Catatonia, Neuroleptic Malignant Syndrome, and Serotonin Syndrome

Definition

Catatonia comprises a constellation of motor and behavioral signs and symptoms that occurs in relation to neuromedical or psychiatric insults. Structural brain disease, intrinsic brain disorders (e.g., epilepsy, toxic–metabolic derangements, infectious diseases), a variety of systemic disorders that affect the brain, and idiopathic psychiatric disorders (such as affective and schizophrenic psychoses) have all been associated with catatonia. Catatonia was first defined by Karl Kahlbaum in 1847. It was among the first studies in the area of mental illness to use the symptom-based approach to diagnose disorders without a known etiopathogenesis. Kahlbaum believed that patients with catatonia passed through several phases of illness: a short stage of immobility (with waxy flexibility and posturing), a second stage of stupor or melancholy, a third stage of mania (with pressured speech, hyperactivity, and hyperthymic behavior), and finally, after repeated cycles of stupor and excitement, a stage of dementia.

Kraepelin, who was influenced by Kahlbaum, included catatonia in the group of deteriorating psychotic disorders named dementia praecox. Bleuler adopted Kraepelin's view that catatonia was subsumed under severe idiopathic deteriorating psychoses, which he renamed the schizophrenias .

Kraepelin and Bleuler both recognized that catatonic symptoms could emerge as part of a mood disorder or medical condition, but, as a result of a nosologic misconception, catatonia was overly associated with schizophrenia until the 1990s. Thanks in large part to the work of Fink and Taylor, the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), finally included new criteria for mood disorders with catatonic features and for catatonic disorder secondary to a general medical condition, as well as the catatonic type of schizophrenia. In DSM-5, the catatonic subtype of schizophrenia was removed, leaving diagnoses of catatonia associated with another mental disorder, catatonic disorder due to another medical condition, and unspecified catatonia. According to DSM-5, a diagnosis of catatonia requires three or more of the following symptoms: stupor, catalepsy, waxy flexibility, mutism, negativism, posturing, mannerism, stereotypy, agitation, grimacing, echolalia, or echopraxia. In the case of catatonia due to another medical condition, the symptoms cannot occur exclusively during the course of a delirium.

Epidemiology, Risk Factors, and Potential Etiologies

Primary catatonia refers to catatonia associated with psychiatric etiologies. Prospective studies on patients hospitalized with acute psychotic episodes place the incidence of catatonia in the range of 7–17%. In patients who suffer from mood disorders, occurrence rates have ranged from 13% to 31% over the past century, and catatonia appears to be particularly common in those with bipolar disorder. Some have contended that the incidence of catatonia has diminished in cases of schizophrenia, but diagnostic and study design variations over the decades make this interpretation problematic. Personality disorders, post-traumatic stress disorder, and conversion disorder have also been cited as causes. Catatonia is more common in patients with neurodevelopmental disorders and in those with autism-spectrum disorders, with up to 17% of patients in the latter group displaying symptoms post-adolescence. Catatonia is idiopathic in many cases.

Neuromedical “organic” etiologies account for up to 46% of cases in various series, and are referred to as secondary etiologies of catatonia. This underscores the need for a thorough neuromedical work-up when catatonic signs are present. Among all patients seen on psychiatry consultation-liaison services, up to 6% may have catatonia. Table 23-1 includes an extensive list of neuromedical causes of catatonia; common etiologies include seizures, posterior reversible encephalopathy syndrome (PRES), central nervous system infections, Wernicke's encephalopathy, and systemic lupus erythematosus. In the case of lupus, all reported cases have occurred in females; common symptoms of catatonia include mutism, withdrawal and negativism, and patients need not have evidence of lupus cerebritis on imaging.

Recent literature has highlighted that limbic encephalitis is frequently associated with catatonia. Etiologies of limbic encephalitis include infectious, autoimmune, paraneoplastic, and idiopathic causes. NMDA-receptor antibody encephalitis, often paraneoplastic secondary to an ovarian teratoma but also associated with other tumors and sometimes occurring in the absence of any identifiable tumor, is the form of limbic encephalitis most commonly associated with catatonic features. A typical course begins with a viral-like illness including headache, fever, gastrointestinal and upper respiratory symptoms for up to 2 weeks. Anxiety commonly follows, often with new-onset panic attacks, and psychiatrists are frequently the first providers to examine such patients. Catatonic symptoms emerge later in the course, and are frequently accompanied by delirium, psychosis, behavioral disturbances, autonomic instability, and seizures. These cases respond well to removal of the tumor, if present. Immunosuppressive therapies can often be very helpful. In some cases, the catatonia recurs cyclically following initial treatment and requires maintenance therapy. Cases of NMDA-receptor antibody encephalitis-related catatonia have been successfully treated with electroconvulsive therapy (ECT) prior to diagnosis, suggesting that ECT may represent a treatment alternative in these cases.

Catatonia-spectrum symptoms are commonly described in the setting of hypoxia. Knowledge of this secondary cause of catatonia is critical, as ECT does not appear to be successful as a treatment for catatonia secondary to cerebral hypoxia. In such cases, other treatment modalities for catatonia should be pursued first, allowing for evaluation of delayed neurologic syndrome before administering ECT.

Drug-related etiologies, including prescribed medications, have also been identified as secondary causes of catatonia. Dopamine antagonist medications (e.g., neuroleptics, metoclopramide) and dopamine-depleting medications (e.g., tetrabenazine) can lead to catatonia, as can the removal of dopamine agonist medications, sedative–hypnotic medications, and clozapine. Some medications, including hydroxyzine, have mild dopamine-blocking properties, about which most practitioners are unaware. Withdrawal from gamma amino butyric acid (GABA)-ergic agents, such as alcohol or benzodiazepines, also represents a common etiology for catatonia. In the case of long-acting benzodiazepines, other signs of withdrawal may be subtle at the outset, and the presentation may be delayed. Recently, the literature has described cases of catatonia secondary to dexamethasone and pegylated interferon-alpha 2b and ribavirin. Tacrolimus has also been identified as an offender in several case reports, as has cyclosporine. Disulfiram and baclofen have been implicated in multiple case reports, and antibiotics including macrolides and fluoroquinolones have been cited as causal. Substances of abuse (e.g., phencyclidine, ecstasy) have also been identified as etiologies of secondary catatonia; of late, catatonia secondary to synthetic cannabinoid use has been described as has catatonia secondary to cannabis withdrawal.

Although a genetic predisposition has not been clearly identified for catatonia, there appears to be increased familial transmission with periodic catatonia that shows a pattern of anticipation from generation to generation. The disease locus for periodic catatonia maps onto chromosome 15q15. There appears to be shared genetic susceptibility on chromosome 15 between catatonia in schizophrenia and autism. In addition, Prader–Willi syndrome, a genetic disorder due to lack of gene expression from paternal chromosome 15q11–q13, is associated with catatonia and data supports GABA dysfunction in Prader–Willi, schizophrenia, and autism associated with catatonia. Catatonia has also been associated with other genetic disorders including fragile X and DiGeorge syndrome.

The 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNP) gene is oligodendrocyte/myelin-associated and found to be reduced in brains of patients with schizophrenia, bipolar disorder, or unipolar depression. A distinct phenotype that includes features of catatonia, such as posturing, emerges with aging in mice and patients with mental illness with reduced expression as CNP. Diffusion tensor imaging in these patients reveals axonal loss in the frontal corpus callosum.

Subtypes of Catatonia

Motoric subtypes of catatonia include stuporous catatonia (catatonic withdrawal; characterized by psychomotor hypoactivity) and excited catatonia (characterized by psychomotor hyperactivity), which may alternate during the course of a catatonic episode.

Kraepelin, in 1908, identified a “periodic” catatonia with an onset in adolescence characterized by intermittent excited states, followed by catatonic stuporous stages and a remitting and relapsing course. More recently authors have argued that periodic catatonia supports the DSM-5 category of “unspecified catatonia,” which can be used to diagnose idiopathic cases of catatonia not associated with primary psychiatric or secondary neuromedical causes. These authors highlight that periodic catatonia is defined by a longitudinal course of cyclical relapsing and remitting psychomotor symptoms interrupted by periods of mild residual symptoms and also report that periodic catatonia may respond better to treatment with antipsychotics rather than conventional treatment for catatonia. In 1934, Stauder described lethal catatonia, distinguished by the rapid onset of a manic delirium, high temperatures, and catatonic stupor; it was said to have a mortality rate of more than 50%. An overlapping syndrome, malignant catatonia, has been described more commonly in recent literature, typically involving fever, autonomic instability, and elevated creatinine kinase. Malignant catatonia, regardless of etiology, is considered a psychiatric emergency, and requires prompt treatment with early consideration of ECT.

Delirious mania is a syndrome with acute onset of excitement, grandiosity, emotional lability, delusions, and insomnia characteristic of mania and the disorientation and altered consciousness characteristic of delirium, as well as fever, tachycardia, hypertension, and tachypnea. It overlaps significantly with descriptions of lethal catatonia, and many would consider it a form of malignant, excited catatonia. Other hallmark features of delirious mania include denuding, water obsession, and inappropriate toileting. The diagnostic evaluation, including careful assessment for catatonic symptoms, is essential; patients with delirious mania are often young females. The onset of mania tends to be more rapid than in classic bipolar disorder, and the mania tends to wax and wane with the delirium. The use of lithium and neuroleptics, common medications for the treatment of mania, may worsen the catatonic symptoms and lead to NMS. Higher-dose benzodiazepines are often needed at the outset, and ECT is considered the treatment of choice for patients with delirious mania.

Under the category of secondary causes of catatonia, some now argue that there should be a catatonia subtype associated with delirium, which would include excited forms (as can occur in delirious mania) and stuporous forms (as often seen in cases of encephalitis). Though the DSM-5 excludes the diagnosis of catatonia in the setting of delirium, there is no empirical basis for this exclusion and there is significant overlap between symptoms of catatonia and delirium. In fact, most cases of catatonia secondary to a neuromedical etiology co-occur with delirium. A recent review identified 13 cases from the literature and three cases from their consultation-liaison (C-L) service as meeting criteria for delirium and catatonia and the most common symptoms the patients presented with were mutism, withdrawal, posturing, and immobility. Another recent study identified that 12.7% to 32% of patients with delirium met criteria for catatonic syndrome, and found that catatonia is more common in patients who had delirium prior to hospitalization, in the hypoactive subtype of delirium, and in women. Further study of this subtype of catatonia is needed, as there are likely diagnostic and treatment implications.

Clinical Features and Diagnosis

Signs and symptoms of the catatonic syndrome are outlined in Table 23-1 (the Modified Bush–Francis Catatonia Rating Scale). The specific number and nature of signs and symptoms required to make a diagnosis of catatonia remains controversial. Some have contended that even one cardinal characteristic has as much clinical significance for diagnosis and treatment as the presence of seven or eight characteristics. The DSM-5 now requires 3 of 12 symptoms, while the widely used Bush–Francis Catatonia Rating Scale requires 2 of 14 symptoms for diagnosis and lists 23 symptoms for severity rating. When assessing the etiology of the catatonia, the psychiatrist should consider secondary causes of catatonia related to underlying neurologic, toxic, or metabolic abnormalities, as well as primary psychiatric causes ( Table 23-2 ). An approach to examining patients for catatonia is outlined in Table 23-3 . Because catatonia is significantly under-diagnosed, it is important to maintain a high degree of suspicion and include a brief catatonia evaluation as part of all exams. A key is to differentiate catatonia from other syndromes with similar manifestations but with different etiologies, such as akinetic mutism, locked-in syndrome, and malignant hyperthermia.