Clinical vignettes

Florence Pasquier, MD PhD

ECNP-2015

DISCLOSURES
ECNP 2015

Florence Pasquier
Last three years
Nature

Sponsors

Investigator of Clinical studies

phases 2-3

Bayer (Piramal), BMS, GE

Healthcare, Lilly, Noscira,
Pharnext, Pfizer, Roche, Et
bientt : Astra-Zeneca, Biogen,
BioCross, MSD, Probiodrug,
Raman

Occasional member of Scientific

Advisory Boards

Alzprotect, Lilly, Sanofi,

Ethypharm, Nutricia, Novartis

No conflic of interest for this presentation

Fees paid to the University Hospital or ADRINOR

Report
A 75-year old right-handed man seen for the first
time
History:

HTA (verapamil and losartan)

Dylipidemia (atorvastatine 20 mg/J)
Hyperuricemia (allopurinol)
Benign prostate hypertrophy (tamsulosine)
Lower limb thrombosis 4 years ago.

Previous Locksmith
Lives with his spouse in a flat, 2 sons
No family history of dementia to his knowledge

History
Sent to the emergency ward for hospitalization at the
request of a third party because of aggression towards
his wife : delusions of jealousy when she came back from
an hospitalization.
For 5 years: cognitive decline with disorientation in
time, memory impairment for recent events, verbal
aggression towards his wife.
Clear reduction of leisure activities, but still goes out
to do some shopping (newspapers) and to watch soccer
games in his neighbourhood, and participates in
household chores.
Autonomous for simple daily life activities (toileting,
dressing..)
Medications managed by his son

Interview
Acknowledges memory troubles but
minimizes them. Unable to tell the recent
events.
A few lack of words and circumlocutions
Numerous repetitions, I worked a lot, this
why I am like this
No blank affect: He is convinced that his
wife has a lover and it makes him very sad
and upset.
His behaviour is appropriate during his
hospitalisation, no eating disorders, he
shows his neighbourhood to the medical

What do you ask for?

Cognitive assessment
MMSE : 20/30. Loss of 6 points in orientation, 3
points for the 3-word recall, 1 point at repetition.
Neuropsychological assessement
Mattis DRS : 103/144.
Prominent deficit in verbal and non verbal episodic
memory
Impaired confrontation naming
Additional Impairment in executive functions, and
orientation
Slight impairment in social cognition, simple reasoning
and semantic memory
Posterior functions are spared (visual gnosis,
constructional praxis)

Cognitive assessment

Digit span: 5 / 3
RL-RI 16 items : 0+1 au R1 then stopped
VAT : failed
DMS-48 : Set 1=69%, Set 2=71%
Lexis : confrontation naming =27/64,
dsignation=62/64
Visuoconstructive tasks : BEC96=12/12
Visual gnosis: VOSP letters=19/20, loc. numbers
= 10/10
Social cognition : lack of understanding of the
mental actions, normalised when shown by
multiple choice proposals

What possible clinical

diagnosis (es)?
What work-up?

First Alzheimers disease,

but

Imaging : MRI

Imagint : HMPAO-SPECT

CSF Biomarkers
A : 1043pg/mL (N>700)
Tau totales : 359 pg/mL (N<500)
P-Tau : 49 pg/mL (N<55)

Synthesis
Clinical feature compatible with AD BUT work up
not supportive of the diagnosis
Differential diagnosis : do not fit with neither PPA
criteria, nor bv-FTD

bvFTD Criteria Consortium FTDC

(Raskovsky et al, Brain 2011)

Possible fv-FTD requires 3 of 6 clinically

discriminating features:
1. Disinhibition ventral orbito-frontal cortex and caudate
2. Apathy/inertia prefrontal dorso-medial/ -lateral cortices
3. Loss of sympathy/empathy
4. Perseverative/compulsive behaviours
5. Hyperoralit
6. Dysexecutive neuropsychological profile

So clinical follow-up

Clinical follow-up
M6 :
MMSE 17/30
Increased apathy

M15 :
MMSE 16/30
Increased difficulties in confrontation naming,
numerous circumlocutions
Same neuropsychological profile, more severe

M20 :
MMSE 15/30
Autonomous for toileting, dressing, meals. Rid the
table. Do a bit of shopping at the supermarket
Irritability, apathy, with no other behavioural
trouble

Clinical follow-up
M30 (78 years)
He entered a home-housing with his wife.
Appearance of behavioural disorders since M24
: hyperorality, ritualized purchases
(handkerchiefs), blank affect, restlessness.
Massive reduction of language. Name by use or
gesture. Verbal stereotypies
Perplexity in front of some words cube,
heart
2 years after his first visit : fulfils probable
FTD criteria

What to do next?

Exclusion of PGRN and

C9ORF72 mutation

FTD and episodic memory

FTD and hippocampal dysfunction
Clinical arguments
10% of confirmed FTD have memory
impairment at the early stage of the disease
(Hodges, 2004)

Inaugural severe amnesia possible in

confirmed bv-FTD (Graham, 2005)
AD and bv-FTD patients may have avoir the
same severity of episodic memory
impairment (Hornberger, 2010)

FTD and Memory impairment

FTD and hippocampal dysfunction
anatomical/neuropathological arguments:

Early hippocampal atrophy in FTD

(van Mansfelt, 1954; Broe, 2003)

Hippocampal lesions and FTD: Pick

bodies, tangles, TDP-43inclusions ,
hippocampal sclerosis .

Genetic arguments
Inaugural memory impairment
possible in hereditary forms of FTD
with MAPT mutation (Van Sweeten, 1999;
Doran,2007) and PGRN mutation (Le Ber,
2008; Kelley, 2010)

Imaging : M30

Conclusions
Frequent episodic memory impairment in FTD
Subcortical-frontal profile or hippocampal (encoding
impairment)
Sometimes inaugural: Value of biomarkers (imaging,
CSF) and of long-time clinical follow-up to revise the
syndromic description.

Clinicopathological Heterogeneity of FTLD:

memory impairment more frequent in
temporal forms
Late onset ?
Could they predict neuropathology?

Memory dysfunction is no more considered as

an exclusion criteria for the bv-FTD (Rascovsky,
2011)

A family hydrocephalus

First visit: 11/01/2012

60 year-old man

Benigh prostate hypertrophy

Smoker
3/4 glasses of vine/day

Archivist in a bank (still at work)

Certificat dtudes but learning difficulties
History of the disease
Start in 2007 :
Marche petits pas
Urinary urgency
Sleep attacks
Mild loss of initiative
Brain MRI: ventricular dilatation (V3+++) increasing with time
(2007,2009,2010) with corpus callosum posterior hypoplasia,
posterior parietal atrophy suspected of normal pressure
hydrocephalus : treated with acetazolamide and modiodal

Current complaint :
Attention deficit
Disorientation in space (he drives on a few paths,
always the same)
Difficulties using appliances
Difficulties with planning, organisation
(dysexecutive syndrome)
Ritualized days, very anxious especially in front of
new situations. He arreives at work 1 hour in
advance every day, because he is afraid of being
late).
Autonomy is preserved for everyday basic functions
He is dependent on his wife (she manages shopping
and accounts)

AD at 92 years

1948
Fluctuatin
g affective
disorders

NPH ? Corpus callosum

agenesia
disorientation in space, falls
End of life: bed-ridden
incontinent, difficulities with
swallowing
Death at 72 years (onset
50/60 years)

1950
Eating behaviour troubles

Clinical examination:

Normal steps
Decreased arm swing on the right
No postural instability
Brisk reflexes, left Hoffmann sign

What to do next?

MMSE : 23/30 (-5 for counting backwards, - 1 repetition,

-1 copy drawing)
Neuropsychological assessment
Mattis DRS : 112/144
Impaired performances on executive functions, visuoconstruction, and simple reasoning
Mild difficulties in visual and verbal episodic memory
testing (mainly recall), slight impairment in visual
gnosis , gestual praxis and attention
Speech and language assessment:
Informative language, slight lack of word,
confrontation naming just under the norme, low
verbal fluencies, impaired oral comprehension for
complex items
Impaired spelling
Written calculation just limited and mental calculation
impossible

SPECT : both cortical and subcortical abnormalities

Heterogeneous low uptake in parietal and frontal
region, and superior frontal, slightly decrease in
TPO junctions enlargement of the anterior interhemispheric sulcus
CSF:
A42 : 1037 pg/ml
Tau : 152 pg/ml
P-Tau : 28 pg/ml
IATI : 2.57
Not in favour of AD
Is this related to corpus callus agenesia?

And what about sleep?

First polysomnography:
AHI : 13.5 h/sleep mainly central and
prdominance centrale when supine
2nd PSG :
Ronchopathy, Epworth score : 12/24
AH I : 22,5 h/sleep
No hypersomnia at the sleep latency test
Otolaryngologist consultation: bad dental status
no orthesis

Second assessmet:
20/12/12
Does not always understand news
Difficulties with planning and organisation if not
routine
Increase language difficulties (lack of words,
paraphasias
Worse calculation
Retired (07/2012)
Participate very few to housework chores (dishes,
bins)
Crosswords +++ (nothing else is important)
Less anxious
No affective disorder, no change of character

Examination
A bit disinhibited
Right hypertonia and posture tremor
MMSE : 23/30 (same failures)
Neuropsychological assessment:
Cubcortical and frontal profile with posterior
cortical impairment stable
Mattis DRS 110/144
Collaborative and aware of his troubles
Language
Stable

3rd PSG:
Severe obstructive SAS : AHI : 31.6 h/ sommeil
Treated with positive pressure mask

Consultation 5/12/13 :
New MRI : increased cortico-subcortical atrophy (NPH ?)
Behavioural changes:
Apathy +++ (no initiative anymore, must be constantly
stimulated by his wife)
Unique occupation : Word search (hidden words in a crossword
puzzle (for hours, completely cut off from the world)
Rituals (each Friday night the TV programme must be thrown in
the trash)
Troubles du comportement alimentaire : eat very quickly ,
chocking, gloutonnerie
Pas dapptence pour le sucr, pas de prise alimentaire en dehors
des repas
Pas dindiffrence affective (trs empathique vis--vis de son
pouse)
Pas de strotypies gestuelles
Pas dincurie (se lave seul sans stimulation)
Troubles du jugement

MA 92 ans
1948
Troubles
de lhumeur
fluctuants
Parcimonieu
x
Impulsif

HPN ? Dysgnsie corps calleux

Troubles de
lorientation spatiale, chute,
sd parkinsonien
Fin de vie : grabataire, trouble de
la continence, troubles de dglutition
Dcd 72 ans (dbut des troubles
50/60 ans)

1950
Troubles du
comportement
alimentaires : lgumes blancs
uniquement,
Gloutonnerie,
mutique
Marche petits pas, chute,
incontinence,
HPN ? PL dpltives

23 ans, RCH
Dysgnsie du
corps calleux

HDJ : 4/02/2014
Majoration de la jovialit, comportement parfois enfantin
De plus en plus affectueux vis--vis de son pouse
Activits ritualises
Troubles du comportement alimentaire
Examen clinique :
Syndrome pyramidal, BBK gauche
Pas de dficit moteur
Pas damyotrophie, pas de fasciculation
Hypokinsie bilatrale des MS, roue dente droite

MMSE : 24/30 (calcul, rptition de la phrase)

Evaluation neuropsychologique :
Quelques rires immotivs, lgre impulsivit, manque du mot
Mattis 116/144
Difficults excutives, en mmoire de travail et au niveau de lattention
Difficults plus lgres sur le plan des aptitudes visuo-constructives et des
gnosies visuelles
Lgres difficults de la mmoire pisodique verbale (rcupration) et de la
cognition sociale)
Evaluation orthophonique
Pjoration de la fluence littrale, rares conduites dapproches phonmiques
Texte moins bien intgr (oubli des dtails), lecture laborieuse ( paralexies
morphologiques)
Troubles du calcul et dysorthographie superposables

TEP FDG :
Discrtes htrognits de fixations diffuses, bilatrales
du ruban cortical npargnant que les aires visuelles
primaires, sans topographies systmatises. Elargissement
des sillons inter hmisphriques antrieur et postrieur
Pas dorientation vers une pathologie neurodgnrative de
type MA ou DLFT
IRM de flux :
Dilatations des ventricules latraux et du 3me ventricule
Stroke volume faible (30l)
Dosage de la progranuline srique : 131 (100<N<300)

Cs du 15/05 :
Troubles de dglutition
Troubles de la marche avec enraidissement MI
leffort
Dysurie
Examen :
Diminution de la force segmentaire au MIg en
proximal
Spasticit MIg
Sd ttrapyramidal prdominant gauche (BBK)
IRM mdullaire :
Sans particularit

Cs du 20/11:
Aggravation des troubles de la marche, utilise une bquille
Fatigabilit
Voix rauque
Apathie
Pas dindiffrence affective vis--vis de son pouse
Plus de troubles du comportement alimentaire
Mots flchs +++
Proccup par son tat de sant (dit quil va mourir, que
lon va lui couper sa jambe)
Rituel : programme TV
Examen :
Dficit moteur Mig proximal, amyotrophie quadricipitale,
moyen fessier, fasciculations
Sd ttrapyramidal : BBK X2, spastique
EMG : pas datteinte motrice priphrique, dfaut de
recrutement dallure centrale au niveau du MIg

What diagnosis?

C9ORF72 : pathological expansion of

hexanuclotide GGGGCC