical compression myelopathy.

Complications of pre-operative anorexia nervosa in bariatric surgery.

Complications of bariatric surgery: dumping syndrome, reflux and vitamin deficiencies.

Neurologic complications of vaccinations.

Pregnancy Following Bariatric Surgery-Medical Complications and Management.

Neurologic complications of alcoholism.

Neurologic Complications and Treatment.

Neurologic complications of intestinal transplantation.

Neurologic complications of lung cancer.

Neurologic complications of arrhythmia treatment.