When to worry about developmental and psychiatric disorders in … Parker.pdf · ·...

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Identifying atypical signs & symptoms

When to worry about developmental and psychiatric disorders in childhood

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• Welcome

• Timing

• Toilets

• Fire escapes

Welcome, agenda and housekeepingIntroudiction

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• To raise the ability among pychiatrists to spot the red flag signs of progressive disease in children with developmental and psychiatric disorders by…

• Applying the appropriate questioning style in history taking

• Performing an appropriate neurological examination

Learning objectivesIntroduction

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The problemIntroduction

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When you get a case like this –how do you handle it?


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Detection rate:How many do we miss, and does it matter?


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So – how can we ensure that we detect the red flag symptoms?


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Detecting red flag signs and symptoms always begins with a solid history and examination –getting the ”basics” right.

It can go wrong, based on what you have heard and seen.


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In the first part of the session we will focus on knowing what to ask and what to look for :• History taking• Examination• Diagnostic tests:

• Biochemical investigation• Genetic analysis• Neuroimaging • Further, specialised testing…


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Meeting the patient and his/her parents– history taking in practice

History takingStep 2

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Meeting Sally, Jonathan’s mother. Part 1

As you watch the film, note your observations in the workbook.Q1: What strikes you as being of particular importance or interest?Q2: What would you want to clarify further with Sally?


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As you watch the film, note your observations in the workbook.Q1: What strikes you as being of particular importance or interest?Q2: What would you want to clarify further with Sally?


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As you watch the film, again note your observations in the workbook.Q1: What strikes you as being of particular importance or interest?Q2: What would you want to clarify further with Sally?


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As you watch the film, again note your observations in the workbook.Q1: What strikes you as being of particular importance or interest?Q2: What would you want to clarify further with Sally?


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As you watch the film, again note your observations in the workbook.Q1: What strikes you as being of particular importance or interest?Q2: What is your suspicion for Jonathan? What will be your next step?


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As you watch the film, again note your observations in the workbook.Q1: What strikes you as being of particular importance or interest?Q2: What is your suspicion for Jonathan? What will be your next step?


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What are your tips, as experts, on efficient history taking for this population?


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Neurological examination• How do you approach this?• What difficulties do you find?

Performing a neurological examinationStep 3

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As you watch the films, note your observations in the workbook.

A. Introduction & gait B. Dynamic assessment C. Arms & legs

E. Other cranial nervesD. Eyes Play all

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What do you look out for in:1. Introduction & gait

2. Dynamic assessment

3. Arms & legs

4. Eyes

5. Other cranial nerves

Neurological examinationStep 3

Play all

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Play all


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Atypical signs:

Dynamic assessment

Arms & legs

Eyes

Other cranial nerves

Introduction & gait

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Think about where in the brain the symptom indicates there may be a problem

Step 3

Cerebellum

Striatum

Midbrain

Hippocampus, Thalamus

White matter, Subcortical regions

Cause: Changes:Ataxia, Dysarthria

Dystonia

Gaze palsy, Dysphagia, Cataplexy

Memory impairments

Psychosis in young adults

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Summary of the neurological examinations of Jonathan

Q1: What strikes you as being of particular importance or interest?

Q2: What would be your next step in a rational plan of investigation? Note the top three diagnostic tests you would want to conduct.


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Break


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Please begin working through the case description by reading the referral letter.Then continue with the next parts step by step.

A case of teenage depressionStep 4

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History-taking, Victoria, part 1Please summarise your discussion of the interviews with Victoria and her mother.

Q1: What strikes you as being of particular importance or interest?Q2: What would you want to clarify with Victoria or Patricia?


Victoria, 15

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History-taking, Victoria, part 2Please summarise your discussion of the interviews with Victoria and her mother.

Q1: What strikes you as being of particular importance or interest?Q2: What is your suspicion? What would be your next step in assessing Victoria?


Victoria, 15

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Neurological examination,VictoriaPlease summarise your discussion of the examination results.

Q1: Can you identify 4-5 red flag symptoms in her examination?Q2: What would be your differential diagnosis?Q3: Note the top three diagnostic tests you would want to conduct.


Victoria, 15

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Further investigationsStep 5A

Investigating progressive intellectual/neurological degeneration (PIND) What would you do?

Jonathan, 9

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Refer to a specialist – a neurologistWhat would they do?


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30 most commonly reported confirmed diagnoses


Condition No of casesLeigh syndrome 17

NARP (including NARP/MILS) 17

Menkes disease 16

Mucopolysaccharidosis IIA (Hunter disease) 15

Cockayne disease 15

Canavan disease 13

Neuroaxonal dystrophy 12

Vanishing white matter disease 11

Aicardi–Goutieres syndrome 10

Alexander disease 10

Glutaric aciduria type 1 10

Molybdenum cofactor deficiency 10

Ataxia telangiectasia 9

Subacute sclerosing panencephalitis 9

Rasmussen syndrome 8

1114 children out of 2636Verity C et al. Arch Dis Child. 2010; 95:361–364

Condition No of casesNCL late infantile 73

Mucopolysaccharidosis IIIA (San Filippo) 69

Rett syndrome 60

Metachromatic leukodystrophy 59

Adrenoleukodystrophy 56

NCL juvenile 44

GM2 gangliosidosis type 1 (Tay–Sachs) 41

Niemann–Pick Type C 38

Krabbe disease 33

GM2 gangliosidosis type 2 (Sandhoff) 33

GM1 gangliosidosis 23

Huntington disease 22

NCL infantile 22

PKAN/NBIA* 21

Pelizaeus–Merzbacher disease 17

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• Neuronal Ceroid Lipofuscinosis

• Gangliosidoses

• Mucopolysaccharidosis

• Metachromatic leukodystrophy

• Adrenoleukodystrophy


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• Niemann-Pick type C

• Leigh / NARP

• Krabbe disease

• Huntington disease

• N’Deg Brain Iron Accumulation

• Pelizaeus-Merzbacher disease


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First line investigation – key conditions to consider• History

• Huntington, Rett, Menkes, Rasmussen

• Examination • Mitochondrial, Rett, Cockayne, Ataxia Telangiectasia

• Consider the degenerative movement and ataxic disorders without significant intellectual deterioration

• e.g. Friedrich’s Ataxia


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MRI scan


Pelizaeus Merzbacher NBIA

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Biochemistry – White cell enzyme screen• NCL/Batten: infantile/late infantile

• Gangliosidoses

• Many leukodystrophies


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MRI scan• Very long chain fatty acids: adrenoleukodystrophy


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Biochemistry – Organic acidsGlutaric aciduria, n-acetylaspartate and sulphocysteine for molybdenum co-factor deficiencies


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Biochemistry – Organic acidsLater - CSF analysis glucose/lactate matched with plasma- GLUT1 and Mitochondrial, protein and cell count


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Check results• Opthalmology

• Visual and peripheral neurophysiology

• Vacuolated lymphocytes


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Have we missed any conditions?


Condition No of casesLeigh syndrome 17

NARP (including NARP/MILS) 17

Menkes disease 16

Mucopolysaccharidosis IIA (Hunter disease) 15

Cockayne disease 15

Canavan disease 13

Neuroaxonal dystrophy 12

Vanishing white matter disease 11

Aicardi–Goutieres syndrome 10

Alexander disease 10

Glutaric aciduria type 1 10

Molybdenum cofactor deficiency 10

Ataxia telangiectasia 9

Subacute sclerosing panencephalitis 9

Rasmussen syndrome 8

1114 children out of 2636Verity C et al. Arch Dis Child. 2010; 95:361–364

Condition No of casesNCL late infantile 73

Mucopolysaccharidosis IIIA (San Filippo) 69

Rett syndrome 60

Metachromatic leukodystrophy 59

Adrenoleukodystrophy 56

NCL juvenile 44

GM2 gangliosidosis type 1 (Tay–Sachs) 41

Niemann–Pick Type C 38

Krabbe disease 33

GM2 gangliosidosis type 2 (Sandhoff) 33

GM1 gangliosidosis 23

Huntington disease 22

NCL infantile 22

PKAN/NBIA* 21

Pelizaeus–Merzbacher disease 17

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If the neurologist still does not have the answer• Complex case review with colleagues in same centre• Consider discussing with colleagues in other centres,

e.g. Amsterdam


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Seeming to regress – common causes• Non-neurological

• Bullying• Stress• School absence• Autism/dyslexia• Factitious illness• Endocrine/autoimmune


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Seeming to regress – common causes• Neurological

• Medication, e.g. epilepsy therapy• Depression/psychosis• Raised intracranial pressure• Epilepsy• Evolving sensory impairment, e.g. blindness


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Investigating static developmental delayWhat would you do?

Marcus, 9

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Genetic analysis• Karyotype

• Fragile X

• Comparative Genomic Hybridisation (CGH)


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Biochemistry• Electrolytes/renal function• Liver function• Thyroid function• Lactate• Ammonia• Plasma amino acids• Creatine Kinase• Urine amino/organic acids• CSF studies


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Biochemistry• Note neonatal thyroid and phenylalanine levels, make

sure these are actually seen • Doing more has a very, very low yield unless indicated

on history/examination• e.g. encephalopathy, consanguinity, ethnic group,

dysmorphic features• Although you may find abnormalities, there is not a

rational system in particular, plasma amino acids will not yield


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MRI head• Consider the yield… 1-60% in a

series of investigations• With static mild to moderate

developmental delay, and nothing else in the history and examination the yield is likely to be <5%, probably <2% of useful information


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UK Eastern region multidisciplinary review 2003-5www.phgfoundation.org/file/2366


http://www.phgfoundation.org/file/2366

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A teenager with psychiatric and neurological symptomsWhich conditions should you consider?


Victoria, 15

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• Epilepsy• Particularly temporal lobe

• Brain tumours• Frontal, temporal

• Nutritional deficiency• e.g. B12

• Endocrine disease• e.g. Addison, Cushing


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• Infectious disease • e.g. encephalitis

• Neuroinflammation• e.g. multiple sclerosis, SLE, sarcoid

• Chromosomal abnormalities


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Main treatable IEM associated with schizophrenia


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Clinical signs• Tremor, dystonia, dysarthriaEye exam• Kayser Fleischer ringsBiological markers• Caeruloplasmin

Disorder?• Wilson


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Clinical signs• Confusion, abdominal pain, nausea, vomitingContext• Protein diet, post surgery, drugs (valproate/corticoids)Biological markers• Ammonaemia

Disorder?• Urea cycle


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Clinical signs• Thromboembolism, scoliosis, marfan-like, cerebellar

signsContext• Protein diet, post surgeryEye exam• Severe myopia, ectopic lensBiological markers• Homocysteiniemia, methioninemia

Disorder?•Homocysteiniemia (CbS)


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Clinical signs• Black or red urine, constipation, confusion, abdominal pain,

nausea/vomitingContext• PeriodicBiological markers• Porphobilinogens (URINE)

Disorder?• Porphyria


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Disorder:• Cerebrotendinous xanthomatosis

Clinical signs• Chronic diarrhea, spastic paralysis Eye exam• Juvenile cataractBiological markers• Cholesteanoemia


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Practical approach to the investigation of psychiatric cases where there is concern about organic conditionsThorough history, consider:

• Positive family history• Consanguinity• Encephalopathy

Careful examination, look for:• Dysmorphic features• Chromosomal abnormalities• Signs of endocrine disturbance• Evidence of autoimmune disease • Neurological signs

Consider epilepsy and non-convulsive static epilepticus


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Should you do an EEG?• Only to investigate non-convulsive static epilepticus• Not to ask if child has epilepsy


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If still suspicious• Simple metabolic investigations to identify the main

treatable IEM e.g. Caeruloplasmin

• Discuss and refer to a neurologist

• Consider MRI scan and/or EEG, whilst awaiting neurological opinion


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What were the final diagnoses, and how are the patients managing now?

Conclusions for casesStep 5B

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Findings from further tests:• Standard investigations for a

PIND disorder normal• MRI scan showed subtle white

matter changes and reduction in cerebellar volume

Diagnosis?• More testing required• What would you do?


Jonathan, 9

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Findings from further tests:• In view of VSGP, a skin biopsy

was performed. Filipin staining abnormal

• Genotyping showed a homozygous deletion of NPC1

Diagnosis?• Niemann-Pick type C


Jonathan, 9

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Niemann-Pick type C (NPC)• Autosomal, recessive, neurovisceral storage disorder• 30% of patients adolescents/adults


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Niemann-Pick type C (NPC)• In children, presents with key signs:

• Prolonged neonatal jaundice (Jonathan)• Hepatosplenomegaly• Learning disability/school failure• Seizures• Gelastic cataplexy• Ataxia• Vertical gaze palsy• Dystonia


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Niemann-Pick type C (NPC)• In adults, presents with key signs:

• Ataxia• Vertical gaze palsy• Dystonia• Dementia and/or psychosis• Gelastic cataplexy


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Niemann-Pick type C (NPC)• Disorder of intracellular sterol trafficking• Not a classical enzyme-deficiency disorder• Abnormal build-up of cholesterol and production of toxic

levels of gangliosides• Disrupts white matter in widespread fashion• Affects particular grey matter regions: hippocampus,

thalamus, striatum, cerebellum and midbrain


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Niemann-Pick type C (NPC)

Cerebellum

Striatum

Midbrain

Hippocampus, Thalamus

White matter, Subcortical regions

Changes in: Cause:Ataxia, Dysarthria

Dystonia

Gaze palsy, Dysphagia, Cataplexy

Memory impairments

May together be psychotogenic in young adults

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Disease modification• Referral to specialist centre for

lysosomal storage diseases• Started on miglustat

Supportive • Speech-, occupational and

physiotherapy• Anti-epileptic drug treatment• Specialist educational unit


Jonathan, 9

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Findings from further tests:• Kayser-Fleischer rings• Caeruloplasmin levels well below

normal range• Genetic analysis

Diagnosis:• Wilson disease


Victoria, 15

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Kayser-Fleischer rings Victoria, 15

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Wilson disease• Autosomal, recessive genetic disorder of copper

metabolism; copper accumulation in brain (chorea), liver, eyes

• Mapped on to chromosome 13• May not be as common as originally thought• Detected by neurological examination, slitlamp

examination, MRI, serum caeruloplasmin • Can have a normal caeruloplasmin, and therefore with

high index of suspicion metabolic advice on further investigation essential


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Treatment / Interventions:• Penicillamine chelation

• Anti-depressants continued

• Support from community psychiatric nurse


Victoria, 15

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Modifying treatments for degenerative diseases• Dietary, for example PKU• Chelation therapy, e.g. penicillamine for Wilson• Substrate reduction therapy, e.g. miglustat for NPC and

Gaucher disease type 1• Chaperone therapy, e.g. pyrimethamine in GM2

gangliosidosis• Enzyme replacements therapy, e.g. Fabry and Gaucher

disease• Bone marrow transplant, e.g. ALD• Gene therapy? GM2 gangliosidosis

SummaryStep 6

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Questions?

SummaryStep 6

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Key learning points• Diagnosing these conditions as early as possible, is likely

to improve outcome• A thorough history is critical in informing further

assessment/investigation• A competent clinical examination is essential in all cases,

although some clinicians have found this challenging, we hope that you now have a system, and of course… practice makes perfect

• Onward referral, for expert advice, is critical

SummaryStep 6

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Subject matter expert• Dr Alasdair Parker, Lead for Paediatric Neurology, Addenbrooke's

Hospital, and Associate Lecturer, Cambridge University

Videos of patients with symptoms• Lysosomal Diseases Unit, Addenbrooke's Hospital, Cambridge

University Hospitals NHS Foundation Trust • Biochemical Genetics Unit, St. Mary’s Hospital, Central Manchester

University Hospitals NHS Foundation Trust

Sponsor• Actelion Pharmaceuticals Ltd

Learning design and production• Symbal Communications

Thank youStep 6

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A. Introduction & gait


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B. Dynamic assessment


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C. Arms & legs


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D. Eyes


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E. Other cranial nerves


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Play all


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1. Introduction & gait


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2. Dynamic assessment


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3. Arms & legs


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4. Eyes


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5. Other cranial nerves


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