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Home , Hypokalemia

Case in Point Parkinsonism and C Deficiency

Thomas M. Brown, MD

Patients with vitamin C deficiencies and parkinsonism can show rapid improvement with vitamin C replacement therapy.

itamin C (ascorbic acid) de- which had not been present in ex- of the right hand tremor and cog- ficiency is known to affect aminations conducted in the pre- wheeling 20 hours after starting the brain function and is associ- vious 3 years. Mr. A had no prior vitamin C IV. Mr. A refused a repeat V ated with parkinsonism.1 In history of a tremor. He had no cer- serum vitamin C assay. 1752, James Lind, MD, described ebellar findings and no evidence Laboratory studies initially re- emotional and behavioral changes of asterixis or of tremulousness as- vealed that Mr. A had that herald the onset of and sociated with high-output cardiac with a serum of 121 mmol/L precede hemorrhagic findings.2 The states, such as de Musset sign. (normal range: 133 to 145 mmol/L) World Health Organization (WHO) Mr. A reported he had experi- as well as hypokalemia with a serum today refers to this stage as latent enced the tremor for a month and of 3.2 mmol/L (normal scurvy.3 The 2 case studies that fol- that it had been worsening. He also range: 3.5 to 5.0 mmol/L). He was low present examples of patients was having difficulty using his dom- hypoosmolar, with a serum osmolal- with vitamin C deficiencies whose inant right hand, for routine daily ity of 276 mOsm/kg (normal range: parkinsonism responded robustly activities. Mr. A was oriented, and 278 to 305 mOsm/kg). His vitamin C to vitamin C replacement. These his short-term memory was intact. level was low at 0.2 mg/dL (normal cases suggest that vitamin C defi- He was ill-appearing, irritable with range: 0.4 to 2.0 mg/dL). Mr. A also ciency may be a treatable cause of psychomotor slowing, and did not had a serum vitamin C level drawn parkinsonism. wish to rise from his bed. He had 2 years prior that showed no symp- no gingival or periungual bleeding toms of EPS, and at that time, the CASE 1 and did not bruise easily. He had no reading was 0.7 mg/dL. At admis- Mr. A, a 60-year-old white male, was corkscrew hairs. The patient was sion to Services, Mr. A had admitted to the Medicine Service started on no medications known a serum alcohol level of 211 mg/dL. for alcohol detoxification. The pa- to cause extrapyramidal symptoms Neuroimaging revealed diffuse cere- tient had a history of alcohol depen- (EPS). bral and cerebellar volume loss. dence, alcohol withdrawal seizures, In the hospital, the tremor per- Normal laboratory results in- tobacco dependence, and hyperlip- sisted unabated for 2 days. On the cluded serum levels of vitamin B12, idemia. He took no medications as third day, Mr. A was started on red cell folate, homocysteine, methyl- an outpatient. On admission Mr. A’s 1,000 mg vitamin C IV twice daily. malonic acid, free and total carnitine, body mass index (BMI) was 27.2. He received a total of 2,000 mg IV alkaline phosphatase, manganese, An initial examination revealed a that day, but the IV fell out, and and zinc. A urine drug screen was marked resting tremor of the pa- he refused its replacement. Several negative. tient’s right hand with cogwheeling, hours later, Mr. A stated that he felt much better, got out of bed, and CASE 2 Dr. Brown is a mental/behavioral health psychia- trist at Audie L. Murphy Memorial VAMC in San asked to go outside to smoke. The Mr. B, a 69-year-old black male, Antonio, Texas. author noted complete resolution was admitted to the hospital for

28 • FEDERAL PRACTITIONER • AUGUST 2017 www.fedprac.com depression complicated by alcohol dependence. He also had tobacco Table 1. Proposed Criteria for a Diagnosis of dependence, type 2 diabetes mel- Neuropsychiatric Scurvy litus, , and gout. The patient’s BMI at admission was For a diagnosis of neuropsychiatric scurvy, the patient must satisfy each of the 16.1. Mr. B appeared ill, was wor- following 3 criteria: ried about his health, and remained 1. The patient has either a or b: recumbent unless asked to move. a. Psychomotor retardation plus evidence of an affective disturbance (either apathy, He reported that his right hand had anxiety, or irritability); begun to shake at rest in the month b. Extrapyramidal findings. 2. The patient has some systemic evidence of hypovitaminosis C as manifested by either: prior to admission. The tremor a. Some disturbance of collagen metabolism, such as classic hemorrhagic findings or made it difficult for him to drink. corkscrew hairs; He pointed out stains on his hospi- or tal gurney from an attempt to drink b. Biochemical evidence of deficiency, such as a low serum vitamin C level. orange juice prior to being assessed. 3. The above findings respond to replacement of vitamin C. A physical examination revealed a distinct resting tremor with cog- wheeling of the right hand; there was no other evidence of EPS, nor acting with others. Mr. B said he felt suggests that neuropsychiatric find- was there evidence of cognitive, cer- he was “doing well.” A repeat serum ings precede the hemorrhagic.6 In- ebellar, or skin abnormalities, such vitamin C level was 0.2 mg/dL on deed, classic skin findings, such as as hemorrhages or corkscrew hairs. that day. The improvement was sus- petechiae or corkscrew hairs, may Asterixis was absent as was evi- tained over 3 days, and Mr. B was develop years after the onset of neu- dence of a high-output cardiac state discharged to home. ropsychiatric changes.7,8 that might produce a tremor, such Despite WHO characterizing it as as de Musset sign. A serum vitamin DISCUSSION latent scurvy, the distinct syndromal C level was obtained and returned Both Mr. A and Mr. B presented with presentation of hypovitaminosis C at 0.0 mg/dL. A head computed to- a typical picture of latent scurvy and with parkinsonism along with the mography scan obtained the next the additional finding of parkinson- rapid response to vitamin C replace- day revealed mild cerebellar vol- ism. These cases are important for ment argues for its recognition as a ume loss. A serum alkaline phos- 2 reasons. First, the swift and full distinct clinical entity and not just a phatase level was elevated slightly response of these patients’ parkin- prelude to the hemorrhagic state. To at 136 U/L (normal range: 42 to sonism to vitamin C replacement assist in recognizing neuropsychiatric 113 U/L). Normal serum values were underscores the importance of con- scurvy, the author suggests the op- returned for zinc, B12 and sidering a vitamin C deficiency when erationalized approach described in folate, rapid plasma reagin, sodium, confronted with EPS. And second, Table 1.9 and serum osmolality. A urine drug both patients lacked signs of bleed- screen was negative, and serum alco- ing or of impaired collagen synthesis. Pathophysiology hol level was < 5.0 mg/dL. This differs from the classic presenta- Vitamin C has an intimate role in the Mr. B took no medications ex- tion of scurvy as a disorder primarily normal functioning of the basal gan- pected to cause EPS. He received no of collagen metabolism.4 glia. It is involved in the synthesis of micronutrient replacement until the Lind described the onset of scurvy catechecholamines, the regulation of day after admission when he began as one in which striking emotional the release and postsynaptic activi- receiving oral vitamin C 1,000 mg and behavior changes developed ties of various neurotransmitters, and twice a day. After receiving 3 doses, and later were followed by abnor- managing the oxyradical toxicity of Mr. B’s resting tremor and cogwheel- mal bleeding and even death.2 These aerobic metabolism. Table 2 outlines ing completely resolved. He noticed early changes also were recognized some of the normal brain functions he had stopped shaking and could by Shapter in 1847.5 Furthermore, of vitamin C and the potential con- now drink without spilling fluids. He the evidence that exists about the sequences of inadequate central vita- also got out of bed and began inter- time-course of scurvy’s development min C.9,10 Risk factors for vitamin C

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best known as inherited disorders of Table 2. Suspected Pathophysiologic Factors in metabolism.21 Manganese intoxica- Neuropsychiatric Scurvy tion also may present as a movement disorder.22 Vitamin C Actions Result of Reduced Vitamin C Availability

Cofactor in synthesis Reduced production of Treatment Treatment of neuropsychiatric scurvy Inhibits acetycholine release in rabbit Potential to disinhibit acetylcholine release and has relied on IV administration of vi- caudate nucleus promote EPS tamin C. Although the bioavailabil- ity of oral vitamin C among healthy Regulates postsynaptic actions of GABA Loss of this regulatory factor may tend to adult volunteers is nearly complete and glutamate promote EPS up to about 200 mg a day, a patient Antioxidant Loss of antioxidant activity may replicate the with neuropsychiatric scurvy may pathophysiology of Parkinson disease need substantially more than that amount to accommodate total body Abbreviations: EPS, extrapyramidal symptoms; GABA, gamma-aminobutyric acid. deficiencies and increased demands.23 The IV route allows serum vitamin C levels up to 100 times higher than by deficiency include those affecting the C levels even as target tissue levels the oral route.24 Mr. B is, in fact, the uptake, response to, and elimination fall. An interesting example of this first person reported in the literature of this vitamin (Table 3).11-14 is the 0.2 mg/dL value that each pa- with neuropsychiatric scurvy to re- The potential role of alcohol use tient registered. In Mr. A’s case, this spond to oral vitamin C replacement by both patients also warrants men- reflected a systemic deficit of vitamin alone. Once repletion of vitamin C tion. Current data suggest a nonlin- C, while in Mr. B’s case it correlated is complete, it is useful to consider a ear relationship between alcohol use with the onset of effective repletion maintenance replacement dose based and neurotoxicity. Epidemiologic of body’s stores. on a patient’s risk factors and needs. data show that moderate alcohol con- A fall in urinary output of vitamin A healthy adult should ingest sumption protects against the devel- C is another marker of hypovitamin- about 120 mg of vitamin C daily. opment of such neurodegenerative osis C. When available, this labora- Smokers and pregnant women may processes as Parkinson disease and tory test can be used with the serum require more, but this recommenda- Alzheimer disease.15,16 But the cases level to assess total body stores of vi- tion was intended to address their here reflect excessive use of alcohol. tamin C. Lymphocytes, neutrophils, needs as well.25 Many commercial In this situation, a variety of progres- and platelets also store vitamin C. multivitamins use the old recom- sive insults, such as those caused by These target tissues tend to saturate mended daily allowance of 60 mg, oxyradical toxicity as well as malnu- when the oral intake ranges between so it may be safest to recommend trition may foster the development of 100 mg to 200 mg a day. This is the specifically a vitamin C tablet with basal ganglia dysfunction.17 same point at which serum vitamin at least 120 mg when ordering vita- C levels peak and level off in normal, min C replacement. Measuring Deficiency healthy adults.18,19 Once again, the Tight control of the serum vita- A deficiency of vitamin C may be de- limited availability of target-tissue as- min C concentration means that termined in several ways. The most says puts these studies out of reach little additional vitamin C will be frequently used laboratory measure for most clinicians. taken up by the gut beyond 200 mg of vitamin C status is the serum vi- No evaluation is complete without orally a day, which helps minimize tamin C level. This level is included some assurance of what the disease any concerns about long-term tox- in the WHO’s recommendations is not. Deficiencies of biotin, zinc, icity. It takes several weeks to de- for diagnosis.3 However, this assay folate, and B12 all may affect the plete vitamin C from the human is limited because when facing total function of the basal ganglia.20 The body when vitamin C is removed body depletion, the kidneys may re- biotin deficiencies literature is par- from the diet, so a patient with a strict the elimination of vitamin C ticularly robust. Biotin deficiencies previously treated deficiency of and tend to maintain serum vitamin affecting basal ganglia function are vitamin C should wait a month

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Table 3. Patient-Specific Risk Factors for Vitamin C Deficiency

Factors That Decrease Availability Factors That Cause Tissue Resistance or or Uptake Increase Demand Factors That Accelerate Elimination

• or starvation • Hypoosmolar state • Smoking: may double the normal rate • Gut disease, including Crohn • Hyponatremia of vitamin C consumption disease and celiac disease • Acidosis • : enhance renal elimination of • Severe psychiatric illness affecting • resistance or deficiency water-soluble vitamins food intake • Stress or catabolic states (eg, healing, burns, • Alcohol: speeds elimination of • Hypotestosteronemia: a cause of pregnancy, , infection) vitamin C anorexia • Inflammatory states (eg, infection, peripheral arterial • Oral contraceptives: reduce serum •  or substance abuse disease) vitamin C levels • Food allergies and related • Oxidizing medications (eg, benzocaine, dapsone, lidocaine, • Renal insufficiency: can markedly disorders (eg, atopic dermatitis) , metoclopramide) reduce the ability to recapture • Processed foods • Hypotestosteronemia water-soluble vitamins Promotes catabolism • : removes water-soluble Promotes insulin resistance vitamins • Genetic variation in vitamin C uptake and use before a repeat serum vitamin C level although these cases are rare.28 Fur- end-stage case of the disease.31 In the measurement. thermore, some authors advocate right clinical setting, it is reasonable The half life of vitamin C is nor- for the use of ascorbic acid to treat to think of a vitamin C deficiency mally ≤ 2 hours. When renal func- methemoglobinemia associated with before the patient develops bleeding tion is intact, vitamin C in excess of G6PD deficiency, when methylene gums and corkscrew hairs. And as immediate need is lost through renal blue is not available.29 It may be rea- is typical of vitamin deficiencies, the filtration. Toxicity is rare under these sonable to begin treatment with oral treatment of a vitamin C deficiency conditions.26 When vitamin C toxic- vitamin C for patients with NPS and usually results in swift improvement. ity has been reported, it has occurred G6PD deficiency. This is equivalent Finally, for those who treat move- in the setting of prolonged supple- to a low-dose form of vitamin C re- ment disorders or who prescribe mentation, usually when a patient al- placement and may help avoid the agents such as antipsychotics that ready experienced a renal injury. The theoretically pro-oxidant effects of may cause movement disorders, it is main toxicities attributed to vitamin larger, IV doses of vitamin C.30 important to recognize vitamin C de- C are oxalate crystal formation with ficiency as another potential explana- subsequent renal injury and exacer- CONCLUSION tion for EPS. ● bation of glucose 6- dehy- The recent discovery of movement drogenase deficiency (G6PD).24 disorders in scurvy has enlarged the Author disclosures Oxalate formation due to vitamin picture of vitamin C deficiency. The The author reports no actual or poten- C replacement is uncommon, but pa- cases here demonstrate how hypo- tial conflicts of interest with regard to tients with preexisting calcium oxa- vitaminosis C with central nervous this article. late stones may be at risk for further system manifestations may be iden- stone formation when they receive tified and treated. This relationship Disclaimer additional vitamin C.27 This is most fits well within the established basic The opinions expressed herein are those likely to occur when treatment with science and clinical framework for of the author and do not necessarily parenteral vitamin C is prolonged, scurvy, and the clinical implications reflect those of Federal Practitioner, which is not typical for patients with for scurvy remain in many ways un- Frontline Medical Communications neuropsychiatric scurvy who tend to changed. First, must Inc., the U.S. Government, or any of its respond rapidly to vitamin C replen- be considered even when a patient’s agencies. This article may discuss un- ishment. Reports of acute hemolytic habitus suggests he is well fed. Also, labeled or investigational use of certain episodes among patient with G6PD it is more likely to see scurvy with- drugs. Please review the complete pre- deficiency receiving vitamin C exist, out all of the classic findings than an scribing information for specific drugs

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