Redeeming Salomon’s Prophecy Reversible Neuropsychological

Deficits of INPH Michael A. Williams, MD, Cynthia A. Smith, PhD,

Neena Cassell, MS, Nikhil Prasad, BSc (Bristol, UK) Adult Hydrocephalus Center, Sinai Hospital

Sandra and Malcolm Berman Brain & Spine Institute Baltimore, MD

Disclosures Within the last 12 months:

I receive grant support from NeuroDx Development for work related to SBIR R43NS067770-01A1

I own a 5% interest in Mensana Therapeutics My life partner owns stock in: Ecolab <$20K,

GE <$15K, Life Technologies <$15K, Medtronic <$20K, Pfizer <$15K

I am a neurointensivist by training Glasgow Coma Scale (3-15) was my only

neuropsychological test for many years

Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 2

Prophecy The art of prophecy is very difficult,

especially with respect to the future. Mark Twain

Dark and difficult times lie ahead. Soon

we must all face the choice between what is right and what is easy.

—Dumbledore in Harry Potter and the Goblet of Fire, J.K. Rowling

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NPH Story Arc 1965-2012 Prophesy Exuberance (irrational) Catastrophe Skepticism Rejection Research Renaissance Redemption

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Prophecy

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Rescuing from Oblivion

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Yes, those are Salomon’s words, as shown in his translated thesis.

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1965 - 1992 Exuberance (irrational) Catastrophe Skepticism

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Rejection

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Michael A. Williams, MD

2012 Hydrocephalus Research Conference / Seattle, WA

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R.I.P.

Pooled data of recent literature show that for three or four patients with substantial improvement one patient with a severe complication has to be accepted. In our group with INPH, the price for one patient with substantial benefit was even much higher (B/H ratio 1.7), but not shunting high-risk patients would have favorably increased the B/H ratio.

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And difficult to resurrect

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1992-2012

Research Renaissance

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Our team found 18 articles

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I present here neither a systematic review of the literature nor a meta-analysis. I present my interpretation of the neuropsychology literature on NPH. Here are several important papers.

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Significant improvement in overall neurocognitive outcome was defined as a 4-point improvement in MMSE or improvement by 1 SD in 50% of the administered neurocognitive subtests.

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52% showed overall neurocognitive improvement Significant improvement in tests of verbal memory and psychomotor speed

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“Improvements in mental tracking speed and sustained attention 6 months after shunt” Also, improvement in NPIQ and NPIQ-Caregiver Distress scores, and independent ADLs “The fact that postshunt cognitive changes appear to precede clear functional recovery argues that neuropsychological measures may be sensitive and early markers of iNPH outcome.”

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All tests improved

≥ 1SD threshold

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All tests improved but one

≥1 SD Threshold

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All Improved

None Improved

LIAS, LOVA, SHYMA

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Is INPH dementia reversible? Yes. In my opinion. Numerous studies have proven this point Improvement is not from practice effect in

properly structured batteries and selected tests But no consistency in threshold for

improvement among studies Cohort statistical significance ≥ 1SD improvement threshold

Do we need to keep proving this point? Depends, perhaps, on the audience we’re trying to

persuade (patients, neurologists, or neurosurgeons)

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Is the recovery meaningful? Yes. The magnitude of improvement in

cohorts is far greater than ever seen in in trials of the degenerative dementias

But we haven’t yet demonstrated this as convincingly as we should Patient reported outcomes QoL measures

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Is recovery sustained? Probably yes, based on some

publications and our practice experiences Depends on maintaining shunt function Depends on distinguishing and properly

attributing worsening due to INPH from worsening due to vascular dementia, AD, FTD, etc., as well as the cognitive influences of medications Neuropsychology can help here

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Redemption Reversible, meaningful and sustained Salomon’s prophecy was correct

But our work isn’t finished

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What does the future portend? Two years ago, I was asked

by Masatsune Ishikawa to predict hydrocephalus 2030

My response is that we need to start thinking in terms of population health and its impact on health care expenditures and on patients and families

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Fortune Teller Sanzo Wada (1883-1967)

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http://www.mhlw.go.jp/english/database/db-hw/dl/81-1b2.pdf

These will be the elderly in 2030

Elderly Population Effect is Greater in Japan in 2030

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Source: U.S. Census Bureau, International Data Base, Nov 21, 2010

These will be the elderly in 2040!

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Socio-economic Impact 2030 Evaluation of possible INPH is:

1. Encouraged or required by national health ministries, governments, and insurers because the evaluation is cost-effective based on the savings associated a) with treating hydrocephalus, and b) with not shunting patients who will not improve

2. Expected by patients and families, who either care for the patients at home, or who pay a significant portion of their long-term care – Quality of Life

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The Future is Now We have a strong obligation as a

research community to organize and conduct the research that will improve population health

We need to structure research so that it both reveals insight into the nature of reversible cognitive deficits, and also is clinically useful for making individual patient decisions

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Research Questions (1) What is the clinical purpose of neuro-

psychological testing in INPH? What is the most expedient and reliable cross-

cultural battery? What is the threshold for individual improve-

ment to decide on shunt surgery? Should neuropsychological testing be used to

preclude testing or treatment for INPH? Is baseline profile or pre/post CSF drainage

change predictive of shunt response? Is either necessary?

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Research Questions (2) How do cognitive impairment and

recovery compare to gait or incontinence in QoL measurements?

What is the impact on caregiver burden of cognitive impairment and recovery?

What is the role of patient reported outcomes in INPH research?

What are the legal and ethical implications of reversible cognitive deficits, including capacity?

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Applied Cognition –

General Concerns

In the past 7 days

I had to read something several times to understand it.

5= Never 4= Rarely (once) 3= Sometimes (2-3 times) 2= Often (once a day) 1= Very Often (several times a day)

I had trouble keeping track of what I was doing if I was interrupted. I had difficulty doing more than one thing at a time. I had trouble remembering new information, like phone numbers or simple instructions. I had trouble thinking clearly.

My thinking was slow. I had to work really hard to pay attention or I would make a mistake. I had trouble concentrating.

Applied Cognition –

Executive Function

How much DIFFICULTY

do you currently have…

checking the accuracy of financial documents, (e,g., bills, checkbook, or bank statements)?

5= None 4= A little 3= Somewhat 2= A lot 1= Cannot Do

counting the correct amount of money when making purchases?

reading and following complex instructions (e.g., directions for a new medication)?

planning for and keeping appointments that are not part of your weekly routine, (e.g., a therapy or doctor appointment, or a social gathering with friends and family)?

managing your time to do most of your daily activities?

taking care of complicated tasks like managing a checking account or getting appliances fixed?

keeping important personal papers such as bills, insurance documents and tax forms organized?

learning new tasks or instructions?

Research Questions (3) What are the neurobiologic mechanisms

of reversible dementia? Pressure, ISF composition, partial ischemia,

cellular metabolism, demyelination, stretch Connectivity (dendritic or brain-wide)

Could these mechanisms inform research in other dementias? Toxic moiety clearance Prion hypothesis of degenerative dementia

How do we engage the neurology AD research enterprise?

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Research Questions (4) What is the clinical purpose of

neuropsychological testing in SHYMA? In “asymptomatic” pts, is baseline or

longitudinal testing needed? Need for treatment or demonstration of

disability Is this group at risk for early onset

dementia? Is a randomized trial of shunting

needed? Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 48

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Thank you for your kind attention

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