Redeeming Salomon s Prophecy

Transcription

1 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

2 Disclosures Within the last 12 months: I receive grant support from NeuroDx Development for work related to SBIR R43NS A1 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

3 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 Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 3

4 NPH Story Arc Prophesy Exuberance (irrational) Catastrophe Skepticism Rejection Research Renaissance Redemption Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 4

5 Prophecy Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 5

6 Rescuing from Oblivion Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 6

7 Yes, those are Salomon s words, as shown in his translated thesis. Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 7

8 Exuberance (irrational) Catastrophe Skepticism Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 8

9 Rejection Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 9

10 2012 Hydrocephalus Research Conference / Seattle, WA Michael A. Williams, MD 10

11 Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 11

12 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. Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 12

13 Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 13

14 And difficult to resurrect Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 14

15 Research Renaissance Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 15

16 Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 16

17 Our team found 18 articles 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. Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 17

18 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. Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 18

19 52% showed overall neurocognitive improvement Significant improvement in tests of verbal memory and psychomotor speed Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 19

20 Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 20

21 Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 21

22 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. Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 22

23 Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 23

24 All tests improved 1SD threshold Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 24

25 Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 25

26 All tests improved but one Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 26

27 1 SD Threshold Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 27

28 Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 28

29 A l l I m p r o v e d N o n e I m p r o v e d Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 29

30 LIAS, LOVA, SHYMA Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 30

31 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) Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 31

32 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 Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 32

33 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 Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 33

34 Redemption Reversible, meaningful and sustained Salomon s prophecy was correct But our work isn t finished Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 34

35 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 Fortune Teller Sanzo Wada ( ) Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 35

36 These will be the elderly in Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 36

37 Elderly Population Effect is Greater in Japan in 2030 These will be the elderly in 2040! Source: U.S. Census Bureau, International Data Base, Nov 21, 2010 Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 37

38 Michael A. Williams, MD Hydrocephalus Research Conference / Seattle, WA 38

39 Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 39

40 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 longterm care Quality of Life Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 40

41 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 Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 41

42 Research Questions (1) What is the clinical purpose of neuropsychological testing in INPH? What is the most expedient and reliable crosscultural battery? What is the threshold for individual improvement 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? Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 42

43 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? Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 43

44 Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 44

45 I had to read something several times to understand it. Applied Cognition General Concerns In the past 7 days 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. 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 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)? 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? 5= None 4= A little 3= Somewhat 2= A lot 1= Cannot Do 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? Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 45

46 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? Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 46

47 Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 47

48 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

49 Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 49

50 Thank you for your kind attention Michael A. Williams, MD 2012 Hydrocephalus Research Conference / Seattle, WA 50