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Catatonia

Another Neuropsychiatric Presentation of Vitamin B₁₂ Deficiency?

Received June 17, 1997; revised September 4, 1997; accepted September 23, 1997. From the Department of Psychiatry and Behavioral Medicine, University of South Florida College of Medicine, Tampa; the Psychiatry Service, James A. Haley Veterans' Hospital, Tampa, Florida; the Department of Internal Medicine, University of Florida College of Medicine, Gainesville; and the Department of Internal Medicine, Oregon Health Science University, Portland. Address reprint requests to Dr. G. Catalano, TGH-University Psychiatry Center, 3515 East Fletcher Avenue, Tampa, FL 33613.

Key Words: Catatonia • Vitamins • Cobalamin

The recommended amount of vitamin B₁₂ for an adult is roughly 2.5 µg per day. Since vitamin B₁₂ is only produced by specific microorganisms, it must be obtained by eating dairy products, fish, or meat.¹ In a study of nonvegetarians with vitamin B₁₂ deficiency, 27% of the subjects had a dietary deficiency.² Vitamin B₁₂ deficiency may take years to develop in previously healthy individuals³ and takes much longer to develop than folate deficiency secondary to the ratio of each vitamin's requirement relative to the body's stores.^4,5 Vitamin B₁₂ deficiency should be considered in patients with either nutritional or absorption problems.³ In studies of general psychiatric inpatients, the incidence of vitamin B₁₂ deficiency has ranged between 4% and 6%.^6,7

Decreased levels of vitamin B₁₂ are associated with anemia and an increased mean corpuscular volume (MCV). However, a patient may be vitamin B₁₂-deficient despite normal hematological indices. In one study, 28% of the patients with vitamin B₁₂ deficiency had normal hematocrit, MCV, and mean corpuscular hemoglobin content.⁸ Goodkin et al. suggest that cobalamin deficiency be assessed by increased serum homocysteine and methylmalonate levels, as elevation in one of these tests would mean a true state of significant cobalamin deficiency.⁹ Vitamin B₁₂ is a cofactor in the pathway changing homocysteine to methionine,¹⁰ and with vitamin B₁₂ deficiency, homocysteine levels could rise, resulting in homocystinuria¹¹ and possible central nervous system toxicity.¹² However, these tests are not routinely performed in most hospitals, and there can be lengthy delays before results are available from outside laboratories.

The role of vitamin B₁₂ in neuropsychiatric illness remains under study. Herbert felt that the neurologic effects of vitamin B₁₂ deficiency are likely due to homocysteine toxicity.¹² Steiner et al. postulated that some of the neurologic damage is secondary to an autoimmune neuronal demyelinization.¹³ Dommisse felt that a possible cause of mood disorders due to vitamin B₁₂ deficiency is axonal degeneration and nerve-sheath demyelination, especially in the median forebrain bundle area.¹⁴ Shorvon et al. found that peripheral neuropathy was the most common neurologic manifestation⁴ and that it occurred in 40% of vitamin B₁₂-deficient patients. The only mental status abnormalities noted by Addison in his description of pernicious anemia were delirium and confusion.¹⁵ Dommisse felt that B₁₂ deficiency was the cause of "a significant proportion" of diagnosed cases of Alzheimer's disease, mood disorders, and paranoid psychosis.¹⁴ Zucker et al. found that the most common psychiatric sequelae were depression, violence, paranoia, and organic brain syndrome.¹⁶ The researchers also noted that vitamin B₁₂ deficiency can cause a condition indistinguishable from a bipolar disorder.¹⁶ Published reports disagree whether vitamin B₁₂ deficiency is a significant cause of dementia.^17–19

We now report a case of catatonia associated with vitamin B₁₂ deficiency.

Case Report

The patient was a 59-year-old man who was brought to the Emergency Department (ED) by his family because of worsening mental and physical status. His mental status had deteriorated over the previous 2 months. He had poor concentration; psychomotor retardation; and slow, slurred speech. The patient was having increasing difficulty walking, with significant worsening in the 3 days before this visit.

The patient's psychiatric history was significant only for "behavioral changes" that began after a closed head injury in 1973. These behaviors were controlled with chlorpromazine (200 mg qhs) until 3 months prior, when he was switched to risperidone (3 mg bid) for unknown reasons. He was noted to be compliant with his medication regimen. The patient was examined by his psychiatrist on the day before this ED visit. The patient was noted to be lethargic and to have slurred speech and decreased concentration. He had a shuffling gait and cogwheeling of his extremities. The risperidone was discontinued, and the patient was switched back to chlorpromazine (200 mg qhs). He had received only one dose of chlorpromazine before his return to the ED the next morning, when his condition had further deteriorated.

Upon presentation to the ED, he was described as catatonic. He was stuporous, with greatly slowed movements and waxy flexibility. He displayed masked facies, a flat affect, odd posturing, and a depressed mood. He had slow, dysarthric speech, although he was also described as mute by others in the ED. The rest of the physical examination was remarkable only for a moderate tachycardia, decreased strength, and upper extremity cogwheeling. The patient was afebrile, had a normal blood pressure, and was not diaphoretic. The patient's medical history was significant for chronic back pain, congestive heart failure, and a myocardial infarction in the distant past. There was no history of gastrointestinal surgery or of absorption difficulties. His other medications were furosemide, propoxyphene, and ibuprofen. His family noted that he had a long history of poor dietary intake and of eating only foods with poor nutritional value.

Upon admission, all of his medications were discontinued and further laboratory studies were obtained. The only significant abnormalities on the initial blood-chemistry panel were an elevated LDH (lactate dehydrogenase) of 6,511 u/L and an elevated CPK (creatine phosphokinase) of 174 u/L. The alcohol and drug screens were both negative, and the electrocardiogram was significant only for tachycardia.

A computed tomography scan of the head without contrast was normal, as were the results of a lumbar puncture. Blood, urine, and cerebrospinal cultures were negative, as was the syphilis screen. Thyroid-function tests were within normal limits. An arterial blood-gas analysis revealed an increased pH of 7.49 units, a low PO₂ of 72 mmHg and a low PCO₂ of 31 mmHg on room air.

Results of the patient's complete blood count revealed a macrocytic anemia of 101 fL and pancytopenia with a peripheral smear showing moderate poikilocytosis and anisocytosis. The white count was low at 2.9 k/µL; hemoglobin and hematocrit were decreased at 4.4 g/dL and 12.4%, respectively; and the platelet count was decreased at 62 k/µL. The reticulocyte count was 1.9%.

The patient was immediately transfused and received 6 units of packed red-blood cells. His hemoglobin level increased to 10.2 g/dL without significant clinical improvement. Further laboratory tests were obtained to find the cause of the pancytopenia.

Iron studies revealed a decreased total iron-binding capacity of 215 µg/dL, an increased percent saturation of 53.5%, an increased ferritin level of 314 ng/mL, and a normal iron level. Intrinsic factor, parietal cell antibody, and HIV (human immunodeficiency virus) antibody screens were negative. The patient's folate level was within normal limits, but his vitamin B₁₂ level was markedly decreased at 1.07 pg/mL (normal range: 220–1,140). The team felt that this low vitamin B₁₂ level explained the patient's mental status changes.

The patient was immediately started on vitamin B₁₂ (1,000 µg intramuscularly daily) to correct his deficiency. As the vitamin supplementation progressed, the patient's condition improved. His mental status cleared, and he became alert, active, and fully oriented. By the day of discharge (Hospital Day 16), the patient was speaking spontaneously in sentences, had a wide emotional range, and was interacting with the other patients. He was able to ambulate on his own, with improved balance and coordination. His waxy flexibility and cogwheel rigidity disappeared. There were no psychotic or depressive symptoms seen. Bone-marrow biopsy and Schilling test were not pursued because of the patient's robust response to the vitamin B₁₂ supplementation. The team felt that the patient's low vitamin B₁₂ level was most likely a result of his poor diet. He was not tested for homocystinuria. The patient's discharge vitamin B₁₂ level was within normal limits at 643 pg/mL, and his LDH was 534 u/L. At discharge, vitamin B₁₂ supplementation was continued (1,000 µg intramuscularly every week), and he was restarted on furosemide.

Discussion

Catatonia is a condition that includes symptoms such as catalepsy, stupor, rigidity, posturing, and waxy flexibility. Negativism, mutism, and catatonic excitement are other common symptoms.²⁰ Catatonia can be a subtype of schizophrenia, a symptom of the mood disorders, or an entity caused by a medical condition or substance.²⁰ Medical conditions associated with the development of catatonia include homocystinuria, hypercalcemia, porphyria, seizure activity, hepatic encephalopathy, and diabetic ketoacidosis.^20,21

While many laboratories have low normal ranges of vitamin B₁₂ near 200 pg/ml, Smith noted that this value was based on hematologic, not psychiatric, criteria.²² Dommisse felt that the minimum acceptable level for serum vitamin B₁₂ was 600 pg/ml and suggested that everyone's serum vitamin B₁₂ level should be between 1,000 pg/ml and 2,000 pg/ml to optimize their mental function.¹⁴ While these levels may seem high, in one study patients with serum vitamin B₁₂ levels of up to 827,000 pg/ml reported no side effects.²³ Some have suggested that vitamin B₁₂ levels be checked in all newly diagnosed psychiatric patients because of the treatable nature of illness caused by vitamin B₁₂ deficiency.²⁴ However, there seems to be a narrow window of opportunity in regard to vitamin B₁₂ replacement to treat these disorders.¹⁷ This window is estimated to be less than 1 year in duration^17,25 and that the "most robust" respondents are symptomatic for less than 6 months.²⁵ Martin et al. noted that late vitamin B₁₂ deficiency may not be reversible secondary to myelinolysis.²⁵

Vitamin B₁₂ deficiency has been linked to many psychiatric entities, and our patient likely developed catatonia secondary to a low vitamin B₁₂ level, which improved after supplementation. Our patient had many symptoms of catatonia, including stupor, mutism, rigidity, posturing, and waxy flexibility. Treatment response was rapid and robust, which is consistent with prior studies that note that treatment should begin as close to the onset of symptoms as possible to obtain optimal improvement.^17,25 Our patient was symptomatic for less than 4 months before the start of treatment. It was also significant that our patient had a very low vitamin B₁₂ level (1.07 pg/mL). Previous reports note that neurological changes are common with vitamin B₁₂ levels under 200 pg/mL.²⁶ Also, our patient had depressive symptoms, which are commonly seen in vitamin B₁₂ deficiency.¹⁶ To our knowledge, there have been no other reports linking catatonia to vitamin B₁₂ deficiency in the literature to date. However, it is possible that previous cases of catatonia associated with homocystinuria were actually caused by an occult vitamin B₁₂ deficiency, which caused the homocystinuria.

In regard to our case, there were some other factors that need to be addressed. First, the patient's increased LDH at admission was an unexpected finding. However, an increased LDH level is often seen in megaloblastic anemia⁵ but this level can be rapidly resolved with appropriate therapy. Our patient's LDH level decreased to 534 u/L after roughly 2 weeks of therapy, which suggests a temporal relationship to the resolution of the megalobastic anemia. Another concern is whether our patient had neuroleptic malignant syndrome. While this was considered as a possibility secondary to our patient's mildly increased CPK and muscular stiffness, it was eventually rejected because our patient was afebrile throughout the hospitalization, never displayed diaphoresis, had no leukocytosis, and displayed no blood-pressure abnormalities.²⁷ Also, while our patient was found to have some cogwheeling, there was never any lead-pipe rigidity noted. While it was also possible that our patient's catatonic symptoms were caused by his pancytopenia, it is not likely because there was no rapid clinical improvement after the transfusion and normalization of our patient's blood counts.

Consideration was given to the idea that our patient's catatonia was neuroleptic induced. Neuroleptic-induced catatonia (NIC) is regarded as an extreme parkinsonian-like extrapyramidal syndrome caused by neuroleptic medications.²⁸ However, it was unlikely that the chlorpromazine was the cause of the catatonia, as the patient had already begun to deteriorate before the drug's reinstitution. Also, neuroleptics with high muscarinic-blocking effects, such as chlorpromazine, have rarely been associated with NIC.²⁹ The role of risperidone in this case should also be discussed. While risperidone can cause somnolence and parkinsonian symptoms,³⁰ we feel that it is not likely the cause of our patient's catatonia because NIC is most commonly associated with high-potency neuroleptics such as haloperidol, fluphenazine, and thiothixene.²⁹ Also, NIC most commonly develops in the first few weeks after beginning neuroleptic treatment or after a dose increase.^28,31 Our patient had been on risperidone for over 3 months. Temporally, the clinical information points toward vitamin B₁₂ deficiency as being the cause of our patient's catatonic reaction.

The psychiatric implications of occult vitamin B₁₂ deficiency remain unclear and require further investigation. Still, it would be wise to consider vitamin B₁₂ deficiency in patients with neuropsychiatric symptoms, even if there are no classic hematologic signs.³

Also, obtaining vitamin B₁₂ levels in all psychiatric patients should be considered, because mild vitamin B₁₂ deficiency could have been present and undetected for long periods of time.¹⁴

Even low normal vitamin B₁₂ levels can result in neuropsychiatric abnormalities²⁰; therefore, consideration should be given to supplementing a patient's level to at least 600 pg/ml. It would be interesting to determine vitamin B₁₂ levels in all patients with catatonia to assess the frequency of such an association.

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