Effect of topiramate on eating behaviours in Prader-Willi syndrome: TOPRADER double-blind randomised placebo-controlled study.

Prader-Willi Syndrome (PWS) is a rare genetic syndrome leading to severe behavioural disorders and mild cognitive impairment. The objective of this double-blind randomised placebo-controlled trial was to study the efficacy and tolerance of topiramate on behavioural disorders in patients with PWS. Participants (aged 12-45 years) had genetically confirmed PWS and severe irritability/impulsivity, eating disorders and/or obesity, and skin picking. Thirty-two participants received a placebo (PBO), and 30 participants received topiramate (TOP) (50-200 mg/day) for 8 weeks. The primary outcome was the rate of responders using the Clinical Global Impression-Improvement (CGI-I) scale. The secondary outcome measures included the Aberrant Behaviour Checklist, the Dykens Hyperphagia Questionnaire (DHK), the Self-Injurious Behaviour Scale (SIBS) and the body mass index (BMI). We found no significant difference in the primary outcome (the CGI-I): 9 (30%) patients were very much or much improved in the TOP group compared to 7 (22.6%) patients in the PBO group. However, the DHK behaviour and severity scores improved significantly more over time in patients treated with topiramate versus those receiving a placebo, with a significant dose-effect relationship. DHK scores were also significantly associated with genetic subtypes and hospitalisation status. The effects of topiramate on eating behaviours remained significant after adjusting for genetic subtype and hospitalisation. Topiramate had therefore a significant effect on eating disorders, with a dose-effect relationship. Given the burden of eating disorders in PWS, we believe that topiramate may become the first psychotropic option within the global care of obesity in individuals with PWS.

Trastornos psiquiátricos secundarios a enfermedades neurometabólicas / Psychiatric Disorders Secondary to Neurometabolic Disorders

Hay algunas enfermedades secundarias a errores innatos del metabolismo que se asocian a trastornos psiquiátricos o síntomas neurológicos menores. La existencia de algunos pacientes con signos únicamente psiquiátricos representa un desafío diagnóstico y terapéutico. El objetivo del presente artículo es describir 6 enfermedades neurometabólicas tratables que se presentan con síntomas psiquiátricos que camuflan su origen orgánico, con el propósito de que se las tome en cuenta en la consulta psiquiátrica. Se describen los trastornos del metabolismo de la homocisteína y del ciclo de la urea, la enfermedad de Wilson, la enfermedad de Niemann-Pick tipo C, la porfiria aguda y la xantomatosis cerebrotendinosa. El análisis de la literatura lleva a proponer una lista de síntomas psiquiátricos asociados con dichas afecciones, que abarcan desde los cambios insidiosos del afecto y el curso del pensamiento hasta síntomas atípicos, como alucinaciones visuales, efectos paradójicos de los medicamentos antipsicóticos y trastornos del comportamiento de niños y adolescentes que conllevan degradación de la autonomía. Asimismo se listan los signos neurológicos más frecuentemente relacionados, como las alteraciones del estado de conciencia, los trastornos de la conducta motora y el equilibro, la catatonia o el déficit cognitivo progresivo. Se hace hincapié en la importancia de considerar la resistencia al tratamiento antipsicótico como una señal importante para sospechar organicidad y la mejoría significativa de la alteración psiquiátrica cuando se instaura un tratamiento eficaz y precoz.

Some diseases secondary to inborn errors of metabolism are associated with psychiatric, disorders or minor neurological symptoms. The existence of some cases with exclusively psychiatric symptoms represents a diagnostic and therapeutic challenge. The aim of this article is to describe seven treatable neurometabolic disorders that should be taken into account in the psychiatric consultation as they manifest with psychiatric symptoms that mask the organic origin of the disorder. Homocysteine metabolism and urea cycle disorders, Wilson's disease, Niemann-Pick disease Type C, acute porphyria and cerebrotendinous xanthomatosis are described. Following an analysis of the literature, a list of psychiatric symptoms associated with these disorders are proposed, ranging from insidious changes in affective state and thought to atypical symptoms such as visual hallucinations, as well as paradoxical effects of antipsychotics or behavioural disorders in children and adolescents associated with loss of autonomy. The most frequently associated neurological signs, such as alterations in the state of consciousness, motor behaviour and balance disorders, catatonia or progressive cognitive deficit are also listed. Emphasis is placed on the importance of considering resistance to antipsychotic treatment as a warning sign to suspect organicity, as well as the significant improvement in psychiatric impairment when effective and early treatment is established.

Psychiatric Disorders Secondary to Neurometabolic Disorders. / Trastornos psiquiátricos secundarios a enfermedades neurometabólicas.

Some diseases secondary to inborn errors of metabolism are associated with psychiatric disorders or minor neurological symptoms. The existence of some cases with exclusively psychiatric symptoms represents a diagnostic and therapeutic challenge. The aim of this article is to describe seven treatable neurometabolic disorders that should be taken into account in the psychiatric consultation as they manifest with psychiatric symptoms that mask the organic origin of the disorder. Homocysteine metabolism and urea cycle disorders, Wilson's disease, Niemann-Pick disease Type C, acute porphyria and cerebrotendinous xanthomatosis are described. Following an analysis of the literature, a list of psychiatric symptoms associated with these disorders are proposed, ranging from insidious changes in affective state and thought to atypical symptoms such as visual hallucinations, as well as paradoxical effects of antipsychotics or behavioural disorders in children and adolescents associated with loss of autonomy. The most frequently associated neurological signs, such as alterations in the state of consciousness, motor behaviour and balance disorders, catatonia or progressive cognitive deficit are also listed. Emphasis is placed on the importance of considering resistance to antipsychotic treatment as a warning sign to suspect organicity, as well as the significant improvement in psychiatric impairment when effective and early treatment is established.

Autism spectrum disorder: an early and frequent feature in cerebrotendinous xanthomatosis.

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is an autosomal recessively inherited inborn error of metabolism (IEM) due to mutations in the CYP27A1 gene. The clinical picture ranges from being nearly asymptomatic in early childhood, up to severe disability at adult age. Infantile-onset diarrhea and juvenile-onset cataract are the earliest symptoms in childhood. In the current study, we evaluated the presence of autism spectrum disorder (ASD) in a large cohort of CTX patients. METHODS: We performed a retrospective patient file study in 77 genetically confirmed Dutch CTX patients to determine the frequency of ASD. In addition, we compared plasma cholestanol levels in CTX patients with and without a diagnosis of ASD and tried to establish a relation between CYP27A1 genotype and ASD. RESULTS: In our CTX cohort, 10 patients (13%; nine pediatric and one adult) with ASD were identified. At the time of diagnosis of ASD, most patients only exhibited symptoms of diarrhea and/or intellectual disability without signs of cataract or neurological symptoms. No correlation was found between the presence of ASD and the level of cholestanol or CYP27A1 genotype. The behavioral problems stabilized or improved after treatment initiation with chenodeoxycholic acid (CDCA) in all pediatric patients. CONCLUSIONS: We conclude that ASD is an early and probably underestimated frequent feature in CTX. Metabolic screening for CTX should be performed in patients with ASD when accompanied by diarrhea, intellectual disability, juvenile cataract, and/or neurological involvement. Early recognition allows for earlier initiation of specific treatment and will improve clinical outcome. Our results add CTX to the list of treatable IEMs associated with ASD.

[Treatable neurometabolic diseases. Association with schizophrenia spectrum disorders]. / Maladies neurométaboliques traitables associées aux troubles du spectre de la schizophrénie.

Schizophrenia spectrum disorders are presented on 1% of subjects over general population. Organic pathologies prevalence in schizophrenia spectrum patients is not well determined, and it is probably underestimated. In the present update review, we are going to highlight seven treatable neurometabolic diseases (NMD) associated to sub-clinic neurological symptoms. It is not infrequent to witness the absence of any clinical neurological signs going along with the NMD. Psychiatric symptoms may be the only clinical alarm that can guide physicians to an acute diagnosis. This is why it is a challenging pathology, defying our clinical accuracy as psychiatrist or any other practitioners confronted to this population. Hereby we are going to expose a literature review and comprehensive tables in order to present in a glance the essential clinical features of disorders of homocysteine metabolism, urea cycle disorders, Niemann-Pick disease type C, acute porphyria, cerebrotendinous-xanthomatosis. These conditions are sensible to major improvement strongly correlated to the accuracy of diagnosis. Literature analysis led us to propose a comprehensive list of atypical psychiatric symptoms including highly predominant visual hallucinations, compared to auditory ones, as well as confusion, catatonia or progressive cognitive decline. We highlight the importance of considering antipsychotic treatment resistance as a crucial sign leading to suspect an organic factor beneath the psychiatric features.

Diagnostic and treatment implications of psychosis secondary to treatable metabolic disorders in adults: a systematic review.

OBJECTIVE: It is important for psychiatrists to be aware of certain inborn errors of metabolism (IEMs) as these rare disorders can present as psychosis, and because definitive treatments may be available for treating the underlying metabolic cause. A systematic review was conducted to examine IEMs that often present with schizophrenia-like symptoms. DATA SOURCES: Published literature on MEDLINE was assessed regarding diseases of homocysteine metabolism (DHM; cystathionine beta-synthase deficiency [CbS-D] and homocysteinemia due to methyltetrahydrofolate reductase deficiency [MTHFR-D]), urea cycle disorders (UCD), acute porphyria (POR), Wilson disease (WD), cerebrotendinous-xanthomatosis (CTX) and Niemann-Pick disease type C (NP-C). STUDY SELECTION: Case reports, case series or reviews with original data regarding psychiatric manifestations and cognitive impairment published between January 1967 and June 2012 were included based on a standardized four-step selection process. DATA EXTRACTION: All selected articles were evaluated for descriptions of psychiatric signs (type, severity, natural history and treatment) in addition to key disease features. RESULTS: A total of 611 records were identified. Information from CbS-D (n = 2), MTHFR-D (n = 3), UCD (n = 8), POR (n = 12), WD (n = 11), CTX (n = 14) and NP-C publications (n = 9) were evaluated. Six non-systematic literature review publications were also included. In general, published reports did not provide explicit descriptions of psychiatric symptoms. The literature search findings are presented with a didactic perspective, showing key features for each disease and psychiatric signs that should trigger psychiatrists to suspect that psychotic symptoms may be secondary to an IEM. CONCLUSION: IEMs with a psychiatric presentation and a lack of, or sub-clinical, neurological signs are rare, but should be considered in patients with atypical psychiatric symptoms.

The neuropsychiatry of inborn errors of metabolism.

A number of metabolic disorders that affect the central nervous system can present in childhood, adolescence or adulthood as a phenocopy of a major psychiatric syndrome such as psychosis, depression, anxiety or mania. An understanding and awareness of secondary syndromes in metabolic disorders is of great importance as it can lead to the early diagnosis of such disorders. Many of these metabolic disorders are progressive and may have illness-modifying treatments available. Earlier diagnosis may prevent or delay damage to the central nervous system and allow for the institution of appropriate treatment and family and genetic counselling. Metabolic disorders appear to result in neuropsychiatric illness either through disruption of late neurodevelopmental processes (metachromatic leukodystrophy, adrenoleukodystrophy, GM2 gangliosidosis, Niemann-Pick type C, cerebrotendinous xanthomatosis, neuronal ceroid lipofuscinosis, and alpha mannosidosis) or via chronic or acute disruption of excitatory/inhibitory or monoaminergic neurotransmitter systems (acute intermittent porphyria, maple syrup urine disease, urea cycle disorders, phenylketonuria and disorders of homocysteine metabolism). In this manuscript we review the evidence for neuropsychiatric illness in major metabolic disorders and discuss the possible models for how these disorders result in psychiatric symptoms. Treatment considerations are discussed, including treatment resistance, the increased propensity for side-effects and the possibility of some treatments worsening the underlying disorder.

Medical and developmental risk factors of catatonia in children and adolescents: a prospective case-control study.

CONTEXT: Rare diseases have been associated with more and more genetic and non genetic causes and risk factors. But this has not been systematically assessed in catatonia, one of the psychiatric syndromes, that is most frequently associated with medical condition. OBJECTIVE: We sought to assess the medical and developmental risk factors of catatonia in children and adolescents. METHODS: From 1993 to 2009, 58 youths aged 10 to 18 years were prospectively admitted for catatonia and were followed up after discharge. A multidisciplinary approach assessed patients' medical condition and developmental history. A causality assessment scored medical risk (maximum score=10; κ=0.91). We compared the prevalence of catatonia in these patients to that of 80 inpatients with bipolar I disorder admitted from 1993 to 2003 who were also followed up. RESULTS: We found that 13 (22.4%) patients had medical conditions and 18 (31%) had a history of developmental disorder in the catatonia group, whereas 1 (1.3%) and 17 (22.6%) patients had the same conditions in the bipolar group (p<0.001; p=0.17, respectively). Medical conditions associated with catatonia included auto-immune encephalitis (systemic lupus erythematosus [N=3] and anti-NMDA-receptor encephalitis [N=1]), seizures (N=1), ciclosporin encephalitis (N=1), post hypoglycaemic coma encephalitis (N=1), and genetic or metabolic conditions (chorea [N=2], 5HT cerebrospinal fluid deficit [N=1], storage disease [N=1], fatal familial insomnia [FFI; N=1], and PRODH mutations [N=1]). Six patients responded to a specific treatment approach related to their medical condition (e.g., plasma exchange in the case of auto-immune encephalitis). CONCLUSION: Catatonia in children and adolescents is associated with a high prevalence of medical conditions. This needs to be acknowledged as it may greatly delay the treatment of catatonia and the diagnosis of medically related catatonia. Tragically, this may deny patients treatment opportunities.

Malignant catatonia due to anti-NMDA-receptor encephalitis in a 17-year-old girl: case report.

Anti-NMDA-Receptor encephalitis is a severe form of encephalitis that was recently identified in the context of acute neuropsychiatric presentation. Here, we describe the case of a 17-year-old girl referred for an acute mania with psychotic features and a clinical picture deteriorated to a catatonic state. Positive diagnosis of anti-NMDA-receptor encephalitis suggested specific treatment. She improved after plasma exchange and immunosuppressive therapy. Post-cognitive sequelae (memory impairment) disappeared within 2-year follow-up and intensive cognitive rehabilitation.

Electroconvulsive therapy in adolescents with the catatonia syndrome: efficacy and ethics.

OBJECTIVES: In child and adolescent psychiatry, catatonia is infrequent, but it is one of the most severe syndromes, characterized by the coexistence of psychic and motor symptoms. In this report, we explore the therapeutic experience with electroconvulsive therapy (ECT) in adolescents with catatonia. METHODS: We review the literature (1985-2009) to clarify issues related to the use of ECT in child and adolescent patients with catatonia. RESULTS: Electroconvulsive therapy is used as second-line management after high-dose benzodiazepine trials. Electroconvulsive therapy is an effective, safe, and useful procedure in the treatment of catatonic youngsters as reported in 59 patients. Ethical issues regarding the use of ECT are analyzed and their implications briefly discussed in the light of general medical ethics. CONCLUSIONS: Electroconvulsive therapy is a safe and effective treatment for catatonia in children and adolescents.

Lorazepam, fluoxetine and packing therapy in an adolescent with pervasive developmental disorder and catatonia.

Packing therapy is an adjunct symptomatic treatment used for autism and/or catatonia. Here, we report the case of a 15-year-old boy with pervasive developmental disorder who developed catatonia. At admission, catatonic symptoms were severe and the patient required a feeding tube. Lorazepam up to 15 mg/day moderately improved the catatonic symptoms. On day 36 we added fluoxetine and on day 62 we added packing therapy (twice per week, 10 sessions). After three packing sessions, the patient showed a significant clinical improvement (P<0.001). At discharge (day 96), he was able to return to his special education program. Although we do not consider packing as a psychodynamic treatment, this case challenges the concept of embodied self that has opened new perspectives on a dialogue between psychoanalysis and neuroscience. Indeed, better body representation following packing sessions, as shown in patient's drawing, paralleled clinical improvement, and supports the concept of embodied self. This concept may serve as a link between psychoanalysis and attachment theory, developmental psychology with the early description of "sense of self", and cognitive neurosciences that more and more support the concept of embodied cognition. Further clinical studies are necessary to clarify the efficacy and underlying mechanism of packing treatment and to understand how patient's experience may illustrate the concept of embodied self.

Cerebrotendinous xanthomatosis presenting with severe externalized disorder: improvement after one year of treatment with chenodeoxycholic Acid.

Cerebrotendinous xanthomatosis (CTX) is a rare inborn disorder of sterol storage with autosomal recessive inheritance and a variable clinical presentation. We describe two siblings with an early psychiatric presentation of CTX-associated attention-deficit/hyperactivity disorder and oppositional defiant disorder, also associated with a mild intellectual disability and major behavioral impairments. In both cases, treatment with chenodeoxycholic acid improved externalized symptoms and a partial recovery of cognitive impairments was observed. This suggests that CTX is potentially reversible, demonstrating the need for early diagnosis and treatment of this disorder before irreversible neurological lesions can occur.

Association of adolescent catatonia with increased mortality and morbidity: evidence from a prospective follow-up study.

This paper examined outcomes among youth with catatonic syndrome and determined whether the characteristics suggesting the relevance of chronic catatonic schizophrenia (CCS) at index episode remained stable at follow-up. From 1993 to 2004, 35 individuals aged 12 to 18 years were prospectively admitted for management of catatonic syndrome and followed up after discharge. Mean duration from discharge to follow-up was 3.9 years (range 1-10). Four patients were lost to follow-up. Among the remaining 31 subjects (mean age=19.5 years, range 15-26), life-time diagnosis using the Diagnostic Interview for Genetic Studies was unchanged in 28 patients, and included schizophrenia (all subtypes; N=20), major depressive episode (N=5), bipolar disorder type I (N=4) and brief psychotic episode (N=2). Mortality (all-cause Standardized Mortality Ratio=6266; 95% CI=1181-18,547) and morbidity were severe, with 3 deaths (including 2 suicides), 6 patients presenting with a causal organic condition and 14 subjects needing continuous psychiatric care. All males in the study (N=8) who had chronic catatonic schizophrenia at the index episode still had chronic catatonic signs at follow-up. Catatonia is one of the most severe psychiatric syndromes in adolescents. It is associated with a 60-fold increased risk of premature death, including suicide, when compared to the general population of same sex and age. This increased risk of premature death remains higher than the one measured in former adolescent psychiatric patients (all-cause SMR=221; 95% CI=156-303; Engqvist and Rydelius, 2006), or in schizophrenia irrespective to age and subtype (all-cause SMR=157; 95% CI=153-160; Harris and Barraclough, 1998).

Multidisciplinary approach of organic catatonia in children and adolescents may improve treatment decision making.

Catatonia is an infrequent but severe condition in young people. Organic diseases may be associated and need to be investigated though no specific recommendations and guidelines are available. We extensively reviewed the literature of all the cases of organic catatonia in children and adolescents from January 1969 to June 2007. We screened socio-demographic characteristics, organic diagnosis, clinical characteristics and treatment. We found 38 cases of children and adolescents with catatonia due to an organic condition. The catatonic syndrome occurred in 21 (57%) females and 16 (43%) males. The mean age of patients was 14.5 years (+/-3.39) [range=7-18 years], and three died from their condition. The organic conditions included infectious diseases (N=10), neurological conditions (N=10), toxic induced states (N=12) and genetic conditions including inborn errors of metabolism (N=6). The onset was dominantly acute, and the clinical presentation most frequently stuporous. Although benzodiazepines were recommended as primary symptomatic treatment, they were rarely prescribed. In several cases, therapeutic approach was related to organic cause (e.g., plasma exchange in lupus erythematosus; copper chelators in Wilson's disease). Based on this review and on our own experience of catatonia in youth, we proposed a consensual and multidisciplinary diagnostic strategy to help practitioners to identify underlying organic diseases.

Does catatonia influence the phenomenology of childhood onset schizophrenia beyond motor symptoms?

Childhood onset schizophrenia (COS) and catatonia (C) are rare and severe psychiatric disorders. The aim of this study was to compare the phenomenology of COS with and without catatonia. We examined 33 cases consecutively referred to two major public university hospitals in Paris. There were 18 cases of COS (age=15.9+/-0.8 years) and 15 of COS+C (age=15.4+/-1.4 years). Patients were referred over the course of 3 and 9 years, respectively. Psychiatric assessment included socio-demographic, clinical and psychometric variables: the Brief Psychiatric Rating Scale (BPRS), the Scales for the Assessment of Positive (SAPS) and Negative Symptoms (SANS), and a catatonia rating scale. Patients with COS+C appeared to be more severely ill at admission and discharge compared with COS in nearly all clinical scores. They also exhibited significantly longer episode duration (50.8 weeks+/-4.8 vs 20.6+/-19.5). On the basis of multivariate logistic regression, the only clinical measure which significantly predicted group membership was the SANS Affective Flattening score (odds ratio=1.24; 95% CI=1.06-1.43). Our findings strongly suggest that catatonic COS differs from COS in ways that extend beyond motor symptoms. The SANS and SAPS scales, commonly used in schizophrenia, are not detailed enough to accurately describe catatonia in COS. The use of a catatonia rating scale is recommended to enhance recognition of and research into COS with catatonia.