RESEARCH ARTICLE
Catatonia in an Adolescent With Velo-Cardio-Facial Syndrome Gianni L. Faedda,1,2,3 Lee E. Wachtel,4 Anne Marie Higgins,3 and Robert J. Shprintzen3 1
Lucio Bini Mood Disorders Center, New York, New York
2
Department of Child and Adolescent Psychiatry, NYU Medical Center, New York, New York
3
The Virtual Center for Velo-Cardio-Facial Syndrome, Inc., Manlius, New York Kennedy Krieger Institute, Johns Hopkins University, Baltimore, Maryland
4
Manuscript Received: 5 November 2014; Manuscript Accepted: 15 March 2015
Velo-cardio-facial syndrome (VCFS) is the most common microdeletion syndrome in humans and is probably the most frequent genetic cause of psychosis currently known. Many psychiatric disorders have been reported to occur in people with VCFS including, but not limited to schizophrenia, unipolar and bipolar mood disorders (with or without psychotic features), schizoaffective disorder, psychosis NOS, social phobia, generalized and separation anxiety, obsessive-compulsive disorder, autism spectrum disorder, cognitive impairment, and ADHD. This report describes the psychiatric onset and development of catatonia in an adolescent female with VCFS that was undiagnosed until 15 years of age. Catatonia may be a relatively common presentation in people with VCFS with treatmentrefractory psychiatric manifestations. Ó 2015 Wiley Periodicals, Inc.
Key words: velo-cardio-facial syndrome; 22q11.2 deletion; catatonia; psychosis
INTRODUCTION It was in a Letter to the Editor in the pages of this Journal in 1992 [Shprintzen et al., 1992] that psychosis as a clinical feature of velocardio-facial syndrome (VCFS) was first reported. Almost simultaneous to that report, the cause of VCFS was isolated to a microdeletion from the long arm chromosome 22 at the q11.2 band [Scambler et al., 1992]. This coincidence in time spawned a substantial increase in research involving VCFS in many fields including psychiatry.
Psychosis in VCFS The risk of psychosis in VCFS is at least 25 times that of the general population and it has been reported that approximately 30–40% of people with VCFS will develop psychosis, typically in adolescence or early adulthood [Gothelf et al., 2009]. Therefore, with the possible exception of monozygotic twinning, VCFS is the most frequent genetic predisposition factor for the development of psychosis [Murphy, 2002]. VCFS is the most common microdeletion syndrome in humans with a population prevalence of approximately 1:2,000 [Robin and Shprintzen, 2005; Shprintzen,
Ó 2015 Wiley Periodicals, Inc.
How to Cite this Article: Faedda GL,Wachtel LE, Higgins AM, Shprintzen RJ. 2015. Catatonia in an adolescent with velo-cardio-facial syndrome. Am J Med Genet Part A 9999A:1–4.
2005]. More than 90% of cases have identical break points on chromosome 22. Nearly all cases are deleted for the same 1.5 megabase region of chromosome 22 thereby narrowing the search for genes that might result in psychosis when present in only one copy. VCFS has been reported to constitute 0.3–2% of people with schizophrenia [Karayiorgou et al., 1995; Gothelf et al., 2009] and the frequency of cases detected among psychiatrically ill people is increasing. Detection of the syndrome has been increasing as fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), and comparative genomic hybridization (CGH) microarray analysis have been applied to people with congenital heart disease, cleft palate, immune disorders, and most recently, psychiatric illness. A broad range of psychiatric disorders has been associated with VCFS, including schizophrenia, unipolar and bipolar mood disorders (with or without psychotic features), schizoaffective disorder, psychosis NOS, social phobia, generalized and separation anxiety, obsessive-compulsive disorder, autism spectrum disorder, cognitive impairment, and ADHD [Gothelf et al., 2009; Vogels et al., 2002]. Therefore, although the deletion of DNA is the same for most cases, the expression of psychiatric disorders is variable.
Correspondence to: Robert J. Shprintzen, Ph.D., Director, Chairman of the Board, The Virtual Center for Velo-Cardio-Facial Syndrome, 8138 Solomon Seal Lane, Manlius, NY 13104. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 00 Month 2015 DOI 10.1002/ajmg.a.37087
1
2
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
The Recognition of Catatonia in VCFS
Developmental and Medical History
We would like to describe the onset of psychiatric manifestation with tics progressing to catatonia in an adolescent female with VCFS. VCFS was not diagnosed until 15 years of age at which time the microdeletion was discovered by CGH microarray. Catatonia is a relatively frequent manifestation of psychosis in adults and youths [Dhossche and Wachtel, 2010; Dhossche, 2010; Consoli et al., 2012], and is often associated with neurological diseases and other general medical conditions. Weygandt [1907] described catatonia in children as: “abnormal postures and positions, motions, mimic expressions, grimaces, abnormal speech/verbigeration, order execution automatism, negativism” in line with Kahlbaum’s initial description in 1874 of the classic motor, vocal, and behavioral symptoms [Kahlbaum, 1874]. Common symptoms of catatonia include stupor/immobility, rigidity, posturing, waxy flexibility, negativism, staring, mutism, repetive/purposeless movements, psychomotor agitation, and frequent global skill regression. The malignant variant of catatonia is further complicated by hemodynamic and thermoregulatory instability, which may lead to respiratory failure/collapse, multiorgan failure, coma, and ultimately death (10–20%) without urgent specific treatment [Dhossche and Wachtel, 2010]. Overall, catatonia increases pediatric mortality 60-fold (including suicide). However, when catatonia is diagnosed, it responds rapidly and dramatically to benzodiazepines and/or electroconvulsive therapy (ECT) regardless of its etiology [Dhossche, 2010; Consoli et al., 2012].
The index case was the product of a 38-week uncomplicated gestation, born by spontaneous vaginal delivery with a birth weight of 3175 g and a length of 50.8 cm. There were no prenatal or perinatal problems or evidence of heart problems. She was discharged from hospital after two days. She had no evidence of congenital heart disease. She had three siblings and two halfsiblings, all reportedly normal. Early problems in childhood included chronic constipation, frequent upper respiratory infections, bronchitis, thrush, and other fungal infections (all common problems in children with VCFS). She was diagnosed with asthma at 9 years of age that was treated with Flovent and Albuterol. She had adenotonsillectomy at age 10 years. Chronic middle ear disease has persisted to the present time. She had mild hypotonia as a child, but spoke her first word before one year of age and walked independently at 14 months. She was reported to have a language impairment that was treated in school with speech and language therapy.
CLINICAL REPORT This report describes a case of catatonia and suggests that this condition may be under-recognized in VCFS. The mother of a 15year-old female contacted The Virtual Center for VCFS in March, 2014 shortly after the diagnosis of VCFS was confirmed locally. The Virtual Center is an internet-based service that is an open access 501 (c)(3) charitable organization that provides personalized information to people and families who are seeking research and clinical expertise regarding the management of VCFS at no charge. The Center’s staff is an interdisciplinary group of experts from many different institutions and locations. They interact with the registrants on the web site primarily via video conference calls that may have as many as 12 experts on the call. Prior to speaking directly with the registrants, a detailed history form is downloaded from the web site, filled out, and returned for review by the coordinator and multiple team members to see if additional records need to be obtained and reviewed. This can include video, MR or CT scans, medical records, and photographs. Calls are set up once detailed information for the case has been reviewed. Calls are then scheduled at the registrant’s convenience, including evenings, weekends, or early morning depending on the experts’ availability. The mother was able to provide an excellent history and also forwarded all relevant medical records and video of her daughter in several different environments (summarized below). Several video conferences were held that included members of our team (authors RJS, AMH, and GLF), the mother and the index case who is the subject of this report.
Past psychiatric history. The index case was described as a moody child. She had learning difficulties and psychometric testing at age 10 years yielded a full scale IQ of 58. An assessment for ADHD symptoms by a neurodevelopmental pediatrician at 11 years of age documented age-appropriate activities of daily living (dressing, feeding, toileting) and noted that she was a shy, artistic student who needed redirection but enjoyed roller-skating, biking, and computers. At approximately 12 years of age, she developed significant sleep disturbance consistent with severe anxiety. She also had problems with allergies and recurrent otitis media, and complained of feeling constantly tired. An all-night polysomnogram was done that was not informative. In a return visit to her psychiatrist in April of 2013, she reported severe anxiety and she demonstrated OCD rituals, turning lights on and off compulsively. She was gradually withdrawing socially, and there was a question of bullying at school. She had frequent somatic complaints including headaches and knee pain. Both headaches and joint discomfort, especially in the legs, are common in VCFS and have been attributed to a number of different etiologies, including temporomandibular joint disorders, migraines, anxiety, joint laxity, leg muscle cramping, and persistent pronation during walking [Shprintzen and Golding-Kushner, 2008]. The reported diagnosis from the hospital neurodevelopmental program where she was evaluated was cognitive impairment and possible ADHD. In May 2013 at 12 years of age she had her first period and immediately began taking five showers daily. Over the next several months, she developed tics and what appeared to be a “movement disorder” that was diagnosed as a form of Parkinson disease due to slowed movements. She also had brief but intense laughing fits and rages without any clear environmental trigger accompanied by pupil dilation and sudden unprovoked aggression including hitting, slapping and kicking. Self-injurious behaviors included rhythmic “clawing” at her eye. Sleep deteriorated, and she would often waken in the middle of the night giggling inappropriately. The slowed and abnormal movements continued to progress accompanied by progressive emotional detachment, functional decline and non-responsiveness to her family and environment. Speech
FAEDDA ET AL. deteriorated to frank mutism punctuated briefly by echolalia. Prominent negativism was seen in the form of food refusal with weight loss requiring spoon-feeding to maintain hydration and nutrition. She would stay in bed most of the day without speaking, posturing with her arm suspended over her head and covered with a blanket. Close to her 14th birthday she was given IVIG for possible pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS), repeated 3 months later. After the second IVIG, she was bedridden, mute, and required diapers. She was noted to have hypertension, tachycardia and acrocyanosis at multiple physician visits. She had extensive laboratory and radiographic testing including a liver biopsy and genetic testing to rule out Wilson disease. All testing was negative for presumed diagnoses, and VCFS was never considered as a working diagnosis. At age 14, she was evaluated by a psychiatrist at a teaching hospital and the following diagnoses were provided:
Axis Axis Axis Axis Axis
I: Anxiety disorder NOS, encephalopathy. II: None. III: Acute neurologic syndrome. IV: Moderate to severe given chronic illness. V: 35.
Treatment With Psychoactive Medications and the Diagnosis of VCFS Over the two years preceding the diagnosis of VCFS, the index case underwent multiple psychotropic trials including amantadine (prescribed for the presumed diagnosis of Parkinsonsim), zolpidem, and clonidine, then citalopram for one week for suspected depression. She was also treated with immediate and extended-release methylphenidate for ADHD. She responded poorly to these trials. When given methylphenidate hydrochloride 10 mg in an immediate or extended-release formulation, she was temporarily able to feed herself and get out of bed, and became more alert and active. However, anxiety, aggression and agitation worsened, and methylphenidate was discontinued. Two hospitalizations at a major teaching hospital in a US metropolitan area were prompted by functional decline. Two brain MRI scans and a sleep-wake EEG were performed. Several diagnoses were considered and ruled out including PANDAS, seizure disorder, encephalitis, Parkinsonism, and Wilson disease. Two genetics consults were performed at this hospital in 2012 and 2013, but VCFS was not suspected and neither FISH nor CGA microarray were performed. In 2014, CGH microarray was ordered and a deletion of 22q11.2 spanning the typical approximately 3 megabase region that causes VCFS was found. In March of 2014, her mother registered with The Virtual Center for VCFS and several videoconferences were held that were attended by the mother and her daughter and multiple members of the interdisciplinary team from the Center, including the Center’s psychiatrist (GLF). At the time, the index case was 5 feet, 5.5 inches in height, and 120 pounds. She was taking amantadine, 100 mg daily (for suspected Parkinsonism), clonidine 0.05 mg qhs, and Benadryl 25 mg qhs. According to her mother, she was up
3 until 2:00 A.M. every night, pacing, giggling, and laughing to herself, having arguments with herself, or having crying spells. At night she would become more restless and agitated often repeating “no, no, be nice.” Her level of functioning remained markedly below her premorbid baseline. She was able to feed herself, but needed supervision with showering and had urinary and bowel incontinence, recognized symptoms of catatonia in youth. She needed help dressing, refusing to dress herself, occasionally trying to wear inappropriate clothing, a discrete change from her baseline where she was fully independent in ADLs and prided herself on appropriate dressing and grooming. During the first videoconference, she was lying in bed, minimally responsive to her name being called, with limited motor activity although she moved all of her limbs spontaneously. Overall activity level was decreased. She did not speak spontaneously nor did she respond to direct questioning by her mother. Her alertness fluctuated, from apparently drowsy or sleepy to awake but disengaged. Her degree of orientation could not be formally assessed. At times she appeared to recognize her caretakers and her surroundings. She had a very short attention span with a near total lack of alertness for the duration of the observation. There was no spontaneous speech or verbal communication other than some grunting when asked to prop up to look at the computer screen. Her mother was asked if a diagnosis of catatonia had ever been suggested and the response was negative. The team reviewed the findings associated with catatonia and indicated that in such cases, an in-person evaluation at a center specializing in the treatment of catatonia where a formal assessment could be done might prove useful. Her mother contacted a specialty center from a list provided to her and formal assessment at that center confirmed the diagnosis of catatonia. She returned for inpatient care at the academic hospital where she had been hospitalized previously. Lorazepam therapy was pursued as the first-line intervention for catatonia, with the dosage titrated up to 12 mg daily over a two-week span. The lorazapam was welltolerated and the patient became more alert and responsive. She began conversing with her mother and caregivers, with overall improved engagement, spontaneous communication, and responding. Although not back to her baseline, the treating facility declined to pursue higher dosages of lorazepam, and did not have pediatric ECT services. She was discharged with likely ongoing psychosis and a new treatment plan was instituted by her local psychiatrist consisting of olanzapine and the continuation of 12 mg of lorazapam. Olanzpine was escalated to 15 mg daily and was accompanied by dramatic weight gain. Her weight reached 192 pounds and in one three-month period, she gained over 30 pounds. Although she was somewhat more alert and responsive, she was still psychotic and frequently agitated. Because of the side effects of the olanzapine, her psychiatrist decided to wean her off of the medication and initiate treatment with ziprasidone, 40 mg in the morning and 80 mg at night. She has experienced body aches and tight throat with swallowing problems without clinical improvement in her psychiatric status.
DISCUSSION This case illustrates two distinct difficulties that have come together in this individual: diagnosing catatonia and diagnosing VCFS.
4 Although multiple disciplines were involved in her health care (pediatrics, pediatric neurology, child psychiatry, immunology, pediatric gastroenterology, genetics, speech pathology, audiology, occupational therapy, and physical therapy), the diagnosis of VCFS was not confirmed until she was 15 years of age. Neither mental health nor neurology specialists initially diagnosed catatonia and mistook symptoms common in VCFS and catatonia for other diseases including Parkinsonism, Wilson disease, and PANDAS. While both VCFS and catatonia are relatively rare, they occur with sufficient frequency in clinical populations [Karayiorgou et al., 1995; Cohen et al., 1999] referred for medical or psychiatric disorders that it is important to recognize the association as presented in this case report. The rapid decline in intellectual, emotional, and behavioral functioning combined with both psychomotor disturbances (cognitive impairment, agitation, staring, stupor, and negativism) and mood lability were all initially attributed to either an acute neurological or autoimmune disorder, or related to baseline developmental delays. She had developed self-care, communication, and daily living skills with minor delays but still age-appropriate before losing them. Although the only risk factor for catatonia in the case described was intellectual disability, the anamnesis and clinical presentation were consistent with classic catatonia, and similar to other reports in intellectually disabled subjects. The subsequent identification of VCFS did not help raise the level of suspicion for catatonia because it has not been previously described in detail in VCFS youths or adults. It is noted that a single case of catatonia in an individuals with VCFS was reported by Graf et al. [2001] to have catatonia, but the clinical presentation and course was not described. The case was reported in a series of confirmed VCFS cases that had been found to have elevated levels of dopamine in the central nervous system that responded well to treatment with metyrosine. It is not possible at the present time to determine how commonly VCFS presents with associated catatonia. However, in view of the clinical findings in this case when applied to hundreds of psychotic cases that have been seen over the years may yield a relatively high prevalence among this population as it is likely that this condition has been missed in VCFS. This is highly salient given that catatonia has an excellent response rate to benzodiazepines and/or electroconvulsive therapy, although as also demonstrated in this case, comprehensive implementation of anti-catatonic treatment paradigms is not universal and may unfortunately be further delayed in cases with intellectual disability. This case should also point out the need for VCFS to be recognized as a possibility in differential diagnosis in psychiatric populations given its relatively high prevalence. It is certainly far more prevalent in both the general population and the psychiatric population than disorders such as PANDAS and Wilson disease.
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
REFERENCES Cohen D, Flament M, Dubos P-F, Basquin M. 1999. Case series: Catatonic syndrome in young people. J Am Acad Child Adolesc Psychiatry 38:1040–1046. Consoli A, Raffin M, Laurent C, Bodeau N, Campion D, Amoura Z, Sedel F, An-Gourfinkel I, Bonnot O, Cohen D. 2012. Medical and developmental risk factors of catatonia in children and adolescents: A prospective case-control study. Schizophrenia Res 137:151–158. Dhossche DM. 2010. Etiopathogenesis of catatonia: generalizations and working hypotheses. J ECT 26:253–258. Dhossche DM, Wachtel LE. 2010. Catatonia is hidden in plain sight among different pediatric disorders: A review article. Pediatr Neurol 43:307– 315. Gothelf D, Frisch A, Michaelovsky E, Weizman A, Shprintzen RJ. 2009. Velo-Cardio-Facial Syndrome. J Ment Health Res Intellect Disabil 2:149–167. Graf WD, Unis AS, Yates C, Sulzbacher SI, Dinulos MB, Jack RM, Dugaw KA, Paddock MN, Parson WW. 2001. Catecholamines in patients with 22q11.2 deletion syndrome and the low-activity COMT polymorphism. Neurology 57:410–416. Karayiorgou M, Morris MA, Morrow B, Shprintzen RJ, Goldberg R, Borrow J, Gos A, Nestadt G, Wolyniec PS, Lasseter VK, Eisen H, Childs B, Kazazian HH, Kucherlapati R, Antonarakis SE, Pulver AE, Houseman DE. 1995. Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proc Natl Acad Sci USA 92:7612–7616. Kahlbaum KL. 1874. Die Katatonie oder das Spannungsirresein. Eine klinische Form psychischer Krankheit. Berlin: Verlag August Hirschwald. 104p. Murphy KC. 2002. Schizophrenia and velo-cardio-facial syndrome. Lancet 359:426–430. Robin NH, Shprintzen RJ. 2005. Defining the clinical spectrum of deletion 22q11. 2. J Pediatr 147:90–96. Scambler PJ, Kelly D, Lindsay E, Williamson R, Goldberg R, Shprintzen RJ, Wilson DI, Goodship JA, Cross IE, Burn J. 1992. Velo-cardio-facial syndrome associated with chromosome 22 deletions encompassing the DiGeorge locus. Lancet 339:1138–1139. Shprintzen RJ. 2005. Velo-cardio-facial syndrome. In: Cassidy SB, Allanson J, editors. In Management of Genetic Syndromes, 2nd Ed. New York: Wiley-Liss. pp 615–632. Shprintzen RJ, Goldberg R, Golding-Kushner KJ, Marion R. 1992. Lateonset psychosis in the velo-cardio-facial syndrome. Am J Med Genet 42:141–142. Shprintzen RJ, Golding-Kushner KJ. 2008. Velo-cardio-facial syndrome: volume I. San Diego: Plural Publishing. p 279. Vogels A, Verhoeven WMA, Tuinier S, De Vriendt K, Swillen A, Curfs IMG, Frijns JP. 2002. The psychopathological phenotype of velo-cardiofacial syndrome. Ann Genet 45:89–95. Weygandt W. 1907. Kritische bemerkungen zur Psychologie der dementia praecox. Monat f Psychiat u Neur 22:289–301.
Catatonia in an Adolescent With Velo-Cardio-Facial Syndrome Gianni L. Faedda,1,2,3 Lee E. Wachtel,4 Anne Marie Higgins,3 and Robert J. Shprintzen3 1
Lucio Bini Mood Disorders Center, New York, New York
2
Department of Child and Adolescent Psychiatry, NYU Medical Center, New York, New York
3
The Virtual Center for Velo-Cardio-Facial Syndrome, Inc., Manlius, New York Kennedy Krieger Institute, Johns Hopkins University, Baltimore, Maryland
4
Manuscript Received: 5 November 2014; Manuscript Accepted: 15 March 2015
Velo-cardio-facial syndrome (VCFS) is the most common microdeletion syndrome in humans and is probably the most frequent genetic cause of psychosis currently known. Many psychiatric disorders have been reported to occur in people with VCFS including, but not limited to schizophrenia, unipolar and bipolar mood disorders (with or without psychotic features), schizoaffective disorder, psychosis NOS, social phobia, generalized and separation anxiety, obsessive-compulsive disorder, autism spectrum disorder, cognitive impairment, and ADHD. This report describes the psychiatric onset and development of catatonia in an adolescent female with VCFS that was undiagnosed until 15 years of age. Catatonia may be a relatively common presentation in people with VCFS with treatmentrefractory psychiatric manifestations. Ó 2015 Wiley Periodicals, Inc.
Key words: velo-cardio-facial syndrome; 22q11.2 deletion; catatonia; psychosis
INTRODUCTION It was in a Letter to the Editor in the pages of this Journal in 1992 [Shprintzen et al., 1992] that psychosis as a clinical feature of velocardio-facial syndrome (VCFS) was first reported. Almost simultaneous to that report, the cause of VCFS was isolated to a microdeletion from the long arm chromosome 22 at the q11.2 band [Scambler et al., 1992]. This coincidence in time spawned a substantial increase in research involving VCFS in many fields including psychiatry.
Psychosis in VCFS The risk of psychosis in VCFS is at least 25 times that of the general population and it has been reported that approximately 30–40% of people with VCFS will develop psychosis, typically in adolescence or early adulthood [Gothelf et al., 2009]. Therefore, with the possible exception of monozygotic twinning, VCFS is the most frequent genetic predisposition factor for the development of psychosis [Murphy, 2002]. VCFS is the most common microdeletion syndrome in humans with a population prevalence of approximately 1:2,000 [Robin and Shprintzen, 2005; Shprintzen,
Ó 2015 Wiley Periodicals, Inc.
How to Cite this Article: Faedda GL,Wachtel LE, Higgins AM, Shprintzen RJ. 2015. Catatonia in an adolescent with velo-cardio-facial syndrome. Am J Med Genet Part A 9999A:1–4.
2005]. More than 90% of cases have identical break points on chromosome 22. Nearly all cases are deleted for the same 1.5 megabase region of chromosome 22 thereby narrowing the search for genes that might result in psychosis when present in only one copy. VCFS has been reported to constitute 0.3–2% of people with schizophrenia [Karayiorgou et al., 1995; Gothelf et al., 2009] and the frequency of cases detected among psychiatrically ill people is increasing. Detection of the syndrome has been increasing as fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), and comparative genomic hybridization (CGH) microarray analysis have been applied to people with congenital heart disease, cleft palate, immune disorders, and most recently, psychiatric illness. A broad range of psychiatric disorders has been associated with VCFS, including schizophrenia, unipolar and bipolar mood disorders (with or without psychotic features), schizoaffective disorder, psychosis NOS, social phobia, generalized and separation anxiety, obsessive-compulsive disorder, autism spectrum disorder, cognitive impairment, and ADHD [Gothelf et al., 2009; Vogels et al., 2002]. Therefore, although the deletion of DNA is the same for most cases, the expression of psychiatric disorders is variable.
Correspondence to: Robert J. Shprintzen, Ph.D., Director, Chairman of the Board, The Virtual Center for Velo-Cardio-Facial Syndrome, 8138 Solomon Seal Lane, Manlius, NY 13104. E-mail: [email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 00 Month 2015 DOI 10.1002/ajmg.a.37087
1
2
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
The Recognition of Catatonia in VCFS
Developmental and Medical History
We would like to describe the onset of psychiatric manifestation with tics progressing to catatonia in an adolescent female with VCFS. VCFS was not diagnosed until 15 years of age at which time the microdeletion was discovered by CGH microarray. Catatonia is a relatively frequent manifestation of psychosis in adults and youths [Dhossche and Wachtel, 2010; Dhossche, 2010; Consoli et al., 2012], and is often associated with neurological diseases and other general medical conditions. Weygandt [1907] described catatonia in children as: “abnormal postures and positions, motions, mimic expressions, grimaces, abnormal speech/verbigeration, order execution automatism, negativism” in line with Kahlbaum’s initial description in 1874 of the classic motor, vocal, and behavioral symptoms [Kahlbaum, 1874]. Common symptoms of catatonia include stupor/immobility, rigidity, posturing, waxy flexibility, negativism, staring, mutism, repetive/purposeless movements, psychomotor agitation, and frequent global skill regression. The malignant variant of catatonia is further complicated by hemodynamic and thermoregulatory instability, which may lead to respiratory failure/collapse, multiorgan failure, coma, and ultimately death (10–20%) without urgent specific treatment [Dhossche and Wachtel, 2010]. Overall, catatonia increases pediatric mortality 60-fold (including suicide). However, when catatonia is diagnosed, it responds rapidly and dramatically to benzodiazepines and/or electroconvulsive therapy (ECT) regardless of its etiology [Dhossche, 2010; Consoli et al., 2012].
The index case was the product of a 38-week uncomplicated gestation, born by spontaneous vaginal delivery with a birth weight of 3175 g and a length of 50.8 cm. There were no prenatal or perinatal problems or evidence of heart problems. She was discharged from hospital after two days. She had no evidence of congenital heart disease. She had three siblings and two halfsiblings, all reportedly normal. Early problems in childhood included chronic constipation, frequent upper respiratory infections, bronchitis, thrush, and other fungal infections (all common problems in children with VCFS). She was diagnosed with asthma at 9 years of age that was treated with Flovent and Albuterol. She had adenotonsillectomy at age 10 years. Chronic middle ear disease has persisted to the present time. She had mild hypotonia as a child, but spoke her first word before one year of age and walked independently at 14 months. She was reported to have a language impairment that was treated in school with speech and language therapy.
CLINICAL REPORT This report describes a case of catatonia and suggests that this condition may be under-recognized in VCFS. The mother of a 15year-old female contacted The Virtual Center for VCFS in March, 2014 shortly after the diagnosis of VCFS was confirmed locally. The Virtual Center is an internet-based service that is an open access 501 (c)(3) charitable organization that provides personalized information to people and families who are seeking research and clinical expertise regarding the management of VCFS at no charge. The Center’s staff is an interdisciplinary group of experts from many different institutions and locations. They interact with the registrants on the web site primarily via video conference calls that may have as many as 12 experts on the call. Prior to speaking directly with the registrants, a detailed history form is downloaded from the web site, filled out, and returned for review by the coordinator and multiple team members to see if additional records need to be obtained and reviewed. This can include video, MR or CT scans, medical records, and photographs. Calls are set up once detailed information for the case has been reviewed. Calls are then scheduled at the registrant’s convenience, including evenings, weekends, or early morning depending on the experts’ availability. The mother was able to provide an excellent history and also forwarded all relevant medical records and video of her daughter in several different environments (summarized below). Several video conferences were held that included members of our team (authors RJS, AMH, and GLF), the mother and the index case who is the subject of this report.
Past psychiatric history. The index case was described as a moody child. She had learning difficulties and psychometric testing at age 10 years yielded a full scale IQ of 58. An assessment for ADHD symptoms by a neurodevelopmental pediatrician at 11 years of age documented age-appropriate activities of daily living (dressing, feeding, toileting) and noted that she was a shy, artistic student who needed redirection but enjoyed roller-skating, biking, and computers. At approximately 12 years of age, she developed significant sleep disturbance consistent with severe anxiety. She also had problems with allergies and recurrent otitis media, and complained of feeling constantly tired. An all-night polysomnogram was done that was not informative. In a return visit to her psychiatrist in April of 2013, she reported severe anxiety and she demonstrated OCD rituals, turning lights on and off compulsively. She was gradually withdrawing socially, and there was a question of bullying at school. She had frequent somatic complaints including headaches and knee pain. Both headaches and joint discomfort, especially in the legs, are common in VCFS and have been attributed to a number of different etiologies, including temporomandibular joint disorders, migraines, anxiety, joint laxity, leg muscle cramping, and persistent pronation during walking [Shprintzen and Golding-Kushner, 2008]. The reported diagnosis from the hospital neurodevelopmental program where she was evaluated was cognitive impairment and possible ADHD. In May 2013 at 12 years of age she had her first period and immediately began taking five showers daily. Over the next several months, she developed tics and what appeared to be a “movement disorder” that was diagnosed as a form of Parkinson disease due to slowed movements. She also had brief but intense laughing fits and rages without any clear environmental trigger accompanied by pupil dilation and sudden unprovoked aggression including hitting, slapping and kicking. Self-injurious behaviors included rhythmic “clawing” at her eye. Sleep deteriorated, and she would often waken in the middle of the night giggling inappropriately. The slowed and abnormal movements continued to progress accompanied by progressive emotional detachment, functional decline and non-responsiveness to her family and environment. Speech
FAEDDA ET AL. deteriorated to frank mutism punctuated briefly by echolalia. Prominent negativism was seen in the form of food refusal with weight loss requiring spoon-feeding to maintain hydration and nutrition. She would stay in bed most of the day without speaking, posturing with her arm suspended over her head and covered with a blanket. Close to her 14th birthday she was given IVIG for possible pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS), repeated 3 months later. After the second IVIG, she was bedridden, mute, and required diapers. She was noted to have hypertension, tachycardia and acrocyanosis at multiple physician visits. She had extensive laboratory and radiographic testing including a liver biopsy and genetic testing to rule out Wilson disease. All testing was negative for presumed diagnoses, and VCFS was never considered as a working diagnosis. At age 14, she was evaluated by a psychiatrist at a teaching hospital and the following diagnoses were provided:
Axis Axis Axis Axis Axis
I: Anxiety disorder NOS, encephalopathy. II: None. III: Acute neurologic syndrome. IV: Moderate to severe given chronic illness. V: 35.
Treatment With Psychoactive Medications and the Diagnosis of VCFS Over the two years preceding the diagnosis of VCFS, the index case underwent multiple psychotropic trials including amantadine (prescribed for the presumed diagnosis of Parkinsonsim), zolpidem, and clonidine, then citalopram for one week for suspected depression. She was also treated with immediate and extended-release methylphenidate for ADHD. She responded poorly to these trials. When given methylphenidate hydrochloride 10 mg in an immediate or extended-release formulation, she was temporarily able to feed herself and get out of bed, and became more alert and active. However, anxiety, aggression and agitation worsened, and methylphenidate was discontinued. Two hospitalizations at a major teaching hospital in a US metropolitan area were prompted by functional decline. Two brain MRI scans and a sleep-wake EEG were performed. Several diagnoses were considered and ruled out including PANDAS, seizure disorder, encephalitis, Parkinsonism, and Wilson disease. Two genetics consults were performed at this hospital in 2012 and 2013, but VCFS was not suspected and neither FISH nor CGA microarray were performed. In 2014, CGH microarray was ordered and a deletion of 22q11.2 spanning the typical approximately 3 megabase region that causes VCFS was found. In March of 2014, her mother registered with The Virtual Center for VCFS and several videoconferences were held that were attended by the mother and her daughter and multiple members of the interdisciplinary team from the Center, including the Center’s psychiatrist (GLF). At the time, the index case was 5 feet, 5.5 inches in height, and 120 pounds. She was taking amantadine, 100 mg daily (for suspected Parkinsonism), clonidine 0.05 mg qhs, and Benadryl 25 mg qhs. According to her mother, she was up
3 until 2:00 A.M. every night, pacing, giggling, and laughing to herself, having arguments with herself, or having crying spells. At night she would become more restless and agitated often repeating “no, no, be nice.” Her level of functioning remained markedly below her premorbid baseline. She was able to feed herself, but needed supervision with showering and had urinary and bowel incontinence, recognized symptoms of catatonia in youth. She needed help dressing, refusing to dress herself, occasionally trying to wear inappropriate clothing, a discrete change from her baseline where she was fully independent in ADLs and prided herself on appropriate dressing and grooming. During the first videoconference, she was lying in bed, minimally responsive to her name being called, with limited motor activity although she moved all of her limbs spontaneously. Overall activity level was decreased. She did not speak spontaneously nor did she respond to direct questioning by her mother. Her alertness fluctuated, from apparently drowsy or sleepy to awake but disengaged. Her degree of orientation could not be formally assessed. At times she appeared to recognize her caretakers and her surroundings. She had a very short attention span with a near total lack of alertness for the duration of the observation. There was no spontaneous speech or verbal communication other than some grunting when asked to prop up to look at the computer screen. Her mother was asked if a diagnosis of catatonia had ever been suggested and the response was negative. The team reviewed the findings associated with catatonia and indicated that in such cases, an in-person evaluation at a center specializing in the treatment of catatonia where a formal assessment could be done might prove useful. Her mother contacted a specialty center from a list provided to her and formal assessment at that center confirmed the diagnosis of catatonia. She returned for inpatient care at the academic hospital where she had been hospitalized previously. Lorazepam therapy was pursued as the first-line intervention for catatonia, with the dosage titrated up to 12 mg daily over a two-week span. The lorazapam was welltolerated and the patient became more alert and responsive. She began conversing with her mother and caregivers, with overall improved engagement, spontaneous communication, and responding. Although not back to her baseline, the treating facility declined to pursue higher dosages of lorazepam, and did not have pediatric ECT services. She was discharged with likely ongoing psychosis and a new treatment plan was instituted by her local psychiatrist consisting of olanzapine and the continuation of 12 mg of lorazapam. Olanzpine was escalated to 15 mg daily and was accompanied by dramatic weight gain. Her weight reached 192 pounds and in one three-month period, she gained over 30 pounds. Although she was somewhat more alert and responsive, she was still psychotic and frequently agitated. Because of the side effects of the olanzapine, her psychiatrist decided to wean her off of the medication and initiate treatment with ziprasidone, 40 mg in the morning and 80 mg at night. She has experienced body aches and tight throat with swallowing problems without clinical improvement in her psychiatric status.
DISCUSSION This case illustrates two distinct difficulties that have come together in this individual: diagnosing catatonia and diagnosing VCFS.
4 Although multiple disciplines were involved in her health care (pediatrics, pediatric neurology, child psychiatry, immunology, pediatric gastroenterology, genetics, speech pathology, audiology, occupational therapy, and physical therapy), the diagnosis of VCFS was not confirmed until she was 15 years of age. Neither mental health nor neurology specialists initially diagnosed catatonia and mistook symptoms common in VCFS and catatonia for other diseases including Parkinsonism, Wilson disease, and PANDAS. While both VCFS and catatonia are relatively rare, they occur with sufficient frequency in clinical populations [Karayiorgou et al., 1995; Cohen et al., 1999] referred for medical or psychiatric disorders that it is important to recognize the association as presented in this case report. The rapid decline in intellectual, emotional, and behavioral functioning combined with both psychomotor disturbances (cognitive impairment, agitation, staring, stupor, and negativism) and mood lability were all initially attributed to either an acute neurological or autoimmune disorder, or related to baseline developmental delays. She had developed self-care, communication, and daily living skills with minor delays but still age-appropriate before losing them. Although the only risk factor for catatonia in the case described was intellectual disability, the anamnesis and clinical presentation were consistent with classic catatonia, and similar to other reports in intellectually disabled subjects. The subsequent identification of VCFS did not help raise the level of suspicion for catatonia because it has not been previously described in detail in VCFS youths or adults. It is noted that a single case of catatonia in an individuals with VCFS was reported by Graf et al. [2001] to have catatonia, but the clinical presentation and course was not described. The case was reported in a series of confirmed VCFS cases that had been found to have elevated levels of dopamine in the central nervous system that responded well to treatment with metyrosine. It is not possible at the present time to determine how commonly VCFS presents with associated catatonia. However, in view of the clinical findings in this case when applied to hundreds of psychotic cases that have been seen over the years may yield a relatively high prevalence among this population as it is likely that this condition has been missed in VCFS. This is highly salient given that catatonia has an excellent response rate to benzodiazepines and/or electroconvulsive therapy, although as also demonstrated in this case, comprehensive implementation of anti-catatonic treatment paradigms is not universal and may unfortunately be further delayed in cases with intellectual disability. This case should also point out the need for VCFS to be recognized as a possibility in differential diagnosis in psychiatric populations given its relatively high prevalence. It is certainly far more prevalent in both the general population and the psychiatric population than disorders such as PANDAS and Wilson disease.
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
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