Serum and CSF Anti-NMDAR Antibody Testing in Psychiatry.

OBJECTIVE: The authors examined and compared the clinical presentation of CSF positive and negative N-methyl-d-aspartate receptor (NMDAR) antibody. METHODS: The investigators performed a retrospective chart review of NMDAR-antibody-positive cases (serum or CSF) involving patients presenting to psychiatric services from 2010 to 2018 in Queensland, Australia. Presentation, progress, investigations, and efficacy of treatment are detailed. RESULTS: There were 24 serum or CSF NMDAR-antibody-positive cases and three equivocal serum results. High rates of prodromal cognitive deficits, catatonia, speech disturbance, and antipsychotic sensitivity were observed in the 16 CSF NMDAR-antibody-positive case patients and two CSF NMDAR-antibody-negative case patients, all evident before neurological deterioration with seizures, movement disorder, and autonomic disturbance occurring in the weeks following admission. The majority of these patients (N=17) were treated successfully with immunomodulatory therapy. The nine remaining patients, who were CSF NMDAR antibody negative or equivocal, did not demonstrate any of these features and improved with psychiatric care alone. CONCLUSIONS: These findings suggest that traditional psychiatric care may be appropriate for patients with isolated psychiatric symptoms who have positive serum NMDAR testing when CSF is negative and there are no key clinical features such as cognitive deficits, catatonia, speech disturbance, and antipsychotic sensitivity. However, if these key features are present, a trial of immunomodulatory treatment should be considered with repeated examination of CSF for neuronal antibodies.

Catatonia with GABAA receptor antibodies.

A 22-year-old African woman developed acute behavioural change, against a background of sickle cell disease with strokes requiring a ventriculoperitoneal shunt. She alternated between mutism with prolonged staring and posturing, and a state of agitation with elation and echolalia. Cerebrospinal fluid (CSF) protein was elevated and electroencephalogram showed mild slowing with bitemporal slow and sharp waves. We suspected catatonia secondary to possible autoimmune encephalitis but her condition persisted despite intravenous methylprednisolone. After identifying a positive serum anti-gamma-aminobutyric acid-A (GABAA) antibody, treatment with intravenous immunoglobulin, oral corticosteroids and rituximab led to gradual improvement. Patients with catatonia may show reduced GABAA receptor density and there are two other reports of catatonia with anti-GABAA antibodies. This patient's treatment response supports the antibody's causative role.

Increased serum anti-N-methyl-D-aspartate receptor antibody immunofluorescence in psychiatric patients with past catatonia.

OBJECTIVE: Anti-N-methyl-D-aspartate receptor (NMDAR) antibody was thought to be the cause of anti-NMDAR encephalitis, with manifestations similar to catatonia and schizophrenia. Anti-NMDAR antibody in neuropsychiatric patients who had catatonia before were investigated in a follow-up evaluation. The intensity of antibody immunofluorescence was quantified and compared with healthy controls. METHOD: Nineteen patients (eight males and eleven females) agreed to be followed-up. Thirteen had the diagnosis of schizophrenia, two had the diagnosis of major depressive disorder, two had bipolar disorder, one had postpartum depression, and one had herpes simplex encephalitis. No patient had catatonia during the follow-up. Nineteen sex-matched healthy controls were recruited. RESULTS: Using Mann-Whitney U test, patients had greater intensity of anti-NMDAR antibody immunofluorescence than the healthy controls (121,979 ± 86,526 vs. 47,692 ± 26,102, p = 0.003). No correlation was found between immunofluorescence intensity and catatonia scales or symptom severity scores. Neuropsychiatric patients with past catatonia showed greater anti-NMDAR antibody response than the healthy controls. CONCLUSION: NMDAR dysfunction might play a role in the mechanism underlying catatonia. Further studies are needed to confirm this finding.

Catatonia as an internal medicine disease: infrequent or still underdiagnosed?

Catatonia is a motor and behavioural syndrome with multiple psychiatric, general medical and neurological aetiologies that might be simultaneously present. B12 deficiency is a rare, treatable cause of catatonia, not always easy to rule out. The authors present a case of a woman with catatonia associated with severe cyanocobalamin deficiency, admitted to an internal medicine ward. The benign course was related to an adequate and early diagnosis.

Risk of venous thromboembolism due to antipsychotic drug therapy.

An increasing number of reports suggest a link between venous thromboembolism (VTE) and the use of antipsychotics. To better understand this association the available body of evidence has been critically scrutinised. Relevant articles were identified in the databases Scopus and PubMed. Several observational studies using different methodologies show an increased risk of VTE in psychiatric patients. This elevated risk seems to be related to the use of antipsychotic medication and in particular to the use of clozapine and low-potency first-generation drugs. Many studies investigating the association have, however, methodological limitations. The biological mechanisms involved in the pathogenesis of this possible adverse reaction are largely unknown but several hypotheses have been suggested such as drug-induced sedation, obesity, increased levels of antiphospholipid antibodies, enhanced platelet aggregation, hyperhomocysteinemia and hyperprolactinemia. The association may also be related to underlying risk factors present in psychotic patients. Physicians need to be aware of this possible adverse drug reaction. Although supporting evidence has not been published they should consider discontinuing or switching the antipsychotic treatment in patients experiencing VTE. In addition, although data is lacking, the threshold for considering prophylactic antithrombotic treatment should be low when risk situations for VTE arise, such as immobilisation, surgery and so on.

The role of coagulation marker fibrin D-dimer in early diagnosis of catatonia.

Catatonia is a common but under-diagnosed neuropsychiatric syndrome characterized by the occurrence in a single patient of concomitant affective, motor and behavioral symptoms with a hazardous outcome (called lethal catatonia: LC). Deaths by thromboembolic disease have been previously reported in LC. A 2-year prospective study was carried out to examine D-dimer levels, an early and sensitive coagulation marker, in patients with catatonic disorders. Twenty-five acute catatonic patients and 50 psychiatric control patients - matched on age, gender, psychiatric diagnosis, general psychopathology and neuroleptic medication matched - were investigated and considered in relation to D-dimer blood levels and other biological variables (serum iron, creatine phosphokinase, leukocytosis). All catatonic patients had high D-dimer levels and mean levels were significantly higher in catatonics than in non-catatonic patients, independently of age, gender, immobility, comorbid diagnosis, general psychopathology and neuroleptic medication. No significant association was observed with other biological parameters investigated. These preliminary and exploratory results suggest that catatonia is associated with early coagulation activation.

Catatonic features in major depression relieved by electroconvulsive treatment: parallel evaluation of the status of platelet serotonin transporter.

The aim of this research was to follow parallelly the clinical status of a patient and the dynamics of the serotonin transporter (SERT), a likely player in the effect of electroconvulsive treatment (ECT), a powerful tool against deep depression. A patient affected by major depression with catatonic features, not responding to pharmacological therapy, underwent ECT. Evaluations of the binding of labelled paroxetine to venous blood platelet SERT were parallel to the assessments of clinical improvements. The density of platelet SERT, starting from a low level before ECT, displayed an initial steep increase peaking the day after the third electroconvulsive session (5 days after the start of ECT). This was followed by a rapid decrease, which seemed to precede the process of clinical recovery. These results were found in a case of unavoidable ECT treatment. If generalizable, they suggest interesting ideas about the still mysterious mechanism of ECT antidepressant action.

Electroconvulsive therapy complicated by life-threatening hyperkalemia in a catatonic patient.

Electroconvulsive therapy (ECT) requires brief general anesthesia, and succinylcholine is a depolarizing neuromuscular blocking agent that is frequently used for this procedure. Its use leads to intracellular potassium release into the extracellular space, usually increasing the serum potassium level by 0.5-1 mEq/L, with little clinical significance. However, long-term immobilization has been associated with changes at the neuromuscular junction (up-regulation of nicotinic cholinergic receptors) and subsequent serious hyperkalemia following succinylcholine administration. We report the case of a severely obese patient, immobilized due to her catatonic state, who developed life-threatening ventricular tachycardia after succinylcholine administration for ECT. Resumption of normal physical activity reverses these neuromuscular junctional changes, allowing subsequent safe succinylcholine administration. Current drug development may eliminate the need for succinylcholine use during ECT.

Zuclopenthixol-acetate treatment in catatonic patients: the implication of iron metabolism.

There is some evidence of ferropenia correlating with neuroleptic malignant syndrome and catatonic symptoms. The aim of this prospective and naturalistic study was to investigate the implications of ferremia in patients undergoing an intramuscular injection treatment of Zuclopenthixol-acetate in Visceolo. We recruited 59 catatonic patients (33 females). Age, sex, psychiatric and somatic diagnoses, body mass index (BMI), dosage and duration of Zuclopenthixol-acetate medication and the timing of the changeover from intramuscular to oral prescription, the single dosage of Clopenthixol if initially coadministered, incidence, onset and duration of transient benign hyperthermia, iron, ferritin, transferrin and saturation values, and white and red blood cell counts as well as liver function and electrolytes were registered. A transient and benign hyperthermic reaction (mean degrees: 37.5 + 0.3 degrees C) lasting for an average of 3.0 + 1.9 d was shown by 72.9% patients (N = 43, 22 females), during a mean treatment period of 5.8 + 3.1 d. These patients were medicated with significant different mean doses of Zuclopenthixol-acetate and compared to the patients with normal body temperature (ANOVA P < 0.01). The duration of Zuclopenthixol-acetate application did not vary between these patients groups. Furthermore, significant differences of iron (59.5 + 30.6 micromol/dl vs. 87.8 + 40.8 micromol/dl; ANOVA P < 0.006) and transferrin saturation values (18.3 + 10.4% vs. 27.2 + 17.0%; ANOVA P < 0.02) were found. Ferritin and transferrin were not implicated in the episode of hyperthermia. Diagnoses, sex, white and red blood cell counts also did not vary between these groups. Our findings indicate a possible involvement of ferropenia in catatonic patients, regardless of the diagnoses, and in the development of benign transient hyperthermia, also known as drug fever.

Serum iron in catatonic and noncatatonic psychotic patients.

BACKGROUND: Since low serum iron has been reported in a variety of neuropsychiatric motor disorders, this study was conducted to examine serum iron in patients with a catatonic disorder. METHODS: Forty catatonic and 40 noncatatonic psychotic patients were studied in relation to serum iron levels. The association of serum iron with other clinical variables was also examined. RESULTS: Catatonics had significantly lower mean serum iron than noncatatonics. Ferropenia (serum iron < 50 micrograms/dL) was significantly more prevalent in the catatonic (35%) than in the noncatatonic (7.5%) group. Severity of catatonic symptoms was inversely correlated with level of serum iron, this being due to the negative catatonic symptoms (r = -.34, p = .002). CONCLUSIONS: A subgroup of catatonic patients had ferropenia. Lower serum iron level was associated with both the presence of a categorically defined catatonic syndrome and the severity of the negative catatonic symptoms.

Serum iron in catatonia and neuroleptic malignant syndrome.

BACKGROUND: Preliminary data suggest that decreased serum iron levels predict the progression of catatonia to neuroleptic malignant syndrome (NMS). This study examines the predictive value of low serum iron in this NMS conversion and explores other potential significance of serum iron in catatonia. METHODS: Fifty patients with catatonia were prospectively identified at two psychiatric intensive care units during a 3-year period [incidence of 5% (39/716) and 13% (11/86) respectively]. Serum iron was measured in 39 episodes. Seventeen episodes (44%) showed low serum iron levels. A retrospective chart review of patients identified was conducted, comparing those with low and normal serum iron levels. RESULTS: Low serum iron levels were associated with malignant catatonia, excited catatonia, and poor responses to benzodiazepines. There were 7 episodes of malignant catatonia. All had low serum iron. Neuroleptic were used in 5 of them, and all 5 evolved into NMS. No such NMS conversion was noted in those with normal serum iron or in nonmalignant catatonia with low serum iron. Seven episodes (with low serum iron) failing benzodiazepine therapy responded subsequently to lithium-neuroleptic combination therapy. CONCLUSIONS: Malignant catatonia, associated with low serum iron, is at high risk of evolving into NMS. Low serum iron in nonmalignant catatonia does not predict this NMS conversion. Excited catatonia as a catatonic subtype (associated with low serum iron and unfavorable benzodiazepine responses) deserves more research attention. There appears to be a possible connection between treatment resistance to benzodiazepines, favorable responses to lithium-neuroleptic combination, and low serum iron.

Plasma homovanillic acid concentrations in catatonia.

We investigated the dopamine metabolite plasma homovanillic acid (plasma HVA) levels in 37 catatonic patients on the day of admission before initial medication as well as in 17 healthy controls. In a prospective study catatonic syndrome was diagnosed according to criteria of Lohr and Wiesniwski (1987) and Rosebush et al (1990) whereas comorbid diagnosis was made by Diagnostic and Statistical Manual of Mental Disorders, 3rd ed, revised (DSM III/R) (APA 1987). On the day of admission blood samples were taken before initial medication. Compared to controls (80.1 +/- 40.1 pmol/mliter) catatonic patients showed significantly (P = 0.0286) increased plasma HVA (140.9 +/- 53.6 pmol/mliter). Catatonic patients free of neuroleptic medication (n = 21) differed significantly (p = 0.0416) from controls whereas neuroleptically treated catatonics (n = 16) did not. Our findings of increased plasma HVA in catatonia are explained by an alteration in either mesolimbic or mesocortical dopaminergic function, as is assumed in the case of schizophrenia. As an alternative, it may be due to increased nigrostriatal function, which can lead, as shown in animal experiments with the dopamine agonist amphetamine, to hypokinetic states resembling catatonia in humans.