Catatonia – Pathophysiology, Diagnosis and Management

AETIOLOGY AND PATHOPHYSIOLOGY

The neurobiology of catatonia is believed to originate in disturbances in GABA, glutamate, and dopamine signalling, which are hypothesised to underlie the behavioural, motor, cognitive, and affective symptoms of catatonia [Northoff 2002]:

• Reduced GABA-A receptor activity in the right lateral orbitofrontal and right posterior parietal cortex, which would explain the motor and affective symptoms but not behavioural catatonic symptoms. Furthermore, this explains the efficacy of benzodiazepines, which increase GABA activity and are therapeutically effective in up to 70% of patients.
• Glutamate is an excitatory neurotransmitter and glutamatergic abnormalities in the basal ganglia have been suggested to be a driver of catatonia-related glutamate hyperactivity. Therapeutic recovery with the NMDA-antagonist, amantadine, is gradual and therefore NMDA receptors are likely to be a secondary mechanism (unlike GABA-A receptors)
• Dysfunctional dopamine metabolism was originally hypothesised to be linked to catatonia during the 1970’s however the data is inconsistent. Evidence of sudden and massive dopamine blockade in the striatal dopaminergic system does, however, explain why antipsychotics such as haloperidol can exacerbate the syndrome (i.e. neuroleptic-induced catatonia).
• Catatonia may also be an evolutionary fear response to imminent danger that is similar to the animal defence strategy of tonic immobility. [Moskowitz et al 2004] The ‘death feint’ is an instinctive response to predators that detect movement but in humans of today is now inappropriately triggered by modern-day threats.

DIAGNOSIS

The classical clinical feature of catatonia is stupor, which is characterised by immobility and mutism. Another classic symptom is posturing, whereby the patient positions themselves in an uncomfortable position against gravity with complete akinesia.

Catatonia is an identifiable syndrome that is well characterised and defined in the DSM-V as a separate clinical diagnosis to schizophrenia. [APA 2013]

Although the catatonic subtype of schizophrenia has been deleted from the DSM, catatonia is still included as a specifier for schizophrenia and major mood disorders (bipolar disorder, major depressive disorder, and other mental, and neurodevelopmental disorders).

Catatonia is also a specifier for brief psychotic disorder, schizoaffective disorder, schizophreniform disorder and substance-induced psychotic disorder.

A new residual diagnostic category of catatonia not otherwise specified (NOS) is added in patients with psychiatric conditions other than schizophrenia or mood disorders or when the general medical condition is not immediately recognised. [Luchini et al. 2015]

Classification of Catatonia

There are several proposed classifications of catatonia, which is outside the scope of this article. For further reading, please refer to Luchini F et al., 2015

Taylor and Fink proposed that catatonia should be classified as an independent entity with three subtypes:[Taylor and Fink, 2003]

1. Non-malignant (Kahlbaum syndrome): the most frequent form of catatonia which has a positive response to treatment with benzodiazepines (lorazepam 6-20 mg IV)
2. Delirious catatonia: defined by the presence of excitement, altered states of consciousness and delirium requiring higher doses of BZDs, worsens with antipsychotics (APs) and often requires adjunctive ECT.
3. Malignant catatonia: acute onset, fever, autonomic instability, leucocytosis, increased CK. This type responds to ECT. Due to the similarity with the presentation of neuroleptic malignant syndrome, Fink suggested that malignant catatonia and NMS should be considered the same disorder.

One key difference highlighted between NMS and catatonia is that malignant catatonia starts with psychotic excitement while NMS starts with severe extrapyramidal muscular rigidity.

The alternative clinical classification includes:

1. Retarded catatonia:  characterised by immobility, mutism, staring, rigidity,

2. Excited catatonia: less common presentation in which patients develop prolonged periods of psychomotor agitation

Rating Scales

1. Bush- Francis Catatonia Rating Scale (BCFRS)
2. Modified Rogers Scale (MRS)

It is important to rule out organic causes: 

A systematic review showed that: [Oldham MA, 2018]

• Hospital-wide, 20% of catatonia was medical.
• In acute medical and surgical settings, medical catatonia comprised more than half of the cases.
• At least 80% of older adults seen by consult psychiatry and critically ill patients had a medical cause.
• Two-thirds of medical catatonia involved CNS-specific disease including encephalitis, neural injury, developmental disorders, structural brain pathology, or seizures.

CLINICAL FEATURES OF CATATONIA

Catatonia presents with a range of clinical signs that are relatively non-specific.

The video below shows the signs of waxy flexibility, forced grasping, opposition, negativism and aversion.

1. Stupor – The classic and most striking catatonic sign. It is a combination of immobility and mutism although both can occur independently.
2. Automatic obedience – subject does whatever is asked of him or her, despite being told not to.
3. Ambitendence – alternating cooperation and opposition; the patient makes a movement, but before completing it, starts the opposite movement
4. Aversion – The patient turns away from the examiner when
   addressed.
5. Echopraxia – subject imitates the movements of the interviewer
6. Echolalia – words or phrases are imitated
7. Perseveration – senseless repetition of previously requested movement, i.e. the repetition of a response after the withdrawal of stimulus (palilalia – the perseverated word is repeated with increasing frequency;  logoclonia – perseveration of the last syllable of the last word seen in organic disorders and occasionally in catatonia)
8. Forced grasping – the offered hand is repeatedly grasped and shaken, despite requests not to do so. Seen in frontal lobe lesions
9. Mitmachen – the body can be put into any posture, despite instructions to resist
10. Mitgehen – an extreme form of mitmachen in which very slight pressure leads to movement in any direction; the ‘anglepoise’ effect, despite being told to resist the pressure; often associated with forced grasping
11. Mannerisms – repetitive goal-directed movements
12. Posturing – strange and abnormal postures adopted habitually
13. Perseveration of posture or catalepsy – if the subject’s body is placed in an awkward posture and left, the posture is held for a period before slowly relaxing, despite asking the patient to relax
14. Waxy flexibility – smooth resistant muscle tone is felt to initial movement (.flexibilitas cerea); e.g. ‘psychological pillow’
15. Negativism – A disorder of volition in which patients do the reverse of whatever is asked of them, e.g. resist attempts to stand when asked to stand up
16. Gegenhalten or opposition (‘against hold’) – A form of negativism in which the springy resistance to passive movement increases with the force exerted
17. Obstruction – The patient stops suddenly in the course of a movement and is generally unable to give a reason. This appears to be the motor counterpart of thought block.
18. Positivism – includes echopraxia and mitgehen and automatic obedience

Waxy Flexibility

Psychological Pillow – Catatonia

DIFFERENTIAL DIAGNOSIS OF CATATONIA

Catatonia is often confused with a variety of other conditions that have signs that are similar to catatonia, although the full clinical picture is normally distinguishable: [Bahti et al. 2007; Rasmussen et al. 2016]

• Parkinson’s disease –Akinesia and rigidity are commonly associated with Parkinson’s disease; however, catatonia also has strong affective and behavioural abnormalities that do not generally occur in cases of Parkinson’s disease. Tremor is also notably absent in catatonia.
• Extra-pyramidal side-effects (EPSE) – Adverse events commonly observed with antipsychotics that can present with immobility, rigidity, and staring. Postural instability can be exacerbated by benzodiazepines, and so the distinction between EPS and catatonia is important.
• Neuroleptic malignant syndrome – A serious adverse event associated with antipsychotics that is characterised by rigidity and mutism however, autonomic instability differentiates this syndrome from catatonia.
• Nonconvulsive status epilepticus – Often indistinguishable from catatonia however, an electroencephalogram (EEG) can assist in making the correct diagnosis.
• Abulia or akinetic mutism – Moderate or severely diminished motivation that can result in the absence of speech or movement; however, visual tracking is preserved. It does not present with negativism or echophenomena.
• Locked-in syndrome – Complete paralysis caused by ventral pontine lesions, which may be detectable by MRI or by brainstem potential examination.
• Vegetative state – Often a secondary feature of severe cerebral injury that can be distinguished from catatonia by an abnormal EEG.
• Stiff-person syndrome – An autoimmune disorder characterised by lower extremity stiffness and spasms that are very painful, and as such patients are generally not mute like catatonic patients. A GAD65 antibody seropositive result is indicative of stiff-person syndrome.
• Organic Disorders – metabolic disorders (hyponatraemia, Tay-Sachs disease, Wilson’s disease), infections, drugs.
• Subarachnoid haemorrhages
• Antiphospholipid syndrome
• Systemic Lupus Erythematosus

Risk factors for Catatonia

1. Affective disorders
2. Increasing age
3. Postpartum disorders
4. Abrupt cessation of clozapine
5. Thrombotic thrombocytopenic purpura
6. History of severe infectious disease in childhood, including rheumatic fever, is associated with an increased risk of catatonia
   in adult life
7. Prior brain injury
8. Physical illness at onset of psychosis

INVESTIGATIONS

First-line

• Full blood count
• Renal function tests
• Liver function tests
• Thyroid function tests
• Blood glucose measurement
• Creatine phosphokinase measurement
• Drug screen of urine

Further investigations (depending on findings on physical examination)

• Electrocardiography
• Computed tomography
• Magnetic resonance imaging
• Electroencephalography
• Urine culture
• Blood culture
• Test for syphilis
• Test for HIV
• Heavy-metal screen
• Auto-antibody screen
• Lumbar puncture

TREATMENT FOR CATATONIA

Early treatment is important and clinical research has shown that electroconvulsive therapy (ECT) and/or benzodiazepines are the recommended first-line choices for treating catatonia. Combination therapy is clinically advantageous for increasing GABA neurotransmission. [Escobar et al 2000]

Benzodiazepines

• Lorazepam is particularly effective following a positive Lorazepam Challenge Test (1–2 mg in adults and 0.5–1 mg in children and geriatric patients delivered orally, IM, or IV).
• Dose is increased to 6–16 mg/day although dosage must be kept high (up to <30 mg/day) and treatment prolonged for complete resolution of catatonic symptoms.
• Diazepam and zolpidem are alternatives to lorazepam however much higher doses are required.
• Overall response rate of 70%

Electroconvulsive therapy

• ECT has been used since 1934 with efficacy ranging from 53 to 100% with right unilateral ECT reported to even be effective after one treatment. [Kugler et al 2015; Medda et al 2015]
• Often reserved for patients with treatment-resistant malignant catatonia
• Treatment of choice in malignant catatonia (85 % response) which is less likely to respond to BZDs (40%)
• Consider sessions close to each other (three per week)

BZD and ECT combined can have a synergistic effect.

Alternative treatments such as aripiprazole (partial dopamine agonist), has the potential to be marginally effective however more research is required as most of the data is based on case reports. [Muneoka et al 2017]

High potency antipsychotics should be avoided, however, second-generation antipsychotics may be used to treat comorbid psychosis, which has also been shown to be effective in treating acute catatonia. [Hesslinger et al 2001]

Below is the algorithm by Beach S et al., 2017.

Below is another clinical algorithm by Dr Tyler Black. 

COMPLICATIONS OF CATATONIA

1. Dehydration and starvation
2. Increased risk of Deep vein thrombosis and death due to pulmonary embolism in patients with persistent catatonia
3. Significant risk of harm to self or others in the phase of catatonic excitement
4. Progression to NMS with high mortality if untreated

CONCLUSION

Catatonia is a common syndrome in psychiatric patients and the symptoms and signs of catatonia require careful assessment so that the correct treatment strategy is engaged without delay to avoid precipitating neuroleptic malignant syndrome or severe medical complications.

ECT and/or benzodiazepines are safe and effective interventions with the majority responding to BZDs. Once catatonia is resolved, treatment of the underlying psychiatric or medical illness should begin.

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