Recognizing Catatonia in Medically Hospitalized Older Adults: Why It Matters

Catatonia is a neuropsychiatric syndrome characterized by a variety of motor, behavioral, emotional, and autonomic abnormalities caused by general medical, neurological, and psychiatric disorders, as well as by medications and drugs of abuse. Although there has been a plethora of research on catatonia over the last twenty years, it is still underdiagnosed. Studies of catatonia involving older adults have been sparse, despite its apparent high prevalence, higher risk of serious complications, and of association with non-psychiatric causes. This paper aims to provide an introduction to catatonia as a syndrome, as well as an account of its specificities in older adults, especially those in general hospitals, with the aim to raise awareness of catatonia amongst clinicians working with this age group in acute medical settings, so improvements in its diagnostic rates, treatment, and outcomes can be achieved.


Introduction
Catatonia is characterized by a variety of motor, behavioral, emotional, and autonomic abnormalities caused by general medical, neurological, and psychiatric disorders, and by medications and drugs of abuse [1]. The contemporary concept was introduced by the neuropsychiatrist Karl Ludwig Kahlbaum in 1874 [2].
He described stupor, mutism, rigidity, negativism, catalepsy, and echophenomena in a group of patients with various psychiatric and physical disorders. Kraepelin [3] incorporated catatonia into his concept of dementia praecox (later called schizophrenia) and catatonia was considered a part of schizophrenia. In the late 20th century, a renewed interest in catatonia began [1] situating it again in its rightful place amongst the major neuropsychiatric syndromes.
Notwithstanding the increasing amount of research on catatonia, there have been few studies involving older adults despite its high prevalence, risk of serious complications, and association with non-psychiatric causes in this age group [4,5]. Hence, it is essential that catatonia in older adults in medical settings is detected to improve diagnostic rates, treatment, and outcomes. This paper will consider the specificities of catatonia in older adults, especially in general hospitals, to raise awareness amongst clinicians working with this age group, so better outcomes can be achieved and complications avoided.

Method
A literature search in MEDLINE/PubMed was undertaken from its first registers to April 2018 for suitable articles using the search strategy "Catatonia" and "older adults", and "general hospital", -Catatonic excitement (mainly observed in pure mania and mixed mania) -Abnormal involuntary movements (mainly observed in schizophrenia with stereotypies, echophenomena, posturing/catalepsy, negativism, mannerisms, Mitgehen, and Mitmachen, and also in Tourette's disorder, and perhaps obsessive-compulsive disorder -Volitional disturbance/catalepsy (mainly observed in schizophrenia and mixed mania) -Catatonic inhibition (mainly observed in depression and medical catatonia) The clinical presentation of catatonia in older adults, despite the significantly different rates of the various etiologies, is similar to that of patients in other age groups [5,10,11].

Etiology
Having diagnosed catatonia, an exhaustive search for its cause should start. These etiologies range from primary psychiatric disorders to general medical and neurological disorders, and drugs and substances of abuse [1]. Amongst the psychiatric causes, affective disorders are the most common (bipolar affective disorder and depression) [1,3,12]. Amongst the medical ones, the list is very extensive. Table 1 provides a non-exhaustive list of etiologies. From studies exploring catatonia in older adults, the most frequent diagnoses associated with catatonia were, in no special order, stroke, encephalitis, hyponatremia, urinary tract infection, depression, chronic psychosis, and dementia [5,10,11,13,14]. In three series, all cases presented with at least one vascular risk factor, and in over 50% of cases, there was recent or current exposure to antipsychotic drugs [5,10,14]. In the case of dementia, the available literature would suggest that it tends to present with another disorder, medical or psychiatric, when associated with catatonia [5,10,11,14]. An increasingly recognized cause of catatonia is an encephalitis as a result of antibodies against the NMDA receptors; an autoimmune disorder in which catatonia is found very frequently, often accompanied by significant autonomic dysfunction [15], and that it can also occur in older patients.

How Prevalent Is Catatonia?
Its prevalence is largely dependent on being recognized and the setting, but catatonia is, despite its dramatic presentation and risk of complications (sometimes life-threatening), still underdiagnosed and undertreated [1,16].
The frequency of catatonia attributed to general medical conditions is 21-46% of all catatonia cases [13,17,18]. Catatonia has also been reported to cause diagnostic dilemmas in unresponsive patients attending emergency departments [19], where its frequency due to a general medical condition is up to 41% of all cases [20]. Catatonia has also been reported in intensive care with a prevalence of 3.8% [21], and is reported in a significant proportion of cases of encephalitis due to anti-NMDAr antibodies [15].
In adults over the age of 65, a review of 71 cases found that 28.16% of cases of catatonia were associated with a general medical condition [13]. In two studies of older adults in general hospitals, catatonia was found in 5.5-8.9% of cases [5,10]. In acute psychogeriatric settings, two studies have reported rates of catatonia in patients with dementia of 4.7-12.6% (using the Diagnostic and Statistic Manual-5 (DSM-5) [22] and the Bush-Francis Catatonia Rating Scale (BFCRS), respectively) [11], and 42.8% [14] (using Fink and Taylor [1] and DSM-5 criteria [22]). In older patients with psychiatric disorders in acute psychiatric hospitals, two studies have reported rates of catatonia of 20.8-39.6% [23], and of 6.1-11.2% [11], depending on the diagnostic criteria used. In the former study, cognitive impairment and dementia were found to have a rate of catatonia of 35.3-58.8% [23].
It has been proposed that in catatonic patients, an extensive workup to exclude a general medical cause is necessary before attributing it to a psychiatric disorder [11,19], even when there is a past psychiatric history.

Pathophysiology
The common pathophysiology of catatonia entails a dysregulation of specific neural pathways affecting motor function and emotional regulation that relate to circuitry linking the medial frontal and inferior orbital cortices to the basal ganglia and thalami, with connections to the parietal lobes, cerebellum, and limbic system [1,24,25]. Thus, catatonia would be mediated by hypofunction of cortical (frontal) Gamma-aminobutyric Acid-A (GABA-A) neurotransmission, leading to hypoactivity of subcortical dopaminergic pathways in the basal ganglia, causing immobility and stupor. This is the 'top-down' model of catatonia [24] and explains its retarded-stuporous variant. The neuroleptic malignant syndrome, a drug-induced form of lethal catatonia, would be mediated through an initial subcortical hypofunction of dopaminergic pathways (caused by dopaminergic blockade by antipsychotic drugs), which would then cause cortical GABA-A hypofunction (a 'bottom-up' mechanism) [24]. A similar dysregulation in fronto-hypothalamic circuits explains the autonomic signs observed in catatonia [25]. In addition, glutamate has also been implicated in the pathophysiology of catatonia [26], being a biological antagonist of GABA, and because glutamate antagonists improve catatonia.
Catatonia has also been conceptualized as an evolutionary response to intense fear, including that induced by psychopathological experiences such as hallucinations and delusions; a fear that causes the subject to 'freeze' in order to self-protect from predators stimulated by movement [27]. This freezing would correspond to the immobility, stupor, catalepsy, and mutism observed in catatonia. Alternatively, a catatonic excitement would be analogous to the 'fight-flight' response mediated by the sympathetic nervous system.

Assessment and Diagnosis
Assessment is mostly undertaken by careful observation during the clinical interview and by eliciting specific signs during the neurological examination. Although there is no consensus on how long the signs must be present for a diagnosis, at least one hour during a day has been suggested, or when signs can be reproduced on two or more occasions [1]. The DMS-5 states that a diagnosis of catatonia can be made if there are at least 3 core signs out of 12 present at the time of assessment [22].
In Table 2, the most frequent signs of Catatonia are enumerated, as well as their definition and mode of assessment. This is based on the Bush-Francis Catatonia Rating Scale [28].
Fink and Taylor [1] have also proposed a set of criteria in which timings for duration of signs, as well as a "hierarchy" of signs, is given, reflecting that some signs are more important than others for diagnostic purposes (at least two signs to be present for a diagnosis): (A) immobility, mutism, or stupor for a duration of at least one hour, associated with at least one of the following; catalepsy, automatic obedience, or posturing, observed or elicited on two or more occasions. (B) In the absence of immobility, mutism, or stupor, at least two of the following, which can be observed or elicited on two or more occasions; stereotypy, echophenomena, catalepsy, automatic obedience, posturing, negativism, or ambitendency. The routine use of validated rating scales has also been advocated to facilitate identification of catatonic signs and a diagnosis of catatonia [1,25]. The Bush-Francis Catatonia Rating Scale [28], which consists of a screening instrument (14 items that are scored as present or absent) and a full severity scale (14 plus 9 other items scored 0-3) has been widely recommended for its ease of use and because of its reliability and validity [29]. In this scale, the presence of two or more signs is suggestive of catatonia [28].
A specific screening method for identifying catatonia in acute medical settings has recently been proposed with the mnemonic "A SLIME-posture" [30]: -Acute or subacute onset -Speech: disordered-poverty, whispering, mutism -Latency: increased response latency in speech, affect, or movement -Interaction (stupor): decreased and out of proportion to relatively preserved alertness -Muscle: Increased tension/tone on examination -Eyes: staring -Posture: posturing, including grimacing

Differential Diagnosis
In a general hospital or emergency room setting, a considerable number of conditions that cause stupor and/or abnormal movements will need to be considered. Catatonia should be always thought of in the differential diagnosis of altered states of awareness in emergency departments and acute medical settings [19]. Diagnoses that will need excluding are non-convulsive status epilepticus, delirium, cerebral trauma, acute cerebrovascular disease, locked-in syndrome, stiff-person syndrome, "off" periods in Parkinson's disease and its akinetic-rigid form, malignant hyperthermia, selective mutism, factitious disorder, maladaptive coping with medical illness with non-cooperation and contrary behavior, and malingering [1,30,31]. In epilepsy, catatonia has been reported in ictal, post-ictal, and interictal states, and also as a result of anticonvulsant treatment and of alternative psychoses [32].

Malignant/Lethal Catatonia
Characterized by the sudden development of intense excitement, hyperthermia, catalepsy/posturing, mutism, rigidity, and stereotypies, in the context of delirium; it represents the most severe form of catatonia. There is severe autonomic dysfunction with fever, tachycardia, tachypnea, and hypertension, and multiorgan dysfunction. It is associated with high mortality rates, mainly due to diagnostic delays. The treatment of choice is with benzodiazepines and electroconvulsive therapy (ECT), or both, and should always be accompanied by vital support measures and treatment of the cause of the symptoms.

Neuroleptic Malignant Syndrome (NMS)
NMS has been considered by many as a form of (malignant) catatonia precipitated by exposure to antipsychotic drugs [1,25]. It has been reported to occur in 0.5-1% of patients receiving antipsychotic treatment, usually within two weeks of exposure to either typical or atypical antipsychotics. A very similar syndrome has been observed with exposure to other types of drugs (e.g., toxic serotonin syndrome). Treatment is with lorazepam and ECT [1,25]. Clinical manifestations include rigidity leading to muscle breakdown and renal failure, hyperthermia, altered consciousness, autonomic dysfunction, mutism, staring, negativism, posturing, verbigeration, and echophenomena.

Periodic Catatonia
Recurrent periods of hypokinetic catatonic signs alternating with periods of hyperkinesis, lasting between 4-10 days, and recurring over a period of months or years with symptom-free intervals. Some patients may display grimacing, stereotypies, and negativism in the inter-ictal intervals, especially as they grow older. It is rare and has been observed to segregate within families in an autosomal dominant pattern. There is a linkage to chromosome 15q15 [33]. One case has been described of a 22.q13.3 chromosomal microdeletion [18].

Delirious Mania
Characterized by an acute onset of excitement, grandiosity, emotional lability, delusions, insomnia, and other symptoms typical of mania, and accompanied by delirium. There is often fever and other autonomic dysfunctions. It can be made worse by the incorrect diagnosis of an acute psychosis or of delirium with the subsequent administration of antipsychotics [34].

Catatonia and Delirium
Delirium in patients with catatonia has been increasingly described [5,10,14,23,35,36]. Both syndromes share clinical features, lack specific laboratory findings and biomarkers, and are diagnosed on clinical grounds [35]. Delirium is a prominent clinical manifestation of malignant catatonia, delirious mania, and NMS [30]. In two studies, 30-50% of cases of older adults in acute medical settings with catatonia were found to suffer from co-existing delirium [5,10], whilst in another study of 205 patients with delirium in a general hospital (19% of the sample was older than 65 years of age), catatonia was present in 12.7-30.2% of cases, depending on the diagnostic criteria used [36]. In the first two studies [5][6][7][8][9][10], the clinical presentation of catatonia was generally in the retarded-stuporous form. In the third study [36], mixed and hypoactive delirium subtypes were more frequently encountered in patients with catatonia. Patients with catatonia were also found to have a higher frequency of perceptual disturbances, motor retardation, and onset of delirium prior to admission to hospital [36]. In another study in acute psychogeriatric inpatients, 66.7% of cases who on admission had two or more catatonic signs in the BFCRS, also had delirium [23].
The differential diagnosis between catatonia and delirium is challenging as both present with prominent psychomotor abnormalities. Delirium's classification predominantly relates to its motor aspects, thus divided in hyperactive, hypoactive, and mixed forms [36]. There are also hypoactive and hyperactive forms of catatonia. This can be misdiagnosed as delirium and managed as such, and whilst delirium appears in the list of differential diagnoses of catatonia, the latter rarely figures in that of delirium [35].
The causes of both delirium and medical catatonia greatly overlap [36]. There are, however, differences in their pharmacological management. The treatment of choice in catatonia, lorazepam, is rarely the treatment of choice in delirium except when caused by benzodiazepine withdrawal. The most widely used symptomatic treatment of choice in delirium, antipsychotics, is generally to be avoided in the management of catatonia. Therefore, the ability of clinicians to ascertain a catatonic dimension in cases of delirium will facilitate the selection of the right treatment [36].
On a retrospective chart review of adults with catatonia in a general hospital, 40% had a psychiatric history, 50% had suspected delirium, and 60% had dopamine antagonist exposure prior to catatonia onset [17]. In these patients, an older age, the presence of suspected delirium, and first episode of catatonia, were associated with a greater number of diagnostic tests during admission [17]. Patients with a psychiatric history were less likely to have suspected delirium, and they received less diagnostic tests [17].

Investigations
Since medical causes of catatonia will be very significant in older patients in a general hospital, a psychiatric cause should not be attributed initially, and adequate investigations should be undertaken. In addition to a comprehensive physical and a neurological examination, appropriate hematological and biochemical tests will be required, ranging from full blood count and inflammatory markers; to kidney, liver, and thyroid function tests; calcium; glucose; proteins; and creatine-kinase. A blood and/or urine toxic screen may be needed, as well as a microbiological urine examination [1,25,37]. Depending on the presentation, vasculitic or encephalitic processes may be suspected, and other plasma and/or cerebrospinal fluid (CSF) tests may be required, including various serologies and autoantibody screens. Structural brain imaging will often be required to exclude central neurological pathologies. An electroencephalogram (EEG) may be needed to exclude a non-convulsive status epilepticus presenting with ictal catatonia.
No specific biochemical or hematological abnormalities have been described in catatonia. In malignant catatonia and in NMS, raised leucocytes and creatine-kinase, and low serum iron have often been described [25]. A raised creatine-kinase should alert to severe rigidity and muscle breakdown that can lead to serious complications. A workup for medical catatonia is fully described in a recent evidence-based medicine monograph on catatonia in medically ill patients [30].

Complications
Prolonged catatonia is associated with adverse events that can be life-threatening. Complications tend to be caused by the effects of prolonged immobility, withdrawal causing poor or no food and fluid intake, or autonomic dysfunction. The more severe and longer lasting the catatonia, the higher the risk of complications. Older patients with undiagnosed catatonia have been reported to be at an increased risk of major complications and adverse events [4]. In a retrospective review [38], the frequency of significant complications was of 11%. In the same series, the rate of deep venous thrombosis was 6% and of pulmonary embolism was 2%. In a prospective study of older patients with catatonia in a general hospital, the rate of complications observed was 40% and the mortality rate was 20% [5].
Catatonic patients should be managed in hospitals with specialist multidisciplinary input to ensure treatment of the cause of catatonia; good hydration and nourishment; and prevention of infections, pressure ulcers, contractures, and thrombosis. Table 3 lists the most frequent complications associated with catatonia.

Medical Management
Catatonia is a treatable condition. The therapeutic approach is three-fold. First, the symptomatic treatment of the catatonia itself; second, the treatment of its cause; and third, the supportive measures to prevent complications. Clinicians must be mindful that patients in a state of catatonia are often unable to consent to treatment and that a legal framework to provide this in their best interests should be in place.
Despite the paucity of randomized controlled trials (RCTs), the available literature overwhelmingly suggests that benzodiazepines (in particular lorazepam, but also diazepam, clonazepam, and oxazepam) are very effective in improving catatonia, and they are safe in most patients [30]. This is believed to be through their affinity and effect on GABA-A receptors [37]. Treatment can be dramatically effective, with a complete resolution of signs in 60-80% of acute cases [39]. Treatment should then continue until the treatment for the cause of catatonia is well under way and there are no further signs of catatonia.
The principles of treatment of catatonia are outlined in Box 1, and are adapted to an older adult population [30,37].
Other pharmacological interventions are also available if lorazepam or other benzodiazepines cannot be administered, or as augmentation strategies. The evidence base is currently very limited. These other drugs are also normally administered orally and may not be ideal for those requiring other routes of administration, and tend to be slower in the onset of their effect with the exception of zolpidem (another GABA-A agonist). The following drugs can provide beneficial effects: amantadine and memantine (NMDA receptor antagonists, although it is possible that the effect is via enhancement of dopamine levels in frontal cortex and striatum [30]), bromocriptine, sodium valproate, carbamazepine, and topiramate (see [30] for review).
ECT is also very effective. Eighty to one hundred percent of patients with catatonia respond to ECT [40]. In the United Kingdom, it is approved by the National Institute for Health and Care Excellence (NICE) for the treatment of catatonia [41]. ECT should be considered as first line in malignant catatonia, NMS, and delirious mania [40]. It should also be considered in catatonia unresponsive or partially responsive to benzodiazepines [40]. -Always consider the diagnosis of catatonia -Review the medication regime (especially for dopamine antagonists such as antipsychotic drugs or metoclopramide) and carry out a physical examination and investigations to identify the cause -Start treatment for the cause of catatonia as soon as possible -Administer a therapeutic challenge of lorazepam 0.5-1 mg po/IM. If ineffective, repeat again after 30 min, and then again in another 3 h -An initial positive response usually predicts a more sustained response with further doses and would confirm the diagnosis in 80% of cases - The dosage of lorazepam that was effective in resolving the symptoms should be continued until treatment of the primary disorder is well underway. In older persons, usually 0.5 mg three to four times a day -A premature suspension of treatment with lorazepam is likely to result in a recurrence of catatonic signs -Dose titration should be against sedation -Lorazepam should be switched to oral administration as soon as possible if intramuscular or intravenous administration had been started first -A course of electroconvulsive therapy (ECT) should be considered if there is minimal or no response to lorazepam -If the primary cause of catatonia is a psychotic illness, antipsychotics may be re-introduced when the signs of catatonia have been controlled

Prognosis
Catatonia tends to have a good prognosis if it is detected early, its cause is treated, its symptoms managed, and complications avoided. In medical catatonia, metabolic causes may have a better prognosis than structural brain lesions [31]. Older adults in general hospitals with a longer duration of untreated catatonia may have a worse outcome in terms of complications [5].

Conclusions
Catatonia is not infrequent in older adults in acute general medical settings, where its non-psychiatric causes can represent up to almost a third of all cases [13], and where it can be associated with delirium in up to 50% of cases [5,10]. Undiagnosed and untreated catatonia can lead to an increased risk of complications and mortality [4,5], and it is therefore paramount that clinicians working with older adults in these settings have an increased awareness of this condition in order to implement the appropriate treatment for the symptoms of catatonia and its causes.