This article was originally published in the March 2017 issue of Psychiatric Times.

Authors

Jo Ellen Wilson MD MPH
Lex Denysenko MD
Andrew Francis PhD MD

Checkpoints:

• Delirium and Medical Catatonia are both brain dysfunctions linked to medical conditions, and may co-exist with overlapping signs.
• Medical Catatonia usually responds to lorazepam, the standard initial treatment for non-medical catatonia. Memantine or amantadine may be helpful for augmentation.
• Electroconvulsive therapy (ECT) may salvage severe and persistent cases but must be weighed against risk and benefit, especially in medically compromised cases
• While atypical antipsychotics in concert with benzodiazepines have been considered for psychiatric catatonia without fever or autonomic signs, we lack evidence that these agents are safe or effective for medical catatonia, or delirium with catatonia

Introduction

Catatonia, described by K.L. Kahlbaum in 1874, is a distinct and heterogeneous neuropsychiatric syndrome, with both motoric and behavioral signs. It may be hypokinetic, hyperkinetic or mixed, and includes volitional signs such as mutism, negativism, and automatic obedience (1).  It was formerly relegated as a schizophrenia subtype, or considered extinct after the advent of modern psychopharmacology. A renewed interest and emerging systematic data have highlighted the frequency and pattern of catatonic presentations in psychiatric and medical settings, including in critical illness.

Recognition

Historically, up to 40 signs were recognized, and most are now included in the published scales for detecting and rating the severity of catatonia.  The Bush-Francis Catatonia Rating Scale (BFCRS) is widely used clinically and for research, shows high inter-rater reliability, favorable sensitivity and specificity, and was validated in a mixed medical and psychiatric sample (2). The 23-item BFCRS was derived from classic descriptions of catatonia and modern diagnostic criteria (DSM-III-R, DSM-IV, ICD-10). Cases are defined by the presence of >=2 of the first 14 signs, while the new DSM-5 criteria require >=3 from a similar list of 12 common catatonic signs (3). The BFCRS or DSM-5 items identify diverse clinical features, including motoric, behavioral, volitional, and autonomic signs. Statistical analyses identified subtypes of catatonia, including a retarded and excited form. Malignant catatonia [a severe form with fever and autonomic instability] is uncommon, but is important to identify as it may be fatal if not recognized and aggressively treated (4).

The incidence of catatonia in acute psychiatric settings averaged 9-10% across several prospective studies with varying diagnostic criteria (5). One study suggested up to 10% of the general medical population may exhibit catatonic signs during acute hospitalization (6).  Reports from consultation-liaison services found rates of 1.6-8.9% on medical services, where the prevalence varied by age or underlying medical condition.

Despite effective treatments, patients with any form of catatonia remain at risk from serious complications such as dehydration, muscle breakdown, aspiration, or embolic phenomena (1). Once catatonia is recognized, these risks can be mitigated by effective treatments. Among the most studied treatment modalities, prompt administration of gamma-aminobutyric acid (GABA) receptor agonists [e.g., high-potency benzodiazepines, zolpidem, barbiturates] or ECT for severe or resistant cases usually relieves the symptoms and may be life-saving, regardless of the underling etiology.

Pathology of Catatonia in Context of Medical Illness

Systematic examination of catatonia with genetic and brain imaging studies has been slow to develop. Familial aggregation has been reported for a variant termed periodic catatonia, and preliminary evidence associated this with 15q15 chromosome. SPECT studies using a GABA-A ligand revealed reduced binding in areas of the frontal lobe. More recent studies showed increased cerebral blood flow in the supplementary motor cortex, which correlated with BFCRS severity scores, and apparent loss of frontal and insular grey matter in catatonic schizophrenia (7).

For catatonia in medical populations, the pattern or frequency of catatonic signs does not distinguish “psychiatric” from “medical” catatonia [Catatonic Disorder Due to General Medical Condition (CDGMC) in DSM-IV, and Catatonic Disorder Due to Another Medical Condition (CDAMC) in DSM-5]. A review of case reports on catatonia associated with brain lesions found an association with frontal and basal ganglia damage. The most recent systematic reports of medical catatonia confirm that non-localizing encephalopathies were most common primary diagnoses associated with catatonia, and that a variety of non-specific EEG findings were seen (8,9). Despite these reports, many researchers believe that catatonia is generally under-recognized in the medically ill (10).

Catatonia and Delirium

Of particular interest and potentially great clinical significance is the relationship between catatonia and delirium. Delirium is the classic syndrome of acute brain dysfunction, with disturbed attention, awareness, and cognition (DSM-5), and is predictive of excess mortality, longer hospitalization, costlier care, and long-term cognitive impairment. While delirium is often assessed in critical settings such as the intensive care unit (ICU), catatonia is not (10).  Recognition and study of ICU catatonia has until recently been hindered by the last three DSM editions, including DSM-5, which consistently hold that catatonia cannot be diagnosed in the presence of delirium (3).  No clear evidence supports such an exclusion, and emerging data do not support its premise.

One of us [A.F.] suggested that despite the DSM exclusion, delirium could co-exist with catatonia, perhaps most prominently in the “hypoactive” motoric subtype of delirium. Hypoactive delirium includes decreased motor activity, decreased speech, and behavioral withdrawal, all of which map to catatonic features. Using systematic criteria for delirium and catatonia, our literature review identified 16 cases meeting concurrent criteria for both (11).

The first prospective study of catatonia with delirium was published in 2014 (12). This report systematically assessed 205 consecutive DSM-5 delirium cases from an academic consultation service and showed that 13% met concurrent DSM-5 criteria for catatonia while 32% met BFCRS criteria for catatonia. However, no treatment or outcome data were presented. One of us [JW] has an ongoing prospective study of prevalence, features, and outcome of catatonia in the ICU setting.

The implications of more clinical attention and systematic study of co-morbid delirium and catatonia are many, and include prognosis and management. Treatment of catatonia generally includes avoidance of antipsychotics (which may worsen catatonia or precipitate a lethal or malignant form similar to NMS) and treatment with benzodiazepines (typically lorazepam) and/or electroconvulsive therapy (ECT).  Delirium, alternatively, is approached via addressing the underlying medical condition and environmental factors, along with general avoidance of benzodiazepines [except for known substance-withdrawal deliria], but often includes the use of antipsychotics.

There are no prospective data on the management or outcome of catatonia with delirium. However, a recent study of medical inpatients identified 54 cases of DSM-5 catatonia of whom 43% had prior psychiatric history, while 54% had suspected delirium (9). Comparing CDAMC to catatonia attributed to psychiatric disorders, there was no statistical difference in the rates of treatment attempts using lorazepam, nor in response which was >80%.  However, cases of catatonia co-morbid with suspected delirium were less likely to respond to lorazepam (71%) than cases without delirium (100%), regardless of etiology.  While this was a retrospective study, it supports the assertion that catatonia and delirium can be comorbid (1,12), and suggests that in many cases the treatment of catatonia with benzodiazepines may be successful in the presence of a delirium.

Differential Diagnosis

A variety of medical conditions can produce stupor, which is a decreased awareness and interaction with the external environment. Stupor can occur with preserved alertness, more often seen in catatonia, or with lethargy, more often seen in delirium. Stupor that is associated with a metabolic disorder or that is associated with delirium may present with catatonic features (13,14). Table 1 presents examples of medical conditions associated with catatonia.

NMS, serotonin syndrome, and non-convulsive status epilepticus (NCSE) are other examples of stuporous states associated with catatonia. Some have advocated that NMS and serotonin syndrome are actually medication-induced malignant catatonia (15).

Delirious mania is a rare syndrome linked to bipolar disorder characterized by the rapid onset of delirium, mania and psychosis, with prominent hyperactive catatonia. Delirious mania can be construed as a malignant hyperactive form of catatonia, as well as a hyperactive delirium. Delirious mania has been associated with medical disorders.  The newly characterized Excited Delirium Syndrome, induced by cocaine or other stimulants, has been likened to delirious mania (16). Delirious mania was reported after cerebellar/pontine stroke, which produced a delirium treated with antipsychotics that worsened the catatonia which eventually improved with lorazepam (17).  Delirious mania has also been found in patients with G6PD deficiency (18). Benzodiazepines and/or ECT have been advocated for treatment of delirious mania (19).

Treatment Strategies

Differences between etiologies (i.e., “psychiatric” vs. “medical”) do not appear to alter the general treatment approach for catatonia. Removing suspected offending agents, treating the underlying medical condition, or managing drug withdrawal are essential when treating suspected CDAMC.

For persistent catatonia, rapid initiation with lorazepam or a related benzodiazepine, sometimes requiring cautious titration to higher doses (e.g. 8 mg/day of lorazepam or greater), usually leads to lysis of the disorder. Benzodiazepines (and related agents such as amobarbital and zolpidem) may counteract hypothesized GABA receptor hypofunction in catatonia (1,7). Intravenous lorazepam has more assured absorption and may exert more prolonged clinical effects than the oral form based on differing drug distribution (20).  Potential adverse effects of high-dose intravenous lorazepam include anion gap acidosis from its solvent, propylene glycol.  This risk increases with higher doses and in renal impairment, but toxicity was reported from as little as 2mg/hour.  One ICU study recommended monitoring the osmolar gap (a marker for glycol toxicity) every other day if the lorazepam infusion reaches 1mg/kg/day (21).

Augmentation with memantine or amantadine may also be helpful, based on multiple case series and reports (22). Their hypothesized mechanism is N-methyl-D-aspartic acid (NMDA) receptor antagonism, which may be linked to GABA hypofunction.  Memantine can be started at 5-10 mg/day and titrated based on medical status with monitoring of the QT interval.  Improvement from memantine seems slower than lorazepam, but both can be co-administered. Amantadine is started at 100-200 mg/day and titrated, but should be used with caution if renal impairment or seizure risk is present. Mania, suicidal ideation, and withdrawal-emergent NMS have also been reported.

ECT can be considered for inadequate medication response for persistent and severe catatonia, and may be used more emergently for malignant features (autonomic instability and hyperthermia).  Use of ECT for catatonia in medical settings or with uncertain CNS pathology should be approached cautiously and the potential risks weighed against the known adverse risks of severe and prolonged catatonia. Some reports show benefit of ECT for catatonia for various acute neurological illnesses (23) but for other presentations, such as catatonia after cerebral hypoxia, ECT may have no benefit or worsen neurological status (24).

Atypical antipsychotics were reported to benefit some cases of non-medical catatonia after other treatments failed, or for coexistent catatonia and psychosis when ECT was not feasible (25). Serum iron should be measured since low levels may be predictive of conversion to malignant catatonia (26).  Benzodiazepines should be continued concurrently with the antipsychotic, with monitoring for extrapyramidal or autonomic symptoms portending malignant catatonia/NMS. Antipsychotics in CDAMC or catatonia with delirium have not been studied and we advise caution.

Collaboration with Medical Services

When medical catatonia is identified, the primary hospital service may resist lorazepam treatment, particularly when the patient is medically compromised.  Under-dosing of lorazepam and treatment failure may result. In the experience of one of us [LD], inviting the primary team to witness a lorazepam or zolpidem challenge may help medical specialists appreciate that a “sedating” agent can improve catatonic stupor.

Frequent vital sign assessments, monitoring osmolar gap, and pulse oximetry can improve safety, along with ready access to flumazenil for reversal of potential adverse effects of benzodiazepines. If sedation is a concern, adding non-sedating memantine or amantadine may allow for lower benzodiazepine dosing.

When multiple hospital consultants are involved in complex cases, interdisciplinary meetings are strongly recommended. In such situations, we encourage a clear consensus identifying specific targets for defining both treatment response and adverse effects.

Acknowledgements and Disclosures

Dr. Wilson is an assistant professor in the Department of Psychiatry at Vanderbilt University, Nashville, TN. Dr. Denysenko is an assistant professor in the Department of Psychiatry at Rowan University School of Osteopathic Medicine, Cherry Hill, NJ. Dr. Francis is professor of Psychiatry at Penn State Medical School, Hershey, PA. The authors report no disclosures relevant to this paper.

Table 1: Catatonia due to another medical condition or substance*

Medical Conditions

Substance-induced

NMDA-receptor encephalitis Paraneoplastic limbic encephalitis Systemic lupus erythematous with or without cerebritis Seizures Encephalitis lethargica Herpes simplex encephalitis Subacute sclerosing panencephaltiis Neurosyphilis Borrelia burdorferi infection and sequelae Typhoid fever Adenovirus Disseminated neurocysticercosis Human immunodeficiency virus and sequelae Intracranial mass lesions Multiple sclerosis Uremic encephalopathy Posterior reversible encephalopathy syndrome Glucose-6-phosphate dehydrogenase deficiency Vitamin B12 deficiency Hyponatremia Takotsubo cardiomyopathy Wilson’s disease

Tacrolimus, even at normal levels Cyclosporine Corticosteroids Fluoroquinolones Beta-lactam antibiotics Azithromycin Disulfiram Dopamine antagonists GABA-ergic agonist withdrawal Baclofen exposure/withdrawal Cocaine intoxication MDMA “Ecstasy” intoxication Methylphenidate intoxication Phencyclidine intoxication Methoxetamine intoxication

*Adapted from: Denysenko L, Freudenreich O, Philbrick K, Penders T, Zimbrean P, Nejad S, Chwastiak L, Dickerman A, Niazi S, Shim J, Soellner W, Walker A, Carroll B, Francis A.  (2015, April 17). Catatonia in Medically Ill Patients: An APM-EAPM Clinical Monograph.  Retrieved from: http://www.apm.org/library/monographs/catatonia/

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