Aug. 15, 2022
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Catatonia is a complex syndrome that has undergone considerable evolution since it was initially described as a subtype of schizophrenia. This condition is now thought to result from multiple medical and psychiatric conditions and may be more often linked to affective disorders than schizophrenia. Increasingly, early recognition is thought to be a good prognostic factor, and the diagnosis should be considered in patients who suddenly develop an acute to subacute change in behavior associated with hyperkinetic and hypokinetic movement disorders. Patients most often benefit from treatment with benzodiazepines or electroconvulsive therapy in addition to treatment of the underlying clinical condition; however, there is a paucity of randomized, controlled trials to guide therapeutics. In this updated article, current reports on the association of catatonia with SARS-CoV-2 (COVID-19) are discussed.
• Catatonia is a constellation of symptoms, or a syndrome, characterized by motor manifestations and mental status changes, including posturing, hyperreflexia, immobility, negativism, mutism, and withdrawal.
• Catatonia can be associated with psychiatric conditions, such as schizophrenia and affective disorders, or with a wide array of medical illnesses.
• Imaging studies suggest that changes in cortical and basal ganglia structures are related to motor manifestations; multiple neurotransmitter systems are implicated and include GABAergic, dopaminergic, and glutamatergic pathways.
• Studies of families with inherited vulnerability to catatonia have identified possible loci of interest on chromosomes 15q15 and 22q13.
• Catatonia is primarily treated by addressing the underlying condition and with benzodiazepines or electroconvulsive therapy.
• Pharmacotherapies that modulate the balance between excitatory and inhibitory pathways can be considered as alternative treatments when benzodiazepines or electroconvulsive therapy are not effective or accessible.
Since its original description, catatonia has remained a poorly defined clinical condition that is characterized by disturbed motor behavior initially described in the presence of severe mental illness. In 1874, the term "catatonia" was coined by Kahlbaum to describe a syndrome "with a cyclic, alternating course in which mental symptoms are consecutively as follows: melancholy, mania, stupor, confusion, and eventually, dementia" (52). Kraepelin later suggested that catatonia should be classified phenomenologically with the other forms of dementia praecox: hebephrenia and paranoia (45). Bleuler's work resulted in the term "catatonia," which became synonymous with behavioral immobility and withdrawal, a symptom often linked to schizophrenia (67).
In the mid-1970s, investigators reemphasized the association of catatonia with affective disorders, as well as an idiopathic or primary disorder (01; 52; 17; 113). Furthermore, there was increasing recognition of “secondary” catatonia, which develops in association with organic causes such as neurologic disease (including tumors), drug intoxication or withdrawal, and other metabolic disorders, including paraneoplastic syndromes (27; 10; 69).
Malignant catatonia represents the most severe form of this syndrome and is more often seen in the presence of organic illness, illicit or therapeutic drug toxicity, or other metabolic encephalopathy (115). On a broader scale, catatonia has been linked to other neuropsychiatric syndromes such as delirium, serotonin syndrome, and neuroleptic malignant syndrome (09; 152; 67; 147; 46; 114; 47; 144; 79). In a review, Wijemanne and Jankovic emphasized 2 subtypes of this disorder (153). Malignant catatonia has a much poorer prognosis and is associated with rapid onset, fever, hypertension, and without the distinguishing features of involuntary movements, which is similar to neuroleptic malignant syndrome. Periodic catatonia is characterized by recurrent episodes of illness lasting 4 to 10 days that may occur over many years. This condition appears to be less frequent than the malignant form and has been reported as an autosomal dominant disorder linked to chromosome 15q15 (138).
Catatonia is a clinical syndrome consisting of a constellation of abnormal motor behaviors and responses. Reports and descriptions of catatonic cases include multiple, singular phenomena including excitement, immobility, negativism, mutism, stereotypies, mannerisms, withdrawal (refusal to eat or drink), and echophenomena (123). A wide array of additional behavioral and motor disorders can be described: staring, rigidity, posturing, negativism, waxy flexibility (or catalepsy), verbigeration, grimacing, increased muscular tension, and other findings in the neurologic examination (Table 1) (27).
• autonomic instability (fever, tachypnea, tachycardia)
• emotional lability
• disturbances in thought
• minimally responsive
The diagnosis of catatonia hinges on the recognition of an evolution of motor symptoms that ranges from agitated excitement to severe withdrawal, catalepsy, and mutism (52). With agitated excitement, stereotypic movements, such as rocking, hand waving, or complex repeated movements of the face, trunk, or limbs, may be seen (86). Vocalizations, such as chanting or repetitious utterances (including palilalia or echolalia) can also be present. These periods of excitement often give way to and alternate with episodes of withdrawal and may be superimposed on a background of drug-induced dyskinesias.
In some instances, patients will not communicate or eat, exhibit signs of catalepsy or waxy flexibility, and may require a feeding tube to maintain adequate hydration or nutrition (139).
Patients may also exhibit mitgehen, a condition in which patients are extremely compliant and will assume changes in posture with only slight effort from an examiner (86). This phenomenon is also termed catalepsy or waxy flexibility. Alternatively, gegenhalten or paratonia is characterized as active resistance of any effort to examine or move a patient.
In a literature review of 261 cases of catatonia secondary to general medical conditions, mutism was present in 70.1% of patients, withdrawal in 55.5% of patients, immobility in 44.1% of patients, negativism in 39.1% of patients, posturing in 36.0% of patients, catalepsy in 35.6% of patients, and waxy flexibility in 34.9% of patients (27). Staring, increased muscular tension, and rigidity were seen in approximately one fourth of patients. Stereotypies were present in 16.1% of patients, but echophenomena, mannerisms, positivism, verbigeration, and "bizarreries" were seen less than 10% of the time.
In severe cases, catatonia can progress to the malignant form with rigidity, hyperthermia, and autonomic instability. Malignant catatonia is described as "stuporous exhaustion with extreme hyperthermia followed by coma, cardiovascular collapse, and death" (88). Neuroleptic malignant syndrome, a syndrome associated with the use of neuroleptic drugs, has now been described as a separate disorder (32); however, many authors believe neuroleptic malignant syndrome and malignant catatonia to be nearly identical or conditions on the same spectrum (09; 152; 67; 79), and case reports of "neuroleptic malignant syndrome in the absence of neuroleptics" further emphasize the similarities between these conditions (115). Furthermore, in late stages, both neuroleptic malignant syndrome and malignant catatonia may be virtually indistinguishable (71). Some authors theorize that catatonia may be a risk factor for developing neuroleptic malignant syndrome; indeed, there are case reports of patients developing neuroleptic malignant syndrome after receiving antipsychotics such as clozapine for catatonia (110; 124; 83).
Catatonia is often considered a manifestation of an underlying condition. As a severe form, there are emerging data suggesting that catatonia may be a prodromal stage of diffuse Lewy body dementia. In a longitudinal study of 21 patients with psychotic symptoms who went on to develop Lewy body dementia, catatonia was observed in 9 cases over the observational period (146).
Catatonia in the Diagnostic and Statistical Manual (DSM). Because catatonia is a clinical diagnosis with great variability, there has been an evolution of the criteria used for diagnosis. With the publishing of the Diagnostic and Statistical Manual (DSM) 5 in 2013, criteria for catatonia have been modified to reflect current thinking about catatonia as a syndrome (07). DSM-5 recognizes that catatonia can occur as a 1) feature of a psychiatric disorder, including affective disorders, psychotic disorders, neurodevelopmental disorders, and others, 2) secondary to a general medical condition, and 3) unspecified catatonia. When catatonia is determined to be associated with a psychiatric disorder, it is specifier of that disease (eg, major depressive disorder with catatonia, 293.89). If catatonia is associated with a medical illness such as hypercalcemia, the diagnosis would be “catatonic disorder due to hypercalcemia.” If clinically significant catatonia is observed, but either the underlying etiology is unclear, there is insufficient information, or full criteria are not met, it is given the term “unspecified catatonia” (other symptoms involving nervous and musculoskeletal systems; unspecified catatonia). Regardless of the underlying etiology, the criteria to define catatonia are the same across diagnoses in DSM-5 (Table 2).
In addition to the DSM, rating scales have been developed to quantify symptom burden and severity. These scales can be useful both to identify catatonia but also to track the efficacy of interventions and course of illness. Scales include the Bush-Francis Catatonia Rating Scale, Kanner rating scale, and Northoff Catatonia Scale, which distinguishes itself by including criteria for affective disorders and extrapyramidal hyperkinesias (25; 105; 30). The Bush-Francis scale is used often. In the absence of high-quality data to support 1 scale over another, consistent use of 1 scale is recommended.
Catatonia and delirium are both syndromes that can be attributed to underlying medical conditions and considerable clinical overlap, especially as defined by DSM-5. A study of ICU patients assessed the prevalence of delirium and catatonia assessed by the Confusion Assessment Method for the ICU and Bush-Francis scales, respectively. Of the 136 patients studied, 43% demonstrated delirium, 3% only catatonia, and 31% demonstrated both. Researchers questioned whether the criteria in DSM-5 that exclude coexisting delirium should be reconsidered given the frequency of both diagnoses (154). It is also possible that the DSM-5 criteria for catatonia are too broad. Further research is needed to understand clinical presentations with features of both catatonia and delirium and if they respond differently than the individual conditions or are an intermediate phenotype.
Prognosis for recovery from catatonia depends foremost on the recognition of the syndrome, and subsequent diagnosis and treatment of any underlying medical disorder to prevent the progression to malignant catatonia. In Kahlbaum's original description, 7 of 21 patients are believed to have died from secondary illness, but 8 of the remaining patients did recover (01). An autopsy study of 20 cases of catatonia found pulmonary embolism in all subjects, suggesting vascular complications as a leading cause of death in this population (90). A retrospective study examined the incidence of deep vein thrombosis in involuntarily hospitalized patients who were restrained in catatonic versus noncatatonic patients over a 3-year period in Japan (65). They found that the odds ratio for deep vein thrombosis in catatonia was 3.21 (95% CI 1.54-6.72) and was related to preexisting risk factors for thrombosis. When catatonic patients were delineated by excited versus retarded catatonia, the odds of deep vein thrombosis were only significant in retarded catatonia (OR 4.36; 95% CI 1.85-10.28) (65). This suggests that ensuring deep vein thrombosis prophylaxis is a critical part of a management of catatonia.
Progression of catatonia to its lethal or malignant form is another concern. Malignant catatonia is characterized by hyperthermia, hypertension or hypotension, tachycardia, and tachypnea, and it has been considered on the spectrum with neuroleptic malignant syndrome and can be fatal. If the patient does not respond to benzodiazepines or other pharmacologic treatments, electroconvulsive therapy may be necessary, though it can be challenging to coordinate treatments in an urgent manner (80).
Although the data are limited, recovery from catatonia is possible. Of 19 patients with catatonic depression treated with electroconvulsive therapy, 84% did not require further hospitalization; none of the patients discharged without antidepressant medications were hospitalized, and 3 patients of the 10 patients discharged with medications required readmission during a 3- to 7-year interval (142). Complete remission or marked improvement of catatonic symptoms in 36 patients of 54 patients (66%) treated for bipolar disorder has been documented (01). Not unexpectedly, patients with catatonic schizophrenia demonstrate the poorest prognosis. In a retrospective analysis of 214 subjects, less than 20% of 36 patients meeting only 1 diagnostic criterion for catatonia improved, whereas over 60% of the 22 patients meeting 5 criteria improved (95).
A history of catatonia may be associated with worse performance on tests of verbal fluency and processing speed in patients with schizophrenia spectrum disorders, even when controlling for antipsychotic and benzodiazepine administration (38). This suggests changes in function that persist after resolution of the episodes but could also be a proxy for severity of illness.
The patient is a 22-year-old, previously psychologically and neurologically healthy woman, admitted after a 4-week hospitalization for progressive immobility, mutism, posturing, and tremor. She initially was admitted to the outside institution with a 3-day history of diffuse postural tremor, bizarre behavior, and social withdrawal. Initial evaluation showed a cerebrospinal fluid (CSF) lymphocytosis, elevated liver transaminases, and an electroencephalogram (EEG) with bifrontal slowing. Extensive evaluation was unremarkable, except for positron emission tomographic (PET) scanning that suggested bilateral cortical and asymmetric thalamic hypometabolism. Prior to transfer, she became mute, and required a feeding gastrostomy and urinary catheter. Her initial neurologic examination revealed a mute woman with a staring, frightened expression. Cranial nerves were intact. Examination of muscle tone revealed gegenhalten and, at times, she exhibited catalepsy (waxy flexibility). She had a diffuse, asymmetric tremor, repetitive tongue thrusting, and occasional dystonic posturing of the arms. She had remarkable insensitivity to noxious stimuli, normal reflexes, and flexor plantar responses. Repeat cerebrospinal fluid and liver function testing was normal. Twenty-four-hour EEG demonstrated no abnormalities, other than less than 2 hours slow-wave sleep. Based on her history of intermittent agitation and verbigeration with progression into a mute, immobile state, punctuated with random tremors, stereotypies, and abnormal tone, she was diagnosed with catatonia. Intravenous lorazepam improved her motor symptoms but produced excessive sedation and respiratory compromise. Four treatments with electroconvulsive therapy (ECT), administered over 2 weeks, resulted in dramatic improvement in her symptoms. Repeat FDG-PET was normal. She was discharged to a rehabilitation facility, and at a 6-month follow-up, had made a full recovery (134).
The etiology of idiopathic catatonia is unknown (118; 17). Prior to DSM-5, catatonia was described as “primary” when associated with psychiatric disease such as depression, bipolar illness, and schizophrenia (22; 140). However, catatonia has also been linked with other psychiatric conditions such as Tourette syndrome (33), autism, and obsessive-compulsive disorder (49; 50; 99; 64).
Catatonia secondary to general medical conditions is increasingly recognized. Carroll and associates reviewed 261 documented cases and reported catatonia resulting from neurologic disease (74%), illicit or therapeutic drug intoxication (17%), and metabolic encephalopathy (9%) (27). A vast array of drugs as well as withdrawal states have been reported to cause catatonia (See Table 2).
Neuropsychiatric symptoms have increasingly been recognized as a consequence of infection with the SARS-CoV-2 virus, leading to COVID-19 illness. Case reports emerged in 2020 indicating that patients with COVID-19 had catatonia both during acute infection as well as persisting after the resolution of the pulmonary symptoms (post-infection); one case of catatonia was due to severe depression as a result of the pandemic (128).
At present, catatonia is a clinical diagnosis based on observation and evaluation of the clinical picture; however, there is promise that the emergence of possible genetic loci (15q13-22 and 22q13.33) will eventually assist in the characterization of catatonia (94; 132). In addition, genetic testing can potentially facilitate distinguishing between catatonia and the potentially more common movement disorders associated with neuroleptic or dopamine-receptor blocking drugs (66; 19). However, if catatonia and neuroleptic malignant syndrome (NMS) are on a spectrum, as has been hypothesized, a genetic marker may not be specific (83).
A study of 139 patients with familial catatonic schizophrenia postulates that both an autosomal dominant genetic predisposition and an environmental insult are necessary for the development of recurrent or “periodic” catatonia (137). An accompanying paper that reviewed 135 first-degree relatives with 57 affected subjects, identified 2 candidate loci (chromosome 15q15 and 22q13) for this disorder (137). Subsequently, this group suggested the gene for periodic catatonia localizes distal to the nicotinic acetylcholine receptor (15q13.2) locus at 15q13-22 (94). This lab has also reported a strong linkage in a multiplex family study, linking the periodic catatonia subtype of schizophrenia to 15q15, and has excluded the DLL4 gene within this region (92). This gene is expressed in the developing forebrain and was both a functional and positional candidate for this syndrome. Another candidate gene, zinc transporter SLC30A4, has also been excluded from the 15q15 region (75). The MLC1 gene, located on 22q13, has been linked to periodic catatonia in a single nucleotide polymorphism analysis (132).
Schanze and colleagues assessed variation in conserved and ultra-conserved non-genic sequence elements at a critical 7.35 Mb interval on chromosome 15q15 in 8 unrelated cases of periodic catatonia and 8 controls that were followed in association studies (127). Three variants that were located within these conserved and ultra-conserved non-genic elements were found only in cases of catatonia, but a significant association with catatonia could not be confirmed.
Given the rare occurrence of catatonia and typical resolution with treatment, histopathologic correlates of catatonia are rarely reported in the literature, and only in patients with the lethal form. Hypothalamic necrosis, particularly in the lateral and anterior nuclei, has been seen in these patients and is thought to correlate with hyperthermia, and some brains have demonstrated cerebellar degeneration secondary to hyperpyrexia (122; 27). Other neuropathological changes include degeneration and atrophy of the caudate nucleus, nucleus accumbens with loss of small and large cells, pallidal atrophy with volume loss in internal globus pallidus, and decreased cell density in the mediodorsal nucleus of the thalamus (101).
Imaging studies have revealed specific brain regions that may be involved in catatonia and have largely pointed to cortical and basal ganglia regions involved in movement, sensory processing, and emotion. In 2 subjects, functional MRI (fMRI) has demonstrated reduced contralateral motor cortex activation during sequential finger opposition, when compared to age-matched controls (102). These authors also compared 10 akinetic catatonic subjects with noncatatonic psychiatric and healthy controls and reported alterations in orbitofrontal cortical activation pattern and in the premotor cortex (106). Further fMRI studies comparing catatonic patients versus healthy controls in self-initiated movement paradigms demonstrate decreased activation of the supplementary motor area, prefrontal cortex, and parietal cortex not evident in externally triggered movements (129). fMRI data suggest a role for orbitofrontal cortex and GABAergic pathways in emotional processing in catatonia. In a double-blind design, catatonic patients were monitored for activation patterns related to processing of the Internal Affective Picture System (121). As compared to catatonic patients receiving placebo, exposure to negative emotional pictures in patients with lorazepam led to activity patterns more comparable with health controls.
A study that examined resting-state cerebral blood flow in patients with schizophrenia with and without catatonia versus normal controls demonstrated supplementary motor area resting-state hyperperfusion as a marker of current catatonia as well as grey matter loss in the frontal and insular cortices, reinforcing a role for the premotor areas in catatonia (151).
Similarly, other imaging modalities have also revealed alterations in cortical and subcortical pathways. SPECT scanning has revealed significantly lowered iomazenil binding to GABA-a receptors in the right posterior parietal and prefrontal cortex (107). In addition, SPECT hypoperfusion involving both parietal lobe and frontal lobe has been reported in the catatonic schizophrenic population (126). An FDG-PET study in 3 subjects with catatonia has revealed asymmetric, bilateral, frontal hypometabolism with more prominent changes on the left (77). In F-18-dopa–PET, a patient with catatonic schizophrenia revealed increased left basal ganglia perfusion and decreased right basal ganglia perfusion during catatonic stupor. With resolution of symptoms, blood flow in the basal ganglia increased by 20% on the left and 40% on the right, with resolution of the previous asymmetry (85). In a case study of a 64-year-old woman with catatonia and late-onset psychosis, regional cerebral blood flow demonstrated hypoperfusion in the striatum and thalamus and hyperperfusion in the left lateral frontal cortex and left temporal cortex that resolved with treatment (143). Motor cortex hyperperfusion was seen post-treatment. In contrast, a near infrared spectroscopy study of mutism spells in a patient with residual catatonia reveal increased cortical activation in prefrontal areas with positive and negative stimuli (56).
The role of neurotransmitter systems in the development of catatonia is largely unknown; however, stereotypies, rigidity, and restlessness all have been associated with dopaminergic function and have been believed to result from alterations in the basal ganglia. In addition, the autonomic instability in malignant catatonia may result from altered dopaminergic or noradrenergic activity; however, because complex behavioral changes are associated with this disorder, and it is associated with schizophrenia and affective disorders, cortical changes may also play a role.
Given widespread use of benzodiazepines to treat catatonia, changes at the level of the GABA-a receptor have been postulated as a cause for catatonia. It is well accepted that benzodiazepines are effective agents for treating catatonia (125). Withdrawal from benzodiazepines may precipitate catatonia, further suggesting a role for GABAergic transmission (24). A case report suggests that increased GABA-b receptor activation by baclofen may exacerbate catatonia; however, further research is needed in this area (31). How GABAergic transmission plays a role in catatonia is unclear. A small sample of patients with catatonic schizophrenia were noted to have significant decreases in serum brain-derived neurotrophic factor (BDNF) levels after treatment with lorazepam that were associated with concurrent improvement in catatonia, suggesting a possible role for BDNF in GABAergic transmission (63).
A role for glutamatergic pathways has been implicated given reports of anti-NMDA receptor encephalitis with features of catatonia (13). Furthermore, treatment with plasma exchange and immunotherapy to treat the primary cause has been successful in treating the catatonia (36).
There have also been reports of catecholamine depletion with norepinephrine loss in the hypothalamus, dopamine loss in the striatum, and a marked deficiency of choline acetyltransferase throughout the brain (72). A prospective study of plasma homovanillic acid, a dopamine metabolite, in 37 catatonic patients compared to 17 control subjects, demonstrated significantly elevated levels in the 21 patients who had not been exposed to dopamine receptor-blocking drugs. Plasma samples from the remaining study subjects did not differ from the control population (103). An MRI study of patients with schizophrenia revealed smaller midbrain volumes in patients with catatonia as compared to those without catatonia (51).
The association of dopaminergic and cholinergic neurons in the striatum may be important in the development of catatonia, and a dysfunction in the generation of voluntary movements is postulated in akinetic catatonia (108). Perhaps the changes in the motor cortex, mediated through GABA-a impairment or changes in glutamatergic function, produce additional striatal modulation that can result in the generation of this complex neurobehavioral syndrome.
The frequency of catatonia in the general population is difficult to assess and is thought to be underrecognized (82). A study evaluating patients admitted to an inpatient psychiatric service receiving Bush-Francis Rating scales (N=201) had a prevalence of catatonia of 9.45% with no difference in rate or symptom profile, depending on underlying psychotic versus affective disorder (57).
In 261 cases in the world literature, medical conditions associated with catatonia included structural neurologic lesion (74%), illicit or therapeutic drug toxicity (17%), and metabolic encephalopathy (9%) (27) (Table 2). In a prospective analysis of 138 consecutive admissions to a psychiatric hospital, 16 (11%) of the patients were found to have 2 or more symptoms of catatonia, with all but 1 responding to lorazepam (131).
Recognition of catatonia is enhanced with psychiatric consultation whereas patients with features of echolalia, grimacing, and agitation were more likely to be underdiagnosed with catatonia despite meeting criteria (82).
Catatonia may be particularly common in certain conditions, such as seropositive autoimmune encephalitis in children. Nearly a third of 225 patients with autoimmune encephalitis demonstrated catatonia in a retrospective chart (02).
Early recognition and treatment of unusual motor behaviors and emotional lability may prevent development of severe catatonia. There are little data describing prophylaxis for patients who have recurrent catatonia, but it is likely that such patients need to be maintained on a GABAergic agent and/or memantine.
Some of the features of catatonia (eg, decreased responsiveness, mutism, excitement, staring) can be seen in delirium (59; 109). Because both delirium and catatonia can be related to underlying medical illness and can have evolving and waxing and waning courses, it can be difficult to distinguish between them. This is clinically important because the first-line treatment of catatonia is benzodiazepine therapy, which is typically contraindicated in and may worsen delirium that is not related to GABAergic withdrawal.
Movement abnormalities seen in catatonia may appear similar to drug-induced and tardive dyskinesias. Acute drug-induced dystonia, akathisia, parkinsonism, neuroleptic malignant syndrome, or even frontotemporal dementia may be difficult to separate from symptoms of catatonia, especially in an acute care setting in which a detailed history may not be possible (66; 71; 78; 140; 141). Furthermore, in the patient chronically treated with neuroleptics, tardive stereotypy, dystonia, and akathisia may mask the evolution of catatonic symptoms (135).
After 5 years of therapy, advanced Parkinson disease is complicated by levodopa-related motor fluctuations in 50% of patients (136). In this situation, patients may change from severe bradykinesia and rigidity to marked dyskinesia involving the head, trunk, and all the limbs several times throughout the day. If the patient also develops dopaminergic drug-related psychosis and hallucinations, the possibility of catatonia must be considered. In this instance, motor-behavior changes develop more rapidly than would be seen in catatonia.
Malignant catatonia, in the presence of neuroleptic drugs and neuroleptic malignant syndrome can be indistinguishable from an etiologic and diagnostic standpoint. Rapid fluctuations from hyperexcitability with mannerisms and other stereotypies to immobility, mutism and withdrawal, autonomic instability, rigidity, and hyperthermia are seen in both conditions. Creatine kinase elevations are not as likely to occur in catatonia, but a series found increases in 12 patients of 17 patients (27). Ictal or postictal features may be mistaken for catatonia or may cloud diagnosis in patients with schizophrenia and epilepsy (60).
Diagnosis of catatonia is dependent on the history of fluctuating motor and behavioral activities and the clinical findings of any number of motor features including mutism, catalepsy, withdrawal, stereotypies, excitement, and others (67) (Table 1 and 2).
A clinical history will need to be obtained, and in suspected catatonia, it is unlikely to be possible to elicit this from the patient. Collateral from family or caretakers should include descriptions of recent events and detailed medical, psychiatric, and social histories. The clinician should attempt to determine exposure to medication or drugs, prescribed and illicit. It may be possible to obtain a history of severe or worsening mental illness, or a medical disease. However, in many cases, patients have multiple active exposures, medical and psychiatric comorbidities that should be considered (Table 1).
Physical exam, including full neurologic examination, should be attempted. Lack of engagement in the exam may limit the ability to distinguish lateralizing or focal findings in patients with catatonia. However, assessment of reflex asymmetry and assessment for autonomic abnormalities (ie, tachypnea, tachycardia, urinary incontinence, pupillary abnormalities, hypertension, hyperthermia, and diaphoresis) may be helpful. In the agitated or excited patient, every attempt must be made to collect these data as autonomic abnormalities may herald the onset of malignant catatonia.
Clinical exam should include observation of clinical symptoms such as immobility, echophenomena, stupor, agitation or excitement, mutism, catalepsy, verbigeration, mannerisms, staring, and stereotypies. The exam should include elicited signs of catatonia, including waxy flexibility, automatic obedience, ambitendency, negativism, and stimulus-bound behavior. A rating scale, such as the Bush-Francis scale, can be helpful and should be repeated periodically to assess response to treatment.
In patients presenting in an emergency setting, laboratory assessment should include complete blood count, complete metabolic screen, glucose, serum drug concentration levels, and urinary screen for medications and illicit drugs. Ammonia levels can be considered as hepatic encephalopathy can present with similar features.
If no cause is determined, CT or MRI of the brain, spinal fluid examination, and EEG must also be considered. Brain imaging may demonstrate atrophy, particularly in the frontal lobes, cerebellar vermis, and brainstem (122; 68). Although no specific EEG patterns have been associated with catatonic disorder, a record review of 40 patients identified abnormalities in 17 subjects (28). EEG may be helpful in ruling out nonconvulsive status epilepticus as a cause of altered mental status.
When catatonia occurs in a patient who has a previously diagnosed mental illness such as schizophrenia or a mood disorder, the underlying cause may indeed be that condition; however, it is important to evaluate for nonpsychiatric causes, especially in patients with no prior history of catatonia. A case report describes a patient with schizophrenia diagnosed 20 years prior who developed catatonia and received a full medical work-up, including head imaging that revealed a right frontal glioblastoma lesion (87).
Although there is no formal protocol, a test dose of 2 mg of intravenous lorazepam with close observation may be helpful in confirming a clinical suspicion of catatonia. Patients often demonstrate a brisk response, without expected sedation that wears out as the medication is metabolized. Higher doses may be needed if there is partial response with initial dosing.
Treatment of catatonia, unless the malignant form develops, is highly dependent on identification and treatment of the underlying illness. Supportive care is most important in patients with behavioral withdrawal and mutism to ensure adequate nutrition and to avoid development of stasis ulcers, thrombosis, urinary tract infections, dehydration, or pneumonia. Patients with malignant catatonia must be closely monitored for autonomic fluctuations, including tachycardia, tachypnea, hypertension, hyperthermia, pupillary abnormalities, and urinary difficulty.
Benzodiazepines, such as lorazepam, are considered the primary treatment for catatonia. Because lorazepam can be administered intravenously, it can be quickly and easily administered in a patient that may be unable to take oral medications, and the patient’s response can be observed. The risks of lorazepam include sedation, aspiration, and worsening of any delirium and are possibly more pertinent if the patient does not have catatonia. Benzodiazepines should be continued until catatonia symptoms resolve and then slowly tapered. Some patients will have resurgence of catatonic symptoms if benzodiazepines are tapered too quickly and may need to be maintained on benzodiazepines chronically to prevent recurrence (06).
Despite its widespread use, a Cochrane review of benzodiazepines for catatonia revealed no high-quality, trial-derived data to support this treatment. This likely reflects the difficulty designing systematic, randomized controlled trials in this condition due to the unpredictability of catatonic episodes, consent, and low incidence. Much of the evidence-based use of benzodiazepines for this condition is based on smaller studies and reports (54).
The benefit of benzodiazepines may differ depending on the underlying etiology of the catatonic syndrome. A double-blinded, placebo-controlled trial of intravenous lorazepam in 18 subjects with chronic schizophrenia revealed no significant effect (145). Some have argued that patients with catatonia in the context of schizophrenia show less beneficial response to benzodiazepines as compared to patients with catatonia secondary to other causes (124). Data from first-episode, drug-naive patients with psychosis and at least 3 catatonic signs suggest good response with antipsychotic treatment, although this was not compared to treatment with benzodiazepines (112).
There are multiple anecdotal reports of successful treatment catatonia with non-benzodiazepine medications. Such treatments include neuroleptics, anticonvulsants, amobarbital, bromocriptine, clozapine, dantrolene sodium, levodopa, amantadine, lithium, memantine, methylphenidate, zolpidem and tramadol (111; 98; 119; 100; 156; 104; 81; 157; 42; 43; 148; 91; 20; 29; 11; 55; 48; 61; 96; 116; 15). Use of nonbenzodiazepine medications may be chosen to target the underlying psychiatric cause, such as mania, depression, or psychosis. Some clinicians are hesitant to use neuroleptics in the context of catatonia due to concern for conversion or induction of neuroleptic malignant syndrome.
There are situations in which benzodiazepines are not effective, or there is some other contraindication to benzodiazepine use (such as severe respiratory failure).
Zolpidem, a selective GABAA agonist, has been tried as either as an adjunct or a monotherapy for catatonia in case reports. The peak effect was seen at 1 to 2 hours after administration, with onset around 15 minutes after initiation. Due to its short half-life (2.6 hours), zolpidem needs to be dosed frequently to maintain effect (15). Zolpidem was also successfully used in a case of catatonia associated with paraneoplastic encephalitis resulting from an ovarian-teratoma that was not responsive to electroconvulsive therapy or benzodiazepines, or resection of the tumor (08).
Similarly, decreasing excitatory pathways with NMDA-receptor inhibition can also be used to treat catatonia. Memantine 5 mg twice a day was effective at ameliorating catatonia associated with liver transplantation in a patient that had severe hallucinations with zolpidem (23). A patient with schizophrenia and severe obesity hypoventilation syndrome with recent respiratory failure due to pneumonia who developed catatonia was cared for. Given her respiratory status, she was unable to tolerate lorazepam doses greater than 6 mg per day, which were helpful, but not completely effective in ameliorating symptoms. She was started on memantine 5 mg daily (eventually titrated to 10 mg twice a day) and zolpidem 5 mg at night to augment the benzodiazepine therapy, which completely resolved the catatonic symptoms and allowed for reduction of benzodiazepine dosing as preferred by her pulmonologist (Jakel unpublished data).
If treatment of the underlying cause and benzodiazepine or other pharmacologic therapies do not lead to resolution of symptoms, or if there is concern for malignant catatonia, electroconvulsive therapy should be considered (153). Electroconvulsive therapy has been shown to produce dramatic improvement and should be the treatment of choice in a patient with advanced or malignant catatonia, although there are minimal well-designed clinical trials. In a review of 18 patients, death occurred in 2 of the 13 patients treated with electroconvulsive therapy and in 4 of the 5 patients not receiving this therapy (115). In a nonrandomized study of consecutive patients admitted for catatonia, electroconvulsive therapy had better efficacy when compared to any medication (62). There are case reports of successful treatment of malignant catatonia with electroconvulsive therapy (05; 12). Given the lack of randomized, controlled studies, it has been difficult to assess the efficacy of electroconvulsive therapy in catatonia. A systematic review of 8 open, observational studies showed a response rate of 80% to 100% (84).
Data suggest that beneficial response to electroconvulsive therapy is associated with younger age, presence of autonomic dysregulation at baseline, especially higher body temperature, daily treatments, and longer duration of epileptiform activity at last treatment (149). A retrospective study of electroconvulsive therapy in patients with catatonia showed that patients that were “fast responders” (remission in 4 sessions) were more likely to have higher Bush-Francis Catatonia rating scale measures, shorter duration of catatonia, presence of waxy flexibility, and gegenhalten (120). Patients with echophenomena tended to have a slower response to electroconvulsive therapy.
A study of 26 catatonic patients with bipolar disorder who did not respond to treatment with benzodiazepines and were treated with electroconvulsive therapy showed an 80.8% response rate, with 80% reduction in the Bush-Francis Catatonia Rating Scale. This group consisted of primarily women (88.5%), with more retarded symptoms and prior episodes of catatonia. In this sample, responders were more likely to be on typical antipsychotics, whereas nonresponders were more likely to be on atypical antipsychotics and anticholinergic medications (93).
Given the severity of illness in catatonia, bilateral electroconvulsive therapy treatments are usually administered to garner faster response at the risk of worsened side effects. Case series demonstrate rapid and effective treatment of catatonia symptoms with administration of right unilateral electroconvulsive therapy (conventional and ultra-brief) (35; 74), which may reduce potential side effects of electroconvulsive therapy.
Although there is good evidence for electroconvulsive therapy, and there are no absolute contraindications for electroconvulsive therapy, it is not a first-line therapy for several reasons. Electroconvulsive therapy involves an induced seizure under brief anesthesia and is not without risks, including memory impairment, cardiac concerns, status epilepticus, death, musculoskeletal pain, and injury to the oral cavity. Patients with recent acute coronary syndrome or intracranial mass are at elevated risk with electroconvulsive therapy. Because the risks are significant, patients need to consent for the procedure, which may be more complicated than emergent consent for other procedures depending on state laws. Though the logistics may vary by location, the ability to get a proxy to consent for the procedure (as catatonia diminishes capacity) may depend on obtaining emergency guardianship, which can be time-intensive and logistically difficult (133). For these reasons, clinicians are likely to choose a less invasive treatment first.
In general, there are limited data to determine if catatonia associated with a mental illness should be treated differently than catatonia related to a general medical condition. Typically, the recommended approach is to treat the underlying cause (if known) as well as the catatonia with benzodiazepines, electroconvulsive therapy, or NMDA receptor antagonists (124). Indeed, treating the underlying cause may be sufficient in some patients. A case report described resolution of catatonic symptoms in patients with systemic lupus erythematosus with plasma exchange for catatonia (89).
Given the limitations of the current data, with predominance of case reports, Beach and colleagues proposed a treatment algorithm for catatonia (16). If catatonia is suspected, an initial intravenous lorazepam challenge should be commenced. Typical doses of 2 mg are used to ensure sufficient “challenge”. In cases with positive challenges, maintenance dosing of around 6 mg to 8 mg in divided doses are continued for at least 2 to 3 days (or until stable improvement), with eventual transition to oral dosing. If lorazepam is not effective, then consider electroconvulsive therapy for at least 6 treatments. If electroconvulsive therapy is not available, contraindicated, or not effective, a glutamate antagonist such as memantine or amantadine can be considered. If this fails, consider antiepileptic medications such as valproate or carbamazepine. Their last recommendation is the combined use of antipsychotics with lorazepam with monitoring for emergence of neuroleptic malignant syndrome (16).
Little is known about catatonia in pregnancy, and what is known largely comes from case reports. Persistent catatonia has been observed in a pregnant patient with a history of schizophrenia (03). A case report describing malignant catatonia in a pregnant woman has also been published (44).
Catatonia risks the health of the unborn child in addition to that of the mother as it directly compromises basic self-care, as well as the ability to manage prenatal care, potentially resulting in risks to the fetus that include dehydration and malnutrition. Treatment of catatonia in pregnancy is complicated by all the typical challenges of managing illness in pregnant women (changing volumes of distribution, hypercoagulable state, aspiration risks), including teratogenicity of benzodiazepines in pregnancy and increased risks of electroconvulsive therapy in pregnancy. However, there is no absolute contraindication to either treatment in pregnancy. Because of the risks of catatonia, treatment should not be delayed.
Postpartum secondary catatonia has also been described in a female patient with reversible pontine hyperintensity on imaging consistent with posterior reversible encephalopathy syndrome (PRES) that was refractory to benzodiazepine treatment while the lesions persisted (73). Catatonia may be at increased prevalence in the postpartum period, especially in patients with postpartum psychosis. Of 200 women admitted to an inpatient unit specifically for postpartum mothers and babies who had postpartum psychosis, 20% had symptoms of catatonia. This was associated with longer duration of untreated psychosis and earlier onset (97), suggesting the need for vigilance in this population.
Although more frequently described in adults, there are many published cases of catatonia in children. Underlying conditions include lithium toxicity (39), autism (117), B12 and folate deficiency (41), anti-NMDA receptor encephalitis (130), and systemic lupus erythematosus (04). There is a case report of malignant catatonia in an adolescent with sickle cell anemia who responded to electroconvulsive therapy (40).
A review of published cases revealed a mean age of 14.5 years, with associated conditions of infection, neurologic disease, and toxic and genetic disease rather than a relationship to psychiatric causes (76). Most cases of catatonia in children were acute in onset with a high associated mortality. Benzodiazepines were rarely used, and treatment was frequently aimed at treating the underlying organic condition. A small (N=12) retrospective descriptive study of adolescent inpatients with catatonia found that 3 out of 12 patients had a diagnosed medical cause, and out of the remaining 9 patients, 5 had mood disorders, and 2 had psychotic disorders (34). A study of 52 children admitted to a pediatric psychiatry unit diagnosed with catatonia demonstrated that the majority had underlying schizophrenia (up to 75%), followed by organic etiologies (15.4%) and affective disorders (9.6%). The most common symptoms in this study were mutism, immobility, staring, negativism, and posturing (58). Half responded to lorazepam, with the remaining requiring electroconvulsive therapy.
Catatonia in childhood has been associated with a 60-fold increase in premature death as compared to age-matched controls, and it remains elevated when compared to patients with schizophrenia or history of psychiatric illness without catatonia (37). Use of electroconvulsive therapy is extremely rare in pediatric populations and is largely reserved for patients with catatonia and severe suicidal behavior (18).
A retrospective chart review of children and adolescents deemed to be at risk for catatonia based on diagnosis of a disorder with known risk for catatonia (pervasive developmental disorder, psychosis, intermittent explosive disorder, mental retardation, neuroleptic malignant syndrome) or presence of catatonic symptoms was completed (53). Criteria for catatonia included 3 or more symptoms, including unexplained agitation/excitement, unusual movements, presence of stereotypies, and changes in speech; 17.8% of subjects met the criteria, but only 2 subjects had been previously identified by their providers as having catatonia. Rates of aggression and intellectual disability were higher in the group that met study criteria for catatonia. This suggests that catatonia is likely under recognized in the pediatric population.
Patients diagnosed with autism spectrum disorders demonstrate signs and symptoms that overlap with catatonia, including stereotypes, echolalia, mutism, posturing, grimacing, rigidity, and mannerisms, as described by Dr. Leo Kanner. There are case reports of patients with catatonia and autism, with self-injury, not responding to psychotropic agents that benefit from electroconvulsive therapy (40; 150). In fact, some researchers have postulated whether there is an association between autism and catatonia. Mutations in the SHANK3 gene (22q13.3) have been implicated in catatonia in adults with autistic behaviors. SHANK3 is a scaffolding protein that interacts with NMDA receptors, thus suggesting a biological link with autism and intellectual disability (21).
No information is available concerning the association of catatonia with malignant hyperthermia.
Rebekah Jakel MD PhD
Dr. Jakel of Duke University has no relevant financial relationships to disclose.See Profile
Robert Fekete MD
Dr. Fekete of New York Medical College received consultation fees from Acadia, Acorda, Adamas, Amneal/Impax, Kyowa Kirin, Lundbeck, Neurocrine, and Teva.See Profile
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