Recognizing and Treating Catatonia in Kleefstra Syndrome

Summary

Kleefstra syndrome is a rare genetic condition with numerous effects on the body's functioning. Psychiatric comorbidity in Kleefstra syndrome is common, though reports have been limited. This manuscript highlights the importance of timely catatonia identification and treatment in an adolescent with Kleefstra syndrome.

Abstract

Kleefstra syndrome is a rare genetic disorder (less than 1 in 1,000,000) associated with a mutation of the euchromatic histone lysine methyltransferase 1 gene of the ninth chromosome. This gene controls the production of the enzyme, histone methyltransferase 1, which has widespread impacts on the body's ability to function. There are numerous physiologic impacts of the genetic abnormalities associated with Kleefstra syndrome, including psychiatric and behavioral comorbidities. One of these comorbidities is Catatonia. Catatonia is a neuropsychiatric syndrome that is associated with psychomotor disturbances, with individuals either appearing to be hypokinetic or, less commonly, hyperkinetic. It is defined by a compilation of symptoms that range from changes in communication, movements, and behaviors. Though case reports in the literature are nonexistent, Catatonia is known to be associated with Kleefstra syndrome. Furthermore, the successful treatment of Catatonia associated with Kleefstra has not yet been reported. This case describes a 17-year-old male with a history of Kleefstra syndrome and Catatonia who was successfully treated with scheduled Lorazepam. Discussion of such a case in the literature is important to help other providers appropriately diagnose and treat this often overlooked psychiatric condition in patients with complex genetic syndromes.

Introduction

Kleefstra syndrome (9q34.3 Microdeletion Syndrome) is a rare genetic disorder caused by haploinsufficiency of the euchromatic histone lysine methyltransferase 1 (EHMT1) gene¹. The syndrome is characterized by a variety of dysmorphic features, developmental differences such as intellectual disability (ID) and autism spectrum disorder (ASD), and other comorbid conditions².

Comorbidities of Kleefstra syndrome include hearing loss, congenital heart defects, gastroesophageal reflux disease, renal anomalies, and seizures, among others². Other notable associations include increased prevalence of several psychiatric comorbidities during and after adolescence³. These include aggression, impulsivity, sleep disturbances, functional regression, psychotic/mood disorders, and catatonia¹.

Catatonia is a serious neuropsychiatric syndrome characterized by movements and behaviors that limit activities of daily living and negatively impact quality of life⁴. Catatonia can additionally cause severe and life-threatening complications due to autonomic instability and hyperthermia⁵. Other serious outcomes of Catatonia include deep vein thromboses, pulmonary embolisms, nutritional deficiencies, rhabdomyolysis, pressure ulcers, deconditioning, and contractures. The negative outcomes of both benign and malignant Catatonia make early treatment vital^{6,7,8,9,10,11}.

First-line treatment of Catatonia is benzodiazepines. Catatonia is hypothesized to have an association with decreased activity of Gamma-Aminobutyric acid (GABA)⁷. The marked improvement that patients experience following initiation of benzodiazepine treatment, which increases GABA activity, supports this association⁷. The response to benzodiazepines is estimated to be in the range of 65-100% and occurs within days of treatment initiation. Delayed or inconsistent treatment has been shown to diminish response to benzodiazepines alone and may require additional pharmacological management or regular electroconvulsive therapy (ECT)⁷. Given the diminished response to delayed treatment, early identification is critical.

While treatment guidelines provide guidance for many comorbidities of Kleefstra syndrome, information regarding psychiatric comorbidities is sparse^2,5,6. There are currently no reports on the treatment of Catatonia in a patient with Kleefstra syndrome. One report discussed two adult patients with prominent apathy syndrome, observation of motor signs including rigidity and finger stereotypies, which caused them to score positive on the Bush-Francis Catatonia Rating Scale (BFCRS)³. However, these symptoms persisted over a period of many years; therefore, a diagnosis of Catatonia was considered inappropriate. Additionally, for one patient, the use of benzodiazepines was ineffective for their presenting symptoms³. Benzodiazepines are the accepted first-line treatment for Catatonia.

The BFCRS is a scale developed for the diagnosis and monitoring of catatonic symptoms. It is commonly used as a tool to help in the management of Catatonia. It is a 23-item scale, with the first 14 questions serving as a screening tool. It assesses catatonic symptoms as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5^th edition (DSM-V). Higher scores are representative of a greater concern for Catatonia.

This case highlights symptoms and treatment of Catatonia in a patient with Kleefstra syndrome. Though the diagnostic tools and treatment of the discussed patient's Catatonia were typical, this case presentation brings awareness to an overlooked diagnosis in those with Kleefstra syndrome. Furthermore, this case describes the successful treatment of Catatonia, associated with Kleefstra syndrome, with benzodiazepine in contrast to previous reports in the literature. Of note, those with neurodevelopmental complexity exemplify symptoms of the BFCRS without this being indicative Catatonia. This case presentation serves as a guide to differentiate between baseline symptoms associated with a neurodevelopmental disorder and true Catatonia.

Case presentation

Mr. J presented as a 17-year-old male with a history of Kleefstra Syndrome (deletion of 9q34.3) who presented to the outpatient psychiatric clinic with worsening "frozen-like behaviors". His medical history was significant for conditions associated with Kleefstra syndrome, including autism spectrum disorder (ASD) and intellectual disability (ID). Prior to puberty, the patient had one-word communication with verbal speech and gesturing. He was described as an inquisitive individual who engaged in the world around him and was able to maintain his daily living activities with mild assistance. In the two years prior to initial psychiatric evaluation, parents reported that Mr. J developed upper body movements that were described as "jerks" and long intermittent periods of appearing frozen. These periods of being uncharacteristically still increased in both frequency and duration, until he was "always frozen". Other behaviors noted included progressively decreasing food intake (requiring the parents to hand-feed the patient until he required an all-liquid diet), difficulty with swallowing resulting in choking, loss of any verbal speech, and an inability to participate in any activities of daily living. The patient was also making "a weird pouting face all of the time" and baseline echolalia and echopraxia was no longer observed. Genetics and neurology had been consulted prior to psychiatric evaluation and the patient had normal metabolic and infectious labs with an electroencephalogram (EEG) that showed slowing without evidence of seizure activity, respectively. Parents had tried Charlotte's Web cannabidiol intermittently without any improvement in symptoms.

On initial psychiatric presentation to the academic medical center's neuropsychiatric specialty care clinic, the patient demonstrated psychomotor retardation, had limited eye contact, and was non-interactive. A BFCRS was completed by an attending psychiatrist, and the patient scored a 17 with symptoms including immobility/stupor, mutism, staring, posturing/catalepsy, withdrawal, and appearing motorically stuck. An outpatient lorazepam trial was completed, and Mr. J was titrated to a dose of Lorazepam 2 mg three times a day with no other medication initiation (Figure 1). Twelve months after treatment initiation, with subsequent BFCRS scores completed by the same treating psychiatrist, Mr. J's BFCRS had decreased to a score of 4, with return of verbal speech, engagement in activities of daily living, and tolerance of a normal solid diet.

Diagnosis, assessment, and plan:

Mr. J had baseline symptoms associated with ASD and ID, however, he had an acute change in behaviors that impacted his ability to perform activities of daily living, a decrease in oral intake, slowed movements, and strange postures. A lorazepam trial was initiated with a positive response and therefore, the patient was continued on scheduled Lorazepam with continued improvement (Figure 1). Based on the patient's clinical presentation, BFCRS scores, and positive response to Lorazepam, the team was confident in a diagnosis of Catatonia.

Protocol

This study was approved by the University of Colorado institutional board review for case presentation. Consent for case publication was obtained from the patient's guardian.

1. Establishing the baseline

1. Screening
   1. Changes in the patient's behaviors were discussed with the patient and family to screen for Catatonia. Specific screening questions for catatonic behaviors included immobility, mutism, eye contact, posturing, grimacing, mannerisms, rigidity, negativism, withdrawal, and related features.
   2. The importance of behavioral alterations differing distinctly from the patient's established baseline with family is emphasized.
      NOTE: Screening should give special consideration to behaviors such as stereotypies, echopraxia/echolalia, and poor eye contact, which are common in patients with ASD with or without the presence of Catatonia.
2. Examination
   1. During the discussion with the psychiatrist, both patient and family were engaged. The psychiatrist assessed for the presence of catatonic behaviors and attempted to elicit them using the BFCRS¹². The commercially available scale utilized is included in Supplementary File 1¹³.
   2. Excitement is defined as "extreme hyperactivity, constant motor unrest which is apparently non-purposeful that is not attributed to akathisia or goal-directed agitation"⁴. The patient was observed and evaluated for this behavior, but did not present with excitement.
   3. Immobility/stupor is defined as "extreme hypoactivity, immobile, minimally responsive to stimuli"⁴. The patient exhibited virtually no interaction with the external world but was not stuporous and did respond to stimuli.
   4. Mutism is defined as "verbally unresponsive or minimally responsive"⁴. Verbal engagement was assessed during interactions with the psychiatrist and family. The patient spoke fewer than 20 words in 5 min.
   5. Staring is defined as "fixed gaze, little or no visual scanning of the environment, decreased blinking"⁴. The patient held gaze longer than 20 s with occasional shifts in attention.
   6. Posturing/Catalepsy is defined as "spontaneous maintenance of posture(s), including mundane (e.g., sitting/standing for long periods without reacting)"⁴. The patient exhibited a mundane posture while sitting and maintained this posture without moving during the 90 min visit.
   7. Grimacing is defined as "maintenance of odd facial expressions"⁴. The patient held an odd facial expression for durations longer than 1 min.
   8. Echopraxia/echolalia is defined as "mimicking the examiner's movement/speech"⁴. The examiner placed a hand on the head and assessed for imitation of words spoken aloud. No echopraxia or echolalia was observed.
   9. Stereotypy is defined as "repetitive, non-goal-directed motor activity"⁴. No stereotypy was observed.
   10. Mannerisms are defined as "odd, purposeful movements with abnormality in the act in itself"⁴. No mannerisms were observed.
   11. Verbigeration is defined as "repetition of phrases or sentences"⁴. No verbigeration was observed.
   12. Rigidity is defined as "maintenance of a rigid posture despite efforts to be moved"⁴. The psychiatrist attempted to move the patient's arm without instruction. The patient remained still but was moved without resistance.
   13. Negativism is defined as "apparently motiveless resistance to instructions or attempts to move/examine patient with contrary behavior"⁴. The psychiatrist attempted to move the patient's arm with instructions. No contrary behavior was noted, and the patient was unresponsive to direction.
   14. Waxy flexibility is defined as "patient offering initial resistance to repositioning and then allowing change"¹². The examiner moved the patient's forearm to assess for this feature. Waxy flexibility was absent.
   15. Withdrawal is defined as "refusal to eat, drink, and/or make any eye contact"⁴. Parents reported minimal oral intake and interaction lasting more than 1 day.
   16. Impulsivity is defined as "sudden inappropriate behavior"⁴. No impulsive behaviors were observed.
   17. Automatic obedience is defined as "exaggerated cooperation with examiner's request or spontaneous continuation of movement requested"⁴. The examiner requested the patient to stick out the tongue for a pinprick. Automatic obedience was absent.
   18. Mitgehen is arm raising in response to light pressure of the finger despite instructions to the contrary⁴. Light pressure on the finger did not elicit Mitgehen.
   19. Gegehalten is automatic resistance to passive movement⁴. Passive arm movement revealed no Gegehalten.
   20. Ambitendency is described as appearing "motorically stuck in indecisive, hesitant movement"⁴. The patient exhibited ambitendency, halting at times in the middle of movements (sitting and standing).
   21. Grasp reflex was tested by pressing the palm. No grasp reflex was observed.
   22. Perseveration is defined as "repeatedly returning to the same topic or persisting with movement"⁴. No perseveration was observed. The patient remained silent and still during evaluation.
   23. Combativeness was assessed through observation. No aggressive or combative behavior was observed.
   24. Autonomic abnormality was assessed by measuring temperature, blood pressure, pulse, respiratory rate, and presence of diaphoresis. Vital signs were normal for age, without diaphoresis.
3. Scoring
   1. Information from the patient and family, behavioral observations, and specific examination findings were used to complete the BFCRS. Higher scores were interpreted as indicative of a greater number and severity of catatonic behaviors, whereas lower scores indicated fewer and less severe catatonic behaviors. The results of the initial assessment are displayed in Figure 1.

2. Lorazepam Initiation

1. Treatment initiation
   1. With an elevated BFCRS score and after discussion of risks, benefits, and alternatives with the patient and family, treatment was initiated with oral Lorazepam 1 mg three times daily (TID).
2. Family Education
   1. Education on catatonic symptoms was provided to the family using the BFCRS as demonstrated previously. The family was counseled to monitor these symptoms and track changes in severity at home using the BFCRS.
   2. The family was educated on potential side effects of benzodiazepines, including sedation, using data from pharmacological studies¹⁴.

3. Follow-up assessment

1. Assessment timeline
   1. The patient was re-assessed by the psychiatrist at 1-2 month intervals. Assessments were conducted with the patient and family in the clinical setting.
2. Discussion
   1. As in step 1.1, persistence or changes in behaviors following initiation of benzodiazepine one month earlier were discussed. Focus was placed on catatonic behaviors and potential side effects of benzodiazepine treatment. The effectiveness of treatment was assessed by incorporating familial observations of behavioral changes in the home setting.
3. Examination
   1. Step 1.2 was repeated.
4. Scoring
   1. Step 1.3 was repeated using information from family and clinical examination to complete the BFCRS. The new score was 12, reflecting observations of immobility/stupor, mutism, staring, catalepsy, rigidity, withdrawal, automatic obedience, and ambitendency.
5. Comparison with baseline
   1. The new score was compared with the baseline score prior to lorazepam treatment. A decrease in BFCRS score indicated a response to benzodiazepine therapy.

4. Titration and follow-up assessment

1. Dose adjustment
   1. Improvement in BFCRS scoring and home behaviors was reported by the family. The family was questioned about the occurrence of lorazepam side effects such as sedation. In the absence of these side effects and following discussion and informed consent, the lorazepam dosage was increased to 2 mg TID.
2. Re-assessment
   1. Timeline
      1. Subsequent re-assessments were scheduled and performed at 1-2 month intervals.
   2. Discussion and examination
      1. Steps 3.3 and 3.4 were repeated at subsequent visits.
   3. Scoring
      1. Step 3.4 was repeated, and new BFCRS scores were obtained. These scores are presented in Figure 1.
   4. Assessment for side effects
      1. The family was questioned regarding the presence of lorazepam side effects at home, such as sedation. If side effects negatively impacting quality of life or mood were reported, the lorazepam dosage was decreased by 1 mg.
   5. Subsequent dosage increases
      1. In the absence of reported concerns regarding lorazepam side effects and with improved BFCRS scores compared to prior assessments, the lorazepam dosage was increased by 1 mg TID.
3. Maintenance dosage
   1. Scoring
      1. At the sixth visit, the BFCRS score was 5 for immobility/stupor, mutism, staring, and posturing. The lorazepam dosage at that time was 2 mg TID, as shown in Figure 1.
   2. Comparison to past scores
      1. The score of 5 was compared to prior visits, demonstrating minimal variability from the fourth visit (score of 5 for immobility/stupor, mutism, staring, and posturing) and the fifth visit (score of 6 for immobility/stupor, more pronounced mutism, staring, and posturing).
   3. Comparison to baseline
      1. The family was questioned regarding baseline behaviors with Kleefstra syndrome. The family confirmed the patient had returned to baseline prior to the onset of catatonia symptoms.
   4. Dosage
      1. The patient was maintained on a lorazepam dosage of 2 mg TID. Subsequent re-assessments were scheduled at 3-month intervals.

Results

The BFCRS was used to assess the degree of response to treatment. Increases in the score indicated an increase in either the number of catatonic symptoms or their severity. Conversely, decreases in the score indicated a decrease in either the number of catatonic symptoms or their severity. The decrease in this patient's BFCRS score (Figure 1) demonstrates overall successful treatment of his Catatonia with benzodiazepines. With treatment, the patient had a tot...

Discussion

This article highlights improved catatonia symptoms following treatment with Lorazepam in an adolescent with Kleefstra syndrome and associated Catatonia. Response to treatment was monitored using the Bush-Francis Catatonia Rating Scale (BFCRS), a widely used, validated, and reliable assessment for Catatonia. It is important to note that, of the available scales for assessing Catatonia, only one is directed at pediatric populations, the Pediatric Catatonia Rating Scale, and none take into consideration the overlap of symp...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Bush-Francis Catatonia Rating Scale	Dr. George Bush and Dr. Andrew Francis	N/A	Scale used to assess presences and severity of catatonia symptoms
Lorazepam	N/A	N/A	Medication