Atypical parkinsonism

ATYPICAL PARKINSONISM

DR.SARATH MENON.R, MD(Med.),DNB(Med.),MNAMS

DM RESIDENT

DEPT. OF NEUROSCIENCES

AIMS,KOCHI

OUTLINE

Classifications

Red flag signs

AP- syndromic approach

Diagnostic criteria

Phenotypic spectrum

Atypical AP or mimickers

Investigations

Novel biomarkers

Treatment

Future trends

INTRODUCTION

Common problem in neurology outpatient

departments

Wide variety of sporadic / heredodegenerative

syndromes

Aetiologies vary widely

80-85% -IPD

Differentiation from other syndromes

Very important in prognostication and management

AKINETIC RIGID SYNDROMES -

CLASSIFICATION

Primary (Idiopathic) Parkinsonism

Multisystem Degenerations

. Heredodegenerative Parkinsonism

Secondary (Acquired, symptomatic) Parkinsonism

Primary Parkinsonism Parkinson’s Disease

- Sporadic Parkinson’s Disease

- Hereditary

MULTISYSTEM DEGENERATIONS

(PARKINSONISM PLUS)

Progressive Supranuclear Palsy

Multiple System Atrophy (Shy-Dragger syn.) SND

(MSA P)

OPCA (MSA C)

Corticobasal Degeneration

Diffuse Lewy Body Disease

Lytico-Bodig disease (Parkinsonism Dementia ALS

-Complex of Guam)

Progressive pallidal Atrophy

Parkinsonism dementia Complex

Pallido pyramidal Degenerations

HEREDO DEGENERATIVE

Hereditary Juvenile Dystonia Parkinsonism (AR Parkin

Mutation)

Dopa - Responsive Dystonia

Huntington’s Disease

Wilson’s Disease

Hereditary Ceruloplasmin Deficiency

Frontotemporal dementia with parkinsonism

Mitochondrial Cytopathies with Striatal Necrosis

PKAN (Neurodegeneration associated with brain Iron

accumulation; Hallervorden - Spatz Disease)

Spinocerebellar Degenerations (Eg: MJD)

Gerstmann - Straussler - Scheinker Disease

Familial Progressive Subcortical Gliosis

Familial Basal Ganglia Calcification

Lubag(X Linked dystonia - Parkinsonism)

Ceroid Lipofuscinosis

Neuroacanthocytosis

Hereditary Haemochromatosis.

Neuroferritinopathy

Aceruloplasminemia

SECONDARY PARKINSONISM

Infectious Post- encephalitic

HIV; SSPE; Prion diseases

Drugs Dopamine Receptor Blocking drugs, Reserpine, Tetrabenazine, Alpha

Methyl Dopa, Lithium, Flunarizine, Cinnarizine.

Toxins MPTP, Carbon monoxide, Manganese, Mercury, Carbon

disulfide,Cyanide, Methanol.

Vascular -Multi infarct; Binswangers disease.

Trauma -Pugilistic Encephalopathy.

Parathyroid abnormalities;

Hypothyroidism;

Brain Tumors

Paraneoplastic

NPH

Psychogenic.

IDIOPATHIC PD

UK Brain Bank Criteria

bradykinesia and at least one of the following: rest

tremor, rigidity, or postural instability.

RED FLAGS

Symmetric bradykinesia and rigidity

Absence of tremor

Prominent myoclonus

Limb apraxia

Alien limb phenomena

Impaired down gaze

Facial dystonia

Early loss of postural reflexes

L- dopa induced facial dyskinesias

Ataxia

Stridor

Early dysphagia

Spasticity

Early dementia or hallucinations

Early and prominent dysautonomia

MAJOR SYNDROMES

PSP

MSA

CBGD

DLBD

PATHOPHYSIOLOGY

Accurate diagnosis is necessary to understand

pathogenesis

Two proteins mainly

Alpha synuclein

- Pre synaptic protein

- Aggregates in cell body & neurons – lewy body &

lewy neuritis- PD & DLBD

- glial cytoplasmic inclusion in MSA

TAUPATHY

4 repeat tau accumalates

NFT & in glia

Psp- astrocytic tufts

CBD- astrocytic plaques

PROGRESSIVE SUPRANUCLEAR PALSY

Steele et al—1964

5% of parkinsonian pts

Prevalence—4.9 / 100,000

Incidence 1.7 (50-59yrs) to 14.7(80-89yrs)

Commonly misdiagnosed as PD

Insidious onset

No pathologic proven cases have begun before the

age of 40.

Tauopathy-4-repeat t, 4R tauopathy).

always sporadic, few familial cases-

- MAPT (microtubuli associated protein t) gene mtn.

Mitochondrial dysfunction & oxidative stress -

pathophysiology of PSP

Postural Instability & EP Features :

Falls—backward

Poor postural reflexes

Rigidity –axial

Dysarthria—spastic,

Hypophonic

ataxic

Frontal release signs

Pseudobulbar palsy

L-DOPA UNRESPONSIVENESS

Reduced blink rate and closure of eyelids due to eyelid

dystonia or levator inhibition ( apraxia of eyelid

opening)

square wave-jerks

on doll’s eye maneuver, there is improved range, as

vestibulo-ocular reflex is preserved

Subcortical-type dementia

Typical facies- “surprised look”

NINDS–SPSP DIAGNOSTIC CRITERIA FOR PSP

Possible PSP

Mandatory inclusion criteria:

gradually progressive disorder

onset age 40 or later

Either vertical supranuclear palsy or both slowing of

vertical saccades

postural instability with falls within a year of disease onset

no evidence of other diseases that could explain the

foregoing features, as indicated by exclusion criteria

Mandatory exclusion criteria:

recent history of encephalitis

alien limb syndrome

cortical sensory deficits

focal frontal or temporoparietal atrophy

hallucinations or delusions unrelated to

dopaminergic therapy

cortical dementia of Alzheimer type

prominent, early cerebellar symptoms

unexplained dysautonomia

Supportive features:

symmetrical akinesia or rigidity

proximal more than distal

abnormal neck posture

especially retrocollis

poor or absent response of parkinsonism to levodopa

early dysphagia and dysarthria

early onset of cognitive impairment including two or

more of: apathy, impairment in abstract thought,

decreased verbal fluency, utilisation or imitation

behaviour, or frontal release signs

Probable PSP

Mandatory inclusion criteria

gradually progressive disorder

onset age 40 or later

vertical supranuclear palsy

prominent postural instability with falls within a year

of disease onset

no evidence of other diseases that could explain

the foregoing features, as indicated by exclusion

criteria

Definite PSP

Mandatory inclusion criteria:

clinically probable or possible PSP and

histopathological evidence of typical PSP

PHENOTYPIC SPECTRUM OF PROGRESSIVE

SUPRANUCLEAR PALSY

typical PSP phenotype- Richardson syndrome

PSP-p = PD at least at the initial stages, with asymmetric

parkinsonism, rest-tremor, better levodopa response, longer

mean survival

pure akinesia with gait freezing (PSP-PAGF)

corticobasal syndrome (PSP-CBS),

frontotemporal dementia (PSP-FTD), progressive nonfluent

aphasia

no clinical sign to predict PSP pathologic abnormality

accurately in the non-RS phenotypes

INVESTIGATIONS

clinical diagnosis

MRI-

midbrain atrophy

Superior cerebellar peduncle atrophy.

“morning glory flower sign” and the “hummingbird sign” are

quite specific but show low sensitivity (50% and 68.4%,

respectively

(DATscan) is abnormal in PD and all AP syndromes

differentiate with PD, [123]meta-iodobenzylguanidine

(MIBG) and 123I-iodobenzamide (IBZM) SPECT may be

useful

MIBG is abnormal in PD because of postganglionic

sympathetic denervation, but is typically normal in PSP.

IBZM SPECT assessing the postsynaptic receptors is

abnormal in PSP and normal in PD

IBZM SPECT is abnormal in all APs and therefore

cannot differentiate between PSP and other AP

Novel diagnostic approaches and biomarkers

- csf tau protein

-neurofilament light chain

PATHOLOGY

Neurofibrillary tangles are present in these areas.

Tufted astrocytes (Gallyas-positive) -hallmark

feature of PSP that differentiates other 4R

tauopathies such as CBD (astrocytic plaques

RX

no effective symptomatic or neuroprotective treatments

A trial of levodopa (up to 1 g/d) and amantadine (up to 450 mg/d)

Botulinum toxin injections can be used to treat levator inhibition.

Serotonin reuptake inhibitors (SSRIs) may be used for apathy with no

clear benefit.

A small study with Coenzyme Q10- no RCT study

Recent large, double-blind studies with GSK-3b inhibitors (Tideglusib,

Davunetide) have failed to show any clinical effect.

Tideglusib reduced the rate of brain atrophy in one study.

Supportive measures such as physiotherapy, walking aids, speech

therapy and PEG

MULTIPLE SYSTEM ATROPHY :

Sporadic neurodegenerative disorder clinically any

combination of parkinsonian, autonomic, cerebellar, or

pyramidal signs

Pathologically–

cell loss, gliosis, and glial cytoplasmic inclusions in

several CNS structures.

MSA is an a-synucleinopathy

usually a sporadic disease; however, rarely, familial

cases - mutations in COQ2 gene

Epidemiology :

prevalence of MSA in four studies ranged from 1·9

to 4·9 cases per 100 000 people.

similar to those of other well-known

neurodegenerative disorders such as Huntington’s

disease and motor neuron disease.

no single environmental factor shown to increase

or to reduce risks of MSA

Clinical presentation :

affects both men and women

the sixth decade of life progresses with a mean

survival of 6–9 years.

substantial variation of disease progression with

survival of more than 15 yrs.

main features –

autonomic failure

Parkinsonism

cerebellar ataxia

pyramidal signs in any combination.

TWO MAJOR MOTOR PRESENTATIONS

distinguished clinically–

Parkinsonian features predominate in 80% of

patients (MSA-P subtype),

cerebellar ataxia is the main motor feature in 20%

of patients (MSA-C subtype).

Both similar survival times.

patients with MSA-P have a more rapid functional

deterioration than those with MSA-C

MSA-P-associated parkinsonism :

progressive akinesia and rigidity

jerky postural tremor and tremor at rest.

orofacial or craniocervical dystonia associated with a

characteristic quivering high-pitched dysarthria.

Postural stability is compromised early on in the

disease course

recurrent falls at disease onset are unusual in

contrast to psp.

90% of the MSA-P pts- unresponsive to levodopa in

the long term.

50% have levodopa-induced dyskinesia affecting

orofacial and neck muscles, without motor benefit.

fully developed clinical picture of MSA-P evolves

within 5 years of disease onset, allowing a clinical

diagnosis during follow-up.

MSA –P RED FLAGS

Early instability

Rapid progression

Pisa syndrome,camptocormia,contractures

Bulbar dysfunction

Respiratory dysfn- stridor,insp sighs

Emotional incontinence

2/6 – probable MSA-P – additional criteria

MSA-C :

gait ataxia

limb kinetic ataxia

scanning dysarthria,

cerebellar oculomotor disturbances.

Most patients develop additional non-cerebellar

symptoms and signs

may be indistinguishable from other patients with

idiopathic late onset cerebellar ataxia

Dysautonomia :

urogenital and orthostatic dysfunction.

Early erectile dysfunction is nearly universal in men

with MSA

Female- genital insensitivity

urinary incontinence or retention are common early

in the course or as presenting symptoms

CONSENSUS STATEMENT FOR THE CLINICAL

DIAGNOSIS OF MSA

clinical domains,

features

criteria used in the diagnosis of MSA

Autonomic and urinary dysfunction :

Features

1. Orthostatic hypotension

2. Urinary incontinence or incomplete bladder emptying

Criteria

Reduction of least 30mmHg or in diastolic blood pressure

by at least 15 mm Hg after 3 min of standing

urinary incontinence (persistent, involuntary partial or

total bladder emptying, accompanied by erectile

dysfunction in men) or both

Parkinsonism :

A. Features

1. Bradykinesia

2. Rigidity

3. Postural instability (not caused by primary visual,

vestibular, cerebellar, or proprioceptive dysfunction) 4.

Tremor (postural, resting or both)

B. Criteria

Bradykinesia plus at least one of features 2–4

Cerebellar dysfunction :

A. Features

1. Gait ataxia

2. Ataxic dysarthria

3. Limb ataxia

4. Sustained gaze-evoked nystagmus

Criteria

Gait ataxia plus at least one of features 2–4

Corticospinal tract dysfunction

A. Features

1. Extensor plantar responses with hyper-reflexia

Criteria

Corticospinal tract dysfunction in MSA: no

corticospinal tract features are used in defining the

diagnosis of MSA

prominent and severe spasticity should raise

suspicion for an alternative diagnosis

Consensus statement: exclusion criteria for the diagnosis of MSA :

History

Symptomatic onset under 30 years of age

Family history of a similar disorder

Systemic disease or other identifiable causes

Hallucinations unrelated to medication

DSM IV criteria for dementia

Prominent slowing of vertical saccades or vertical supranuclear gaze palsy

Evidence of focal cortical dysfunction such as aphasia, alien limb syndrome, and parietal dysfunction

Laboratory investigation- Metabolic, molecular genetic and imaging evidence of an alternative cause of features

DIAGNOSTIC CLINICAL APPROACH

Motor signs

Parkinsonism poorly responsive to levodopa

Cerebellar ataxia

Pyramidal signs

Early instability and falls Within 3 years of disease

onset

Rapid progression (wheelchair sign) despite

dopaminergic treatment within 5 years of disease

onset

Orofacial dystonia or dyskinesias

Atypical spontaneous or levodopa induced

dystonia

dyskinesia mainly affecting orofacial muscles,

[resembling risus sardonicus of cephalic tetanus]

Axial dystonia -Pisa syndrome (subacute axial

dystonia with a severe tonic lateral flexion of the

trunk, head, and neck)

early severe camptocormia

Disproportionate antecollis -Chin on chest, neck

can only be passively and forcibly extended to its

normal position with difficulty; despite severe

chronic neck flexion, flexion elsewhere is minor.

Jerky tremor

Irregular myoclonic postural or action tremor of the hands

or fingers

Dysarthria-

- Atypical quivering, irregular and severely hypophonic or

slurring high pitched dysarthria,

- tends to develop earlier and be more severe than in PD

notable dysphagia

Non-motor signs

Severe dysautonomia

Abnormal respiration

Nocturnal (harsh or strained, high pitched inspiratory

sounds) or diurnal inspiratory stridor,

involuntary deep inspiratory sighs and gasps, sleep

apnoea

snoring increased from premorbid level

newly arisen REM sleep behaviour disorder

Emotional incontinence

“RED FLAGS’’

RBD and autonomic failure- pre motor stage

Early falls and postural instability can be seen- look for

eye signs & fronto-subcortical dysfunction for PSP

L-dopa induced oro facial dystonia- MSA

Raynaud phenomenon is a common in MSA

Freezing of gait may be prominent, early, and severe,

causing diagnostic difficulties -PSP -PAGF phenotype

dementia, it is considered a non supporting feature for

the diagnosis of MSA

frank, prominent, early dementia should lead the clinician

to other diagnoses.

Investigations

Autonomic function tests

Cardiovascular function test-within in 2-3 ys

Bladder function tests

standard urine analysis will exclude infection.

The residual volume –usg,cystometry ,UDS

IMAGING

MRI

- Hot cross burn sign- mcp/pons- MSA-c

- Putaminal rim- MSA-p

- DAT scan

- abnormal in all MSA, PSP, and PD

- MIBG scintigraphy

- abnormal in PD, normal in MSA

IBZM SPECT is normal in PD,abnormal in MSA (but

also in PSP and CBD)

NOVEL BIOMARKERS

Mollenhauer and colleagues-

CSF mean a-synuclein levels , not total t, or Ab42 levels

differentiated PD and MSA from neurologic controls (70%

sensitivity, 53% specificity)

a-synuclein and phosphorylated t/total t could differentiate

PD from MSA -sensitivity of 90% & specificity of 71%

Flt3 ligand, a cytokine

PD and MSA with a sensitivity of 99% and a specificity of

95%.

RX

Symptomatic

PD- L-dopa/ dopa agonists- cranio cervical dystonia

postural hypotension

Amantidine- gait disturbances

Orthostatic hypotension-

high salt, fludrocortisone,midodrine

Urinary dysfunction

- UDS- characterise nature

-Neurogenic bladder- Oxybutinin or Tolderotidne

Erectile dysfunction-

- sildenafil

-intracavernosal inj. Or penile implants

Emotional incontinence

- SSRI/TCA

RCT – Rasagiline and rifampicin- no effects

Promising studies

- IVIG

- Intrarterial/IV autologous stem cells

- Future

- Alpha synuclein targeting antibodies

CORTICOBASAL DEGENERATION :

sixth to eighth decades of life,

onset of symptoms at mean age 63 years (SD 7·7)

. sporadic disease

4–6% of parkinsonism,

Clinical presentations

Five initial presentations

The most common presentation (55%) -“useless

arm” (ie, a rigid, dystonic, akinetic, or apraxic arm),

gait disorder (27%)

prominent sensory symptoms

isolated speech disturbance

behavioural disturbance

Clinical features

Motor

Limb clumsiness (asymmetric)

Bradykinesia/Akinesia (asymmetric)

Rigidity (asymmetric)

Tremor (action/postural)

Myoclonus

Limb dystonia (asymmetric)

Blepharospasm

Choreoathetoid movements

Speech abnormalities

Gait disorder

Higher cortical functions

Apraxia (limb more common than orofacial, eyelid-opening)

Dementia

Alien-limb phenomenon

Aphasia

Frontal-lobe-release signs

Cortical sensory abnormalities

Depression

apathy

Anxiety Irritability

Disinhibition

Delusions

Obsessive compulsive disorder

DIAGNOSTIC CRITERIA FOR CORTICOBASAL

DEGENERATION

Inclusion criteria (one of A or B)

A) Rigidity (easily detectable without reinforcement) and

one cortical sign:

apraxia (more than simple use of limb as object;

absence of cognitive or motor deficit sufficient to explain

disturbance)

cortical sensory loss (preserved primary sensation,

asymmetric)

alien-limb phenomenon (more than simple levitation)

B) Asymmetric rigidity, dystonia (focal in limb; present at

rest at onset),

focal reflex myoclonus (spreads beyond stimulated digits

Exclusion criteria

Early dementia (will exclude some patients with

corticobasal degeneration)

Early vertical gaze palsy

Rest tremor

Severe autonomic disturbances

Sustained responsiveness to levodopa

Lesions on imaging studies indicate another

pathological process

PROPOSED CRITERIA FOR THE DIAGNOSIS OF

CORTICOBASAL DEGENERATION

Core features

Insidious onset and progressive course

No identifiable cause (eg, tumour, infarct)

EPS – one of the follow

-focal or asymmetric appendicular rigidity

-lacking prominent and sustained l-dopa response

-focal or asymmetric appendicular dystonia

Cortical dysfunction - at least one of the following

: focal or asymmetric ideomotor apraxia

alien-limb phenomena

cortical sensory loss visual or sensory hemineglect

constructional apraxia

focal or asymmetric myoclonus

apraxia of speech or nonfluent aphasia

Supportive investigations

Variable degrees of focal or lateralised cognitive

dysfunction,

with relative preservation of learning and memory

on neuropsychometric testing

Focal or asymmetric atrophy on CT or MRI imaging,

typically in perifrontal cortex

Focal or asymmetric hypoperfusion on SPECT or

PET, typically maximal in parietofrontal cortex with

or without basal ganglia involvement

NEUROPATHOLOGICAL CRITERIA

Core features

Focal cortical neuronal loss

Substantia nigra neuronal loss

Cortical and striatal Gallyas/tau-positive neuronal and

glial lesions, especially astrocytic plaques and threads, in

both white and grey matter

Supportive features

Cortical atrophy, commonly with superficial spongiosis

Ballooned neurons, in atrophic cortices

Tau-positive oligodendroglial coiled bodies

PHENOTYPIC SPECTRUM OF CORTICOBASAL

DEGENERATION

Classic CBD phenotype- CBS

CBD- present with FTD,RS,PPA,PCA

AD,PSP,FTD present with CBS

Symmetrical bilateral CBS- AD pathology/RS

Early onset PSP – CBD pathology

For which proposed clinical criteria applied

INVESTIGATIONS

Imaging

asymmetric frontal, and parietal cortical atrophy becomes

evident with dilatation of the lateral ventricle

EEG –

-normal at first

- show asymmetric slowing that is maximum over the

hemisphere contralateral to the more affected limb

Dopamine transporter SPECT- abnormal

- differentiate them from those with Alzheimer’s and Pick’s

diseases (in whom this scan is typically normal) early in

the course of the disease.

FDG-PET

- Asymmetric reduction in fronto parietal regions

RX

Anecdotal

L-dopa trial (upto 1 gm/d)/Amantadine- PD symptoms

Valproate, Levetiracetam- myoclonus

Botox inj- dystonic hand

No trials with ACEI – dementia

Palliative rx

“CORTICO BASAL DEGENERATION-LOOKALIKE”

SYNDROMES

atypical manifestations of PSP

-progressive nonfluent aphasia FTD.

Parkinson’s disease

multiple-system atrophy

Wilson’s disease

progressive subcortical gliosis

rigid-akinetic type Huntington’s disease

atypical Pick’s disease

parkinsonism– dementia–amyotrophic-lateral-sclerosis complex

prion related disease

sudanophilic leukodystrophy

neurofilament inclusion disease.

DEMENTIA WITH LEWY BODIES

Central feature (essential for a diagnosis of possible

or probable DLB)

Dementia -progressive cognitive decline of sufficient

magnitude to interfere with normal social or

occupational function.

Prominent or persistent memory impairmen- not occur

in the early stages ,usually evident with progression.

Deficits on tests of attention, executive function, and

visuospatial ability may be especially prominent.

CORE FEATURES (TWO CORE FEATURES ARE SUFFICIENT FOR

A DIAGNOSIS OF PROBABLE DLB, ONE FOR POSSIBLE DLB)

Fluctuating cognition with pronounced variations in

attention and alertness

Recurrent visual hallucinations that are typically well

formed and detailed

Spontaneous features of parkinsonism

SUGGESTIVE FEATURES

REM sleep behavior disorder

Severe neuroleptic sensitivity

Low dopamine transporter uptake in basal ganglia

demonstrated by SPECT or PET imaging

(If one or more of these is present in the presence of one

or more core features, - probable DLB .

In the absence of any core features, one or more

suggestive features is sufficient for possible DLB.

Probable DLB should not be diagnosed on the basis of

suggestive features alone.)

SUPPORTIVE FEATURES (COMMONLY PRESENT BUT NOT

PROVEN TO HAVE DIAGNOSTIC SPECIFICITY)

Repeated falls and syncope

Transient, unexplained loss of consciousness

Severe autonomic dysfunction, e.g., orthostatic hypotension, urinary

incontinence

Hallucinations in other modalities

Systematized delusions

Depression

Relative preservation of medial temporal lobe structures on CT/MRI

scan

Generalized low uptake on SPECT/PET perfusion scan with reduced

occipital activity

Abnormal (low uptake) MIBG myocardial scintigraphy

Prominent slow wave activity on EEG with temporal lobe transient

sharp waves

A DIAGNOSIS OF DLB IS LESS LIKELY

If -CVA evident as focal neurologic signs or on brain

imaging

In the presence of any other physical illness or brain

disorder sufficient to account in part or in total for the

clinical picture

If parkinsonism only appears for the first time at a stage

of severe dementia

TEMPORAL SEQUENCE OF SYMPTOMS

diagnosed when dementia occurs before or concurrently

with parkinsonism (if it is present).

Parkinson disease dementia (PDD) - dementia that occurs

in the context of well-established Parkinson disease.

In research studies in which distinction needs to be made

between DLB and PDD, the existing 1-year rule between

the onset of dementia and parkinsonism - DLB continues

to be recommended.

CLINICAL MANAGEMENT

Motor parkinsonism-

-Levodopa at low doses & titrate up.

-Anticholinergics should be avoided.

Neuropsychiatric symptoms.--cholinesterase inhibitors

(CHEIs) or atypical antipsychotic

“ATYPICAL” ATYPICAL PARKINSONISM

Misdiagnosis PD with AP , as well as FTD,AD,PPA

Mimickers of Atypical PD

Eg:

SCAS/ FTAX- mimic MSA

Neimann Pick C,CTX,prion d/s,mitochondrial- mimic AP

phenotype

- Age of onset

- Tempo of progression

- Family history

- Clinical exam + associated features

SUMMARY

Careful clinical examination

Expanding phenotypic spectrum of AP & expanding pathological spectrum of classic AP phenotypes –diagnostic challenge

AP mimickers

Investigations may be supportive, but their sensitivity and specificity are low.

There are currently no biomarkers available.

There are currently no neuroprotective treatments available.

symptomatic and supportive treatments with usually no sustained effect.

Further research required

THANK YOU