Neurodegenerative NPH

Prof. Kammant Phanthumchinda

Chulalongkorn University

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CSF circulation

Classical CSF circulation Glymphatic system

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CSF dynamic

• CSF space: dynamic pressure system.

• CSF space is responsive to changes in

– CSF formation or reabsorption rates

– Arterial and venous flow

– Compliance of brain parenchyma

• Around 500 ml of CSF is produced every day

• CSF dynamic causes physiological intermittent increased intracranial pressure

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CSF dynamic

• Brain and other intracranial constituents compensate for physiological intermittent increased intracranial pressure via– Compliance of blood vessel , allows for a

smoother influx of arterial blood

– CSF pulsation • CSF pulsation flows back and forth through the cerebral

aqueduct in response to pulsatile blood flow for maintaining intracranial pressure stable

• CSF pulsation occurs in other part of ventricular system

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Intraventricular cerebrospinal fluid pulsation

Third ventricular intraventricularcerebrospinal fluid pulsation

Fourth ventricular intraventricularcerebrospinal fluid pulsation

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Intraventricular cerebrospinal fluid pulsation

Lateral ventricular cerebrospinal fluid flow

Lateral ventricular intraventricularcerebrospinal fluid pulsation

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Hydrocephalus and Dementia

• Communicating hydrocephalus

– Meningitis

– Normal pressure hydrocephalus

• Obstructive hydrocephalus

– Intraventricular obstruction by space occupying lesions

– Ventriculitis

– Aqueductal stenosis

• Central hydrocephalus

– Subcortical small vessel disease

• Hydrocephalus ex vacuo

– Neurodegenerative disease

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Normal pressure hydrocephalus (NPH)

• Clinical triad

– Gait disturbance – psychomotor retardation

– Incontinence

• Urinary incontinence

• Fecal incontinence

– Progressive dementia

• Hydrocephalus – CT scan or MRI

• Normal CSF pressure – lumbar puncture

• Response to CSF drainage

Syndrome of NPH

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Pathophysiology of NPH

• CSF absorption defect

– Idiopathic

– Secondary

• Dilatation of cerebral ventricle

– Stretching of periventricular white matter

– Increased “transmantle pressure”

– Reduction of blood flow and metabolism

• Clinical syndrome of NPH

• Response to CSF drainage

Pathophysiology of NPH

• Distension of periventricular white matter includes sacral motor fibers that innervate legs and the bladder explain– Abnormal gait and incontinence.

• Distension of the brainstem structures (ie, pedunculopontine nucleus) responsible for – Gait dysfunction, particularly the freezing of gait

• Distension of the periventricular frontal and limbic system causes – Dementia

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Etiology of NPH

• Secondary – all age groups

– Traumatic subarachnoid hemorrhage

– Meningitis

– Diseases that interfere CSF absorption at the

arachnoid granulation

• Paget’s disease of the cranium

• Mucopolysaccharidosis of the meninges

• Achrondroplasia

Etiology of NPH

• Idiopathic - 6th and 7th decade

– No inciting event is identified

– Mechanisms

• Asymptomatic fibrosing meningitis

• May be secondary to weakening and dilatation of ventricles

– Periventricular ischemic lesions (epidemic data )

» Hypertension

» Diabetes

» Reduction of high density lipoprotein cholesterol

» Ischemic brain disease

– Neurodegenerative disease

Proposed pathophysiology of NPH

CSF absorption block

↑ ICP ↑ CSF pulsatility

Ventricular dilatation

Stretched periventricular

axons

Periventricular edema

Deep & periventricular

WM compliance

Atherosclerosis

↑ BP

Deep WM

larcunar infarct &

degenerative changes

(Binswanger’s disease)

Periventricular

white matter

damage

Subependymal

microvascular

ischemia

Neurodegenerative disease

Concept of Neurodegenerative NPH

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ESPAY AJ , ET AL . DECONSTRUCTING NORMAL PRESSURE HYDROCEPHALUS: VENTRICULOMEGALY AS EARLY SIGN OF NEURODEGENERATION . ANN NEURO 2017;82(4):503-13

Literature review

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Background

• Diagnosis of iNPH

– Syndrome of NPH

– Ventriculomegaly , excluding secondary hydrocephalic disorders

– Amelioration of gait, urinary, and cognitive difficulties in response to cerebrospinal fluid (CSF) drainage.

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Background

• Full triad present in under 60% of patients

• Individual components of triad are nonspecific: – (1) gait impairment from many other etiologies occurs

in 20% of people aged>75 years

– (2) urinary incontinence is present in 18% of men and 38% of women>60

– (3) prevalence of mild cognitive impairment and dementia is approximately 35% in people>70

– (4) ventricles enlarge with age and with small vessel disease of the brain and neurodegenerative disorders

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Background

• Misconception :

– NPH is among the most common treatable causes of dementia in the elderly based on the concept of the short-term response to CSF drainage of the syndrome

– NPH may predispose to neurodegenerative diseases

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Hypothesis

• Certain neurodegenerative phenotypes may present with clinical syndrome of NPH : neurodegenerative NPH.

• Diagnosis of of truly iNPH– Rule out secondary causes of hydrocephalus,

– Careful consideration of neurodegenerative disorders, most often– Progressive supranuclear palsy (PSP)

– Dementia with Lewy bodies (DLB)

– Alzheimer’s disease (AD)

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Response Rates and Duration of Follow-up

• Full review of literatures : criteria

– (1)>5 patients

– (2) follow-up>2 months,

– (3) objective outcome measures and/or scales for gait as main endpoint were considered for

• Total of 16 studies meeting full criteria for inclusion (Table 1) served to estimate the pooled response after VPS (Table 2).

23Espay AJ , et al .Deconstructing normal pressure hydrocephalus: Ventriculomegaly as early sign of neurodegeneration .

Ann Neuro 2017;82(4):503-13

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Espay AJ , et al .Deconstructing normal pressure hydrocephalus: Ventriculomegaly as early sign of neurodegeneration .

Ann Neuro 2017;82(4):503-13

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Espay AJ , et al .Deconstructing normal pressure hydrocephalus: Ventriculomegaly as early sign of neurodegeneration .

Ann Neuro 2017;82(4):503-13

Results

• All were classified as Class III or IV using the American Academy of Neurology (AAN) classification of evidence

• Included 1,265 NPH patients

• Mean age, 71 years; 53.4%

• Response rate varied across studies

– 8% to 86% among all-shunted

– 33% to 87% among completers.

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Results

• Pooled analysis showed nearly 30% loss to follow up in studies 3 years long.

• Metaregression analysis showed : follow-up duration was associated with response rate among completers and among all-shunted patients.

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Results

• Studies with longer follow-up duration (36 months) had 18% less response rate (95% CI, –0.35 to –0.01; p50.042) among completers and 32% among all-shunted (95% CI, –0.63 to –0.01; p50.042) compared to studies with 10 months of follow-up

• Overall pooled response rate among shunted was – 40% (95% CI, 26–54) by last follow-up

– 52% (95% CI, 38–67) at 12-month

– 25% (95% CI, 17–32) at 36-month

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Summary

• Post -VPS benefits decline with longer follow-up.

• Unclear how long a response must be to qualify as “permanent”

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Neurological center experience

• University of Cincinnati (10-year experience )

– Of 142 patients referred

– 31 were shunted

– 10 (32%) retained benefits by 36 months (only 11.1% of those with an initial diagnosis of NPH )

• Mayo Clinic (over a 9-year period )– Alternative or additional neurological diagnoses were

ascertained in 5 of the 12 shunted NPH patients

– None of whom had sustained improvement by 36 months).

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University of Cincinnati experience

• FIGURE 1: NPH initial diagnosis, outcomes, and diagnosticrevisions at the University of Cincinnati. *Improvement was defined by objective gait measures (change in velocity and stride length >20%) using a portable gait analysis system (GAITRite until 2015, Zeno Walkway by Protokinectsthereafter) and neuropsychological evaluation (global assessment by neuropsychologist, J.L.D.). **Based in clinical judgement by the evaluating neurologist when compared to function before shunt.

• NPH normal pressure hydrocephalus • ELD external lumbar drainage• LVT large-volume tap;• G gait• C cognition• U urinary function• PSP progressive supranuclear palsy• DLB dementia with Lewy bodies,• AD Alzheimer’s disease• VaD vascular dementia.

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Espay AJ , et al .Deconstructing normal pressure hydrocephalus: Ventriculomegaly as early sign of neurodegeneration .

Ann Neuro 2017;82(4):503-13

Clinical pitfalls in iNPH

• Disproportionate involvement of gait has been held as the main motor feature of NPH

– “classic” short-stride, wide-based, externally rotated feet and upright posture

– Reduction in gait velocity and stride length with relative preservation of arm swing

• “higher-level gait disorder,” represented dysfunction of striatofrontal circuits

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Clinical pitfalls in iNPH

• Causes of “higher-level gait disorder,”

– Hydrocephalus

– leukoencephalopathy

– Frontal lobe lesions

– ‘senile’ disorders of gait.”

• Misnomer

– Parkinsonian gait

– Lower-body parkinsonism

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Imaging pitfalls in iNPH

• Simple inspection, whether ventriculomegalyis disproportionate to any parenchymalatrophy

• Subjective approach in interpretation may also contribute to the variability in outcomes diagnosis and outcome

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Imaging pitfalls in iNPH

• Current imaging practice : idiopathic NPH has been a automatically diagnosis although other hydrocephalic conditions may not be critically rule-outpresent

• Other hydrocephalic condition mimic iNPH– Secondary hydrocephalus attributed to subarachnoid

hemorrhage, trauma, or meningitis

– Hydrocephalus exvacuo

– Central hydrocephalus from small vessel disease of the brain

– Arrested hydrocephalus

– Congenital hydrocephalus and aqueductal stenosis

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FIGURE 2: Baseline brain MRIs in shunted NPH patients across different outcomes.

• Axial, midsagittal, and coronal brain MRI of response after VPS – Very short (<12 months)

– Short (<24 months)

– Medium (<36 months)

– Long-term (36 months)

• Relatively similar extent of ventriculomegaly and overlapping degrees of parenchymal integrity despite the differing outcomes

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Espay AJ , et al .Deconstructing normal pressure hydrocephalus: Ventriculomegaly as early sign of neurodegeneration .

Ann Neuro 2017;82(4):503-13

Imaging pitfalls in iNPH

• Periventricular white matter hyperintensities (WMH) on T2-weighted and fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI)– Interstitial edema or transependymal exudate from hydrocephalus

– Lipo-hyalinosis and microatheromatous vasculopathy

– Vasogenic edema from venous collagenosis

– Cerebral amyloid angiopathy

• Most of these WMH pathologies may not be distinguishable based on routine clinical MRI.

• Heterogeneity in the etiology of WMH likely contributes to the variability in reported shunt response rates

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More specific imaging of iNPH

More specific clues

• Tight sulci and gyri in the convexity

• Enlarged sylvian fissures, referred to as disproportionately enlarged subarachnoid-space (DESH)

• Pocket -like sulcal CSF accumulations without gyralatrophy (a pseudoatrophicpattern

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External hydrocephalus of infancy

• Benign clinical entity – Macrocephaly– Increase in volume of the subarachnoid space,

especially overlying both frontal lobes– Normal or only slight increase in volume of the lateral

ventricles.

• Occurs mainly during infancy, and the subarachnoid space enlargement gradually decreases and disappears over the next years

• Most accredited theory seems to be delayed maturation of the arachnoid villi

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16-month-old female with BEH. MRI examination with axial T2-weighted image (A)

and coronal T1-weighted image (B). Note the mild enlargement of the bifrontalsubarachnoid spaces and inter-hemispheric fissure.

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CT-Scan of external hydrocephalus of infancy

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Pitfall in evaluation of response to therapy

• Diagnosis is supported after the response of gait or cognitive endpoints

– Sufficient (but never standardized) fluid diversion.

– Adequate (of varying cut offs across reports)

– Immediate (of unclear duration)

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Sufficient fluid diversion

• Short , but large, volume Tap (LVT) at a single time (LVT, 30–50cc)

• External lumbar drainage (ELD; 10cc/h for 3 days) .

• Imperfect sensitivity and specificity of LVT and ELD to predict response to VPS placement

– *LVT : large-volume Tap

– ELD : external lumbar drainage

– VPS : ventriculoperitoneal shunt

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ADEQUATE AND IMMEDIATE RESPONSE TO LVT/ELD

• No uniform robust LVT/ELD response criteria

• Long-term VPS response is variable and diminishes over time.

• Duration of VPS-related benefits is often reported at 6 or 12 months and only exceptionally beyond that

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No testing is specific for iNPH

• Cisternography

• Computed tomography and magnetic resonance–based imaging findings, such as flow void of the third ventricle, Evan’s ratio, and white matter abnormalities.

• Theoretical scheme for NPH diagnostic certainty(Fig 3)

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Espay AJ , et al .Deconstructing normal pressure hydrocephalus: Ventriculomegaly as early sign of neurodegeneration .

Ann Neuro 2017;82(4):503-13

CSF BIOMARKERS.

• CSF biomarkers may be examined to exclude neurodegenerative disorders with which NPH could be confused–Amyloid

–Tau–etc

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No pathological feature is diagnostic

• Pathological diagnosis of NPH only requires – Presence of dilatation of the lateral and third

ventricles

– Fibrous thickening of the leptomeninges, and gaps in the ependymal lining

– Allows for variable gliosis and “ischemic lesions” in the periventricular white matter.

• Histopathological gold standard for NPH rests on the exclusion of other findings on pathology

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Placebo Effect of VPS

• Single documented case in which the response to LVT was equally favorable after actual and sham procedures

• Magnitude of the placebo effect related to LVT/ELD or VPS has never been measured

• Evaluation of gait and cognitive end-points have invariably been unblinded.

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NPH and neurodegenerative disesease

• Long -term follow-up studies of NPH patients have documented that progressive dementia is a common development

• Brain biopsies taken before intracranial pressure recording or at the time of VPS placement were commonly positive for AD pathology in half to 75% of patients

• Relationship of NPH and neurodegenerative disesease– NPH may have co-occurred with neurodegenerative disorders

by chance – NPH may increases the risk neurodegenerative diseases– NPH may be presenting syndrome of neurodegenerative

diseases

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Neurodegenerative NPH

• High rate of “comorbidity” is beyond what can be accounted for by chance alone

• No plausible biological basic mechanisms for role of NPH as a risk factor in neurodegenerative disease

• NPH may be a presenting feature of neurodegenerative disease

• Pathophysilogy of of Neurodegenerative NPH– Geschwind : an atrophied brain has a greater tendency

than a normal brain to react to the intraventricular pulse-pressure by ventricular dilatation

– Ventricular dilatation may transient respond to VPS

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Red flags

• Motor and gait syndrome : early impairment of postural reflexes, with or without falls should rule out PSP or DLB

• Cognitive syndrome : early cognitive impairment predicts an alternative diagnosis especially AD

• Visual hallucinations and REM sleep behavioraldisorder are a strong clinical biomarker of synucleinopathies eg. PD ,DLB

• Other clues for neurodegenerative disease e.g. Vertical gaze impairment, behavioral syndrome, language syndrome

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Causes of “ so called iNPH “

• iNPH may has different causes which form a pathophysiological continuum

• Different causes of iNPH reflect differences with shunt response and rates of progression.

• More appropriate to refer to these conditions, as

– VD‐associated NPH

– PSP‐associated NPH

– iNPH (idiopathic : CSF absorption defect )

– etc.

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ConclusionCurrent status

• Idiopathic NPH is a diagnosis without specific – Imaging

– Pathological features

– Dependent on variably defined magnitude and duration of response to CSF drainage

• No definitive tests are capable of confirming the diagnosis or accurately estimating the outcome to VPS

• Early LVT- or ELD-based benefits are often not maintained with long-term VPS.

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ConclusionCurrent concept

• NPH can commonly be a presenting feature of neurodegenerative disorders, particularly – PSP

– DLB

– AD

• NPH syndrome may be an early presentation rather than a risk factor for neurodegenerative diseases

• Pathological mechanisms associated with neurodegeneration that could lead to altered CSF dynamics as initial manifestation as NPH should be explored

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ConclusionDistinction of iNPH VS Neurodegenerative NPH

• Reassessment of NPH requires better characterization of imaging or other tests for evaluation of both

– Parenchymal contributions to gait, urinary, and cognitive symtoms

– Hydrodynamic contributions to gait, urinary, and cognitive symtoms

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ConclusionFuture diagnostic tests

• Distinction between idiopathic and neurodegenerative NPH will require consideration of – Additional imaging techniques

• Volumetry and tractography for structural anatomy of the parenchyma,

• 18F fluorodeoxyglucose, amyloid and tau positron emissiontomography [PET] for AD

• DATscan for DLB and PSP• tau PET for PSP

– CSF biomarkers • A b 42/p-tau• Neurofilament light chain• brain biopsy at the time of VPS implantation

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ConclusionTreatment

• Transient response to VPS of any magnitude and duration, supports the contention that VPS placement may remain a reasonable option for short-term symptomatic management even in patients with high likelihood of underlying neurodegenerative disorders.

• VPS may be warranted in selected patients for whom aresponse of any duration may be preferable to noresponse

• Patients and families must be counseled as to the uncertainties of the long-term outlook and the risks of VPS-related adverse effects

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Thank you for your attention

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