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Psychiatric Manifestations of Organic Conditions!Focus on NPC!
Olivier Bonnot, MD, PhD!Department of Child and Adolescent Psychiatry!University of Nantes, [email protected] website: http://u2pea.free.fr !
COPENHAGEN April, 16th, 2015
Outline!
• Overview of organic disorders in psychiatry!
• Focus on treatable IEM and NPC!
• How to build an accurate and efficient algorithm for differential diagnosis?!
• Conclusions!
General Consideration!
• Organic disorders are poorly recognised in psychiatric patients!
• Prevalence is unknown except in few !sub-samples!
• Cross-discipline diseases are obviously more difficult to diagnose!
Nutritional deficiency !
Pellagra!(Vitamin B3 deficiency)!
Biermer!(Vitamin B12 deficiency) Bushman 1999! Other vitamin deficiency?!
Endocrine diseases!
Addison’s Disease! Cushing's Disease Hirsh 2000!Dysregulation of thyroid and !
hyper-parathyroid!
Inborn errors of metabolism!
Homocysteine metabolism disorders (MTHFR and CBs) Reif 2005!
Wilson’s Disease Wichovicz 2006 !
Urea cycle disorders!Porphyria Ellencweig 2006!
Niemann-Pick disease Type C!Xanthomatosis!
Infectious diseases!Cerebral abscess! Encephalitis (HSV ++)! Neuro-syphilis!
Auto-immune diseases!Chorea / Multiple Sclerosis! Lupus / Sarcoidosis! NMDA !
Chromosomal abnormalities! Mac Carthy, Nat Genet 2009; Ingason, Mol Psy, 2011; Abdolmaleky, Am J Med Genet 2005, Stefansson, Nature 2009; Levinson, Am J Psy 2011!
!
1q21, 2p53, 2q29, 15q11.2, 15q11.3, 17q12, 22q11.2! NRXN1 (Neurexin 1)! 7q36.3, 25q11-13, 16p11.2, 16p13.1!
Other CNS diseases! Toxic ! Medication !Epilepsy ! ! !
Main Organic Disorders in Schizophrenia!
Pathology! % in ASD! % with ASD! Genes!Fragile X! 2–5%! 20–40%! FMR1!Tuberous Sclerosis! 3–4%! 43–86%! TSC1-TSC2!Duplication 15q!Angelman / Prader Willi! 1–2%! sup 40%! UBE3A!
GABAr!22q11 deletion!16p11 deletion! 1 %! High but
unknown!SHANK3!PCKB1!
2q37 deletion! ?! 50! K1F1A, GBX2!Joubert Syndrome! ?! 40%! AH1!Timothy Syndrome! ?! 60–70%! CACNA1C!Focal Cortical Epilepsy with dysplasia! ?! 70%! CNTNAP2!
Main Genetic Disorders in ASD
ASD, autistic spectrum disorder!
Diseases! ASD + associated signs! Diagnosis! Treatment!
Phenylketonuria! Neonatal onset, seizure, microcephaly, musty and mousy odour!
Phenylpyruvic acid in urine!Plasma amino acids analysis!
Restricted diet!Amino acids!
Adenylosuccinase deficiency!
Profound retardation!first year!epilepsy, hypotonia!
Succinyl aminoimidazole, carboxamine riboside and succinyl adenosine in urine and CNS!
D-Ribose!
Creatine deficiency! Mental retardation, hypotonia, epilepsy, dyskinetic movements, regression +++!
Blood and urinary creatinine, MRI, Spectroscopy!
Oral creatine!Arginine restriction!Ornithine substitution!
Smith-Lemli-Opitz! Onset in infancy, mental retardation, sensory hyperactivity, sleep disturbance, hypotonia, …!
Abnormal sterol pattern (low plasma and tissue cholesterol and increased plasma and tissue !7-dehydrocholesterol reductase)!
Cholesterol replacement therapy!
Serotonin deficiency ! Various! CNS serotonin level! Serotonin + L-Dopa?!
Cerebal folate deficiency!
Ataxia, abnormal movement!Controversial!
CNS folate! Folic acid!
Main IEM in ASD
ASD, autistic spectrum disorder; CNS, central nervous system; IEM, inborn error in metabolism; MRI, magnetic resonance imaging
Tableau I – Principales causes de retard mental : classification, étiopathogénie, et fréquence estimée (d’après Szymanski et Bryan, 1999)!Classification! Exemples! Etiopathogénie!
Causes prénatales d’origine génétiquea – 32 %!Aberrations chromosomiques ! Syndrome de Down ou Mongolisme! 95 % : trisomie 21 (non transmise) ; 5 % : translocation (peut être
transmise) !Mutations monogéniques! X Fragile!
Phénylcétonurie!Sclérose tubéreuse!
Lié à l’X ; répétition CGG > 230!Autosomique récessif ; déficit enzymatique!
Autosomique dominant!Multifactoriel! Retard mental « familial »! Mixte: génétique, environnementale…!
Microdélétion!Syndrome Vélo-Cardio-Facial!
Syndrome de Prader-Willi!Syndrome d’Angelman!
Syndrome de Williams-Beuren!Délétion sur le chromosome 22 (q11)!
Délétion sur le chromosome 15 (q11-q13) d’origine paternelle!Délétion sur le chromosome 15 (q11-q13) d’origine maternelle!
Microdelétion du chromosome 7 (q11.23)!Metaboliques! 82 causes de pathologies neurométaboliques! enzymatiques!
Causes prénatales d’origine externe – 12 %!Infections maternelles! Infection VIH! Encéphalopathie virale!
Causes toxiques! Syndrome d’alcoolisme fœtal! Exposition in utero à l’alcool!Causes obstétricales! Prématurité! Variable, multifactorielle!
Malformations d’origine inconnue – 8 %!Malformations du SNC! Non fermeture du tube neural! Parfois associé à une hydrocéphalie!
Syndrome poly-malformatifs! Syndrome de Cornelia de Lange! Inconnue !Causes périnatales – 11 %!
Infections! Encéphalite! Infection au virus Herpes Simplex 2!Problèmes pendant la délivrance! Anoxie néonatale! Variable, infarctus cérébral!
Autres! Hyperbilirubinémie! Incompatibilité rhésus mère enfant!Causes post natales – 8 %!
Infections! Encéphalite! Infection virale ou bactérienne!Causes toxiques! Saturnisme! Intoxication au plomb!
Psychosocial! Pathologie de déprivation! Malnutrition, abus, négligence, dépression anaclitique!Autres! Traumatismes ou tumeurs cérébrales! Variable, atteinte du SNC!
Causes inconnues – 25 %!a Le changement dans le matériel génétique n’est pas toujours hérité des parents!
8 2 t r e a t a b l e c a u s e s !o f I E M !
in Inte l lectual Deficiency !
• Thousands!• All inherited!• 40 / 100 000 (Applegarth, Toole 2000, British
Columbia) UNDERESTIMATED!• Frequently associated with Psychiatric signs!
Psychiatric presentations are underestimated particularly when case
are sever and with early onset!
CLINICAL CASE
Brother an Sister, Hanon et al, 2013 Cases
• 22 years old boy • Brief and acute Psycho=c symptoms a@er cannabis
• 14 hospitaliza=ons in 4 years (same symptoms, same context)
• Diagnose is Schizophrenia • AP are poorly efficient
Age 26
• Speech and swallow impairments • Abnormal movements • Blankly stare • Cogni=ve decline
• No change with AP stop or down =tra=on
Age 26
• Choreo-‐dystonic movements • Cerebellum syndrome • Dysmetria / Dysarthria • Frontal Syndrome • SNGP
• Niemann Pick Type C
• Improvement of Psycho=c symptoms with no other treatment than Miglustat
Niemann Pick type C
Sévin M, et al. Brain 2007:130;120–33
Place of Psychiatric Signs in !Niemann-Pick disease Type C!
(1) (1) Hulette et al 1992; Shulman et al 1995; Campo et al 1998; Battisti et al 2003; Turpin et al 2003; Tyvaert et al 2005; Trendelenburg et al 2006; Sandu et al 2009; Walterfang et al 2006
(2) (2) Imrie et al. 2002; Josephs et al 2003; Walterfang et al 2006; Sevin et al 2007; Walterfang et al 2009;
9 case reports(1) + 5 case series(2) :
30 patients with psychiatric signs
24 ataxia: 80%
24 VSNGP: 80%
18 cognitive impairments: 60%
15 large liver or spleen : 50%
Psychiatric Signs
NP-C and Neuropsychological Signs!
• Intellectual deficiency is not systematic, but when it occurs, it’s moderate!
• Cognitive impairments are common but unspecific: lack of working memory, impairment in logic thought1 !
• Developmental delay2!
1. Klarner B, et al. J Inherit Met Dis 2007;30:60–7; !2. van de Vlasakker CJ, et al. Clin Neurol Neurosurg 1994;96:119–23.
A l l a r e v e r y h e t e r o g e n e o u s !
NP-C and Psychiatric Signs!
• Schizophrenia may occur!
• Cognitive impairment !
Disorder! Clinical signs! Context! Eye exam! Biological markers!
Wilson!Tremor!
Dystonia!Dysarthria!
Kayser-Fleischer ring! Coeruloplasmin!
Urea cycle !Confusion!
Abdominal pain!Nausea vomiting!
Protein diet!Post-surgery!
Drugs !(valproate / corticoids)!
Ammoniaemia!
Homocysteinemia (CbS)!
Thromboembolism!Scoliosis!
Marfan-like !Cerebellar signs!
Protein diet!Post-surgery!
Severe myopia !Ectopic lens!
Homocysteiniemia!Methioninemia!
Homocysteinemia (MTHFR)!
Early-onset severe disease usually with microcephaly/
apnea / convulsion!
Homocysteiniemia!Methioninemia!
Niemann-Pick !disease Type C!
Dystonia + ataxia Dysarthria!
Splenomegaly!
Neonatal icterus!Slow progression!
Supranuclear vertical !Gaze palsy!
Skin-biopsy!Filipin test!
NPC1 and NPC2 gene test!Cerebrotendinous
xanthomatosis!Chronic diarrhoea!Spastic paralysis! Juvenile cataract! Cholesteanoemia!
Porphyria!
Urine black or red!Constipation!Confusion!
Abdominal pain!Nausea / vomiting!
Periodic! Porphobilinogens (URINE)!
Main IEM in Schizophrenia !
Atypical Psychiatric Features!
How to …
Atypical Psychiatric Signs of Schizophrenia!
No!0!
Slightly!1!
Evident!2!
Main clinical feature!
3!
Visual hallucinations more important than auditory!
Confusion!
Catatonia!
Progressive cognitive decline!
Treatment resistance!
Fluctuating schizophrenia core symptoms!
Acute onset!
Early onset!
Intellectual disabilities!
Unusual side effects !(level and type)!
0
1
0
0
0
3
1
2
1
0
Atypical Psychiatric Features!
• Suggest the need for a more extensive search!
• Are probably not accurate for acute (infections, toxic)!
Could be a starting point for a large algorithm!
Differential Diagnosis Algorithm!
• A large list of diseases!– 61 disorders!
!
Differential Diagnosis Algorithm!
• An even larger list of signs and symptoms (293) !
• Try to make it simple for clinical use…!
• Not an easy task…!!!
Symptom categories!Physical phenotype! Bone/connective
tissue!Cardiovascular!
Dermatological! Endocrine! Genitourinary!
Haematological! Hearing! Miscellaneous!
Neuroimaging! Neurological! Renal!
Speech! Visceral! Visual!
Differential Diagnosis Algorithm!
Symptom categories!Physical phenotype! Bone/connective
tissue!Cardiovascular!
Dermatological! Endocrine! Genitourinary!Haematological! Hearing! Miscellaneous!Neuroimaging! Neurological! Renal!
Speech! Visceral! Visual!
!
Differential Diagnosis Algorithm!Suspicion of psychosis
[entry criteria to be defined]
Obvious cause? Yes
Abnormal MRI
No
Symptom checker Tier 1
Possible to provide short list of high likelihood diagnoses?
Symptom checker Tier 2
Ranked list of poten=al diagnoses
No diagnosis possible
Assess/addi=onal examina=ons
Diagnosis confirmed?
Treat/Refer Yes
No more poten4al diagnoses
Assess/addi=onal examina=ons
Diagnosis confirmed?
Treat/Refer Yes
Yes
No
1
2
3
4
5
6
7
8
Diagnos=c loop 2
Diagnos=c loop 3
No more poten4al diagnoses
No, but more poten4al diagnoses (i.e. move down the ranked list)
No, but more poten4al diagnoses (i.e. move down the ranked list)
Assess/Treat/Refer
Diagnos=c loop 1
Differential Diagnosis Algorithm!
• Still a work in progress!• Simple and accurate!• IEM and other genetic diseases!• Atypical psychosis signs are a good entry point!• Few discriminative neurological (and / or other)
symptoms must be identified… !
Conclusion and Take Home Messages!
• Schizophrenia is present in 1% of the general population !
• An underestimated proportion may be associated with organic disorders !
• Not only inborn errors of metabolism !• Atypical signs of psychosis are a clear indication !
to perform an extensive search of organic causes!• Think about NPC!
Tak for er opmærksomhed!
