Deficits of Language and Speech in Idiopathic Normal Pressure Hydrocephalus

CitationChung, Esther H. 2018. Deficits of Language and Speech in Idiopathic Normal Pressure Hydrocephalus. Doctoral dissertation, Harvard Medical School.

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Title Page

Scholarly Report submitted in partial fulfillment of the MD Degree at Harvard Medical School

Date: 28 February 2018

Student Name: Esther H. Chung

Scholarly Report Title: Deficits of Language and Speech in Idiopathic Normal Pressure

Hydrocephalus

Mentor Name(s) and Affiliations: Mary-Ellen Meadows, PhD, Dept. of Neurology, Brigham

and Women’s Hospital

Collaborators, with Affiliations: Mark D. Johnson, MD, PhD, Dept. of Neurosurgery, UMass

Memorial Hospital

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Abstract

Title: Deficits of Language and Speech in Idiopathic Normal Pressure Hydrocephalus

Esther H. Chung, BA, Thu-Trang Hickman, MPH, Mary-Ellen Meadows, PhD and Mark D.

Johnson, MD, PhD

Purpose: Idiopathic normal pressure hydrocephalus (iNPH) is a disorder of unknown etiology

characterized by gait instability, incontinence and dementia. Symptoms can be ameliorated by

shunt placement for cerebrospinal fluid drainage. Although language and speech impairments

have not traditionally been associated with iNPH, anecdotal reports commonly indicate

otherwise. This study’s objective was to determine the prevalence and nature of language and

speech difficulties in iNPH, and whether these deficits improve after shunt placement.

Methods: We analyzed the medical records of 529 patients who underwent shunt placement for

iNPH at our institution between July 2001 and March 2015 for deficits in language or speech at

initial presentation. A subset of 71 patients underwent formal pre-operative neurocognitive

assessments, and thirteen of these patients also underwent post-operative testing at least 6

months after shunt insertion. Improvement was assessed using the Reliable Change Index.

Results: In the retrospective study of 529 patients, language deficits were identified in 23.1%,

speech deficits in 12.9% and writing deficits in 4% of patients. Analysis of 71 prospectively

collected pre-operative neurocognitive evaluations revealed semantic verbal fluency and fine

motor impairments in more than two-thirds of patients. Of the 13 patients who underwent both

pre- and post-operative testing, 84.6% experienced significant improvements in language and

executive function.

Conclusions: We demonstrate that 70.4% and 67.6% of patients with shunt-responsive iNPH

originally present with language and fine motor difficulties respectively. Improvement in these

symptoms after shunting indicates that deficits in language are an integral component of iNPH

pathology and should be considered during the diagnosis and management of this disorder.

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Table of Contents

Glossary of Abbreviations 4

Section 1: Introduction 5

Section 2: Student role 6

Section 3: Methods 6

Section 4: Results 9

Section 5: Discussion 12

Section 6: Acknowledgements 15

References 16

Figures 19

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Glossary of Abbreviations

iNPH idiopathic normal pressure hydrocephalus

CSF cerebrospinal fluid

TT tap test

AD Alzheimer’s disease

WTAR Wechsler Test of Adult Reading

MMSE mini-mental state examination

WAIS-III Wechsler Adult Intelligence Scale-III

HVLT-R Hopkins Verbal Learning Test-Revised

PHQ-9 Patient Health Questionnaire-9

IQ Intelligence Quotient

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Section 1: Introduction

Idiopathic Normal Pressure Hydrocephalus (iNPH) is a neurological disorder of unknown

etiology that is characterized by gait instability, incontinence and dementia.(1,2) Imaging

findings include enlarged cerebral ventricles, deep white matter or periventricular white matter

abnormalities and alterations in the size of the subarachnoid spaces.(3) It has been estimated

that about 1.4% of patients over the age of 65 and up to 14% of patients in nursing homes have

iNPH, most of whom are undiagnosed.(4–6) Given that the triad of symptoms in iNPH can be

ameliorated by shunt placement for cerebrospinal fluid (CSF) drainage, this disorder has been

classified as one of the reversible dementias with improvements seen in up to 80% of patients

after CSF drainage.(7–10)

Although most patients undergo lumbar CSF drainage trials to predict outcomes after

shunt placement, the prediction of shunt success has been inconsistent.(11) Evidence-based

literature reviews have established that several diagnostic tests used to identify the syndrome,

including a positive CSF tap test (TT), are insufficient for the accurate diagnosis of iNPH.(12,13)

The low sensitivity and negative predictive value of tests used to identify “shunt-responders”

calls for continued investigation of predictors of disease and shunt response. The Adult

Hydrocephalus Database offers one of the largest cohorts of iNPH patients published to date,

from which we can better assess the clinical picture of this enigmatic syndrome.

The causes of iNPH are not known, but clinical studies of iNPH patients and analyses of

CSF biomarker profiles are beginning to guide etiological hypotheses and clinical management.

To identify patients with iNPH and to better assess candidacy for shunt placement, in-depth

neurocognitive testing serves as an important adjunct to the assessment of gait impairment. The

literature has primarily associated acquired language disorders with the “cortical dementia” seen

in neurodegenerative diseases such as Alzheimer’s Disease (AD) and frontotemporal

dementia.(14–16) Cortical deficits can encompass language, visuospatial abilities and executive

function, depending on the presentation. On the other hand, the dementia of iNPH has been

traditionally characterized as “subcortical,” consistent with changes in general cognitive

processes (i.e. decreased processing speed, attention deficits, severe motor abnormalities),

which can then impact memory and overall cognitive function.(16)

A recent study in a relatively small sample of 32 iNPH and 32 AD patients noted that

deficits in executive function and visuospatial abilities were more profound in iNPH than in AD,

while deficits in language were only noted in the latter.(15) This lends overall support to the

notion that iNPH may actually present with a more mixed cortical and subcortical cognitive

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profile; yet the study still leaves language out of the profile. On the other hand, numerous

anecdotal reports from healthcare providers, patients and their families suggest that the

presence of difficulties with language and speech should not exclude iNPH from the differential

diagnoses. To date, the prevalence and character of language difficulties in iNPH are not well

understood. Very little is known about the progressive impairment in word-finding and other

aspects of expressive and receptive language in patients with dementia and/or

ventriculomegaly.(14) If these specific deficits can be rapidly reversed after shunt placement,

this would not only suggest that iNPH involves more widespread cortical and subcortical

dysfunction, but it would also be useful in more accurately identifying candidates for a trial of

CSF drainage.

Section 2: Student Role

I completed the entire project, with help and advice on the statistical analysis and

interpretation of the results from Dr. Johnson, Dr. Meadows and Ms. Hickman.

Section 3: Methods

Retrospective Study Design and Data Collection

This study was conducted under the auspices of a human subjects research protocol

approved by the Partners IRB Committee. We retrospectively reviewed the medical records of

patients diagnosed with disorders of CSF flow at Brigham and Women’s Hospital between July

2001 and May 2015 to identify patients who underwent evaluation for iNPH. Patients were

selected for evaluation of possible iNPH if they had communicating hydrocephalus on cranial

images, gait disturbance, urinary urgency/incontinence, cognitive impairment, and no clearly

identifiable cause of their symptoms. At the time of the first clinic visit, clinical and demographic

data were collected using a patient questionnaire. We combined this prospectively collected

data with additional notes documented by all care providers in the electronic medical record.

After an evaluation that included a thorough medical history, neurological examination, CT/MR

imaging, and lumbar CSF drainage trials, 529 patients (267 men and 262 women) were

identified to have probable iNPH and subsequently underwent ventriculoperitoneal shunt

placement. The median and mean duration of symptoms prior to evaluation for iNPH were 24

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months and 29.6 ± 20.9 months (mean ± SD), respectively. About two-thirds of patients

presented with the classic triad of gait difficulty, urinary incontinence, and cognitive impairment.

Patients were then coded into three stratified categories: language, motor-related

speech or motor-related writing deficits. Language difficulties were further divided into

subcategories of receptive language, expressive language, and other (i.e. difficulties reading,

non-motor writing, and/or other combinations). Receptive language deficits were defined as

difficulty understanding simple or complex statements or commands during the patient’s

neurological examination. Expressive language deficits were defined as difficulty translating

thoughts into sensible words and sentences expressed in grammatically correct syntax.

Expressive language was further subdivided into difficulties with word-finding or overall verbal

fluency. To be explicit in defining our stratifications, speech difficulties were strictly defined as

motor-related speech disorders arising from deficits in the motoric mechanics of oral

communication. As opposed to expressive language, which refers to the ability to communicate

information, speech deficits were defined by dysfunction in neuromuscular activity. This latter

category was further subdivided into dysarthria (slurred speech), stuttering, overall slowness of

speech, and combined and/or uncharacterized presentations. The categorizations of this

retrospective study are represented in Figure 1.

Prospective Study Design and Data Collection

Formal pre-operative neurocognitive evaluations of patients awaiting shunt placement

(n=71) were conducted by a clinical neuropsychologist. The pre-surgical battery for iNPH

included the following cognitive tests: Wechsler Test of Adult Reading (WTAR) for premorbid

estimate of IQ,(17) the mini-mental state examination (MMSE) as a basic cognitive screen of

attention (WORLD reversal, Serial 7 Subtraction tests),(18) Digit Span subtest from the

Wechsler Adult Intelligence Scale-III (WAIS-III), Phonemic (FAS) and semantic (Animals) for

verbal fluency,(19) Trails Making Test A for processing speed and Test B for executive

function,(20) Grooved Pegboard Test for fine motor skills,(21) Hopkins Verbal Learning Test-

Revised (HVLT-R) for verbal learning and verbal memory,(22) clock drawing for visuospatial

function, and Patient Health Questionnaire-9 (PHQ-9) for emotional function. Specifically

regarding the verbal fluency assessments, the FAS test evaluates phonemic fluency, whereas

the Animals test evaluates semantic fluency. Each category of verbal fluency has distinct neural

correlates with a relative importance of the left inferior temporal cortex in semantic versus

phonemic, and of the pre-supplementary motor area and head of caudate bilaterally in

phonemic versus semantic.(23) Additionally, the Grooved Pegboard test for upper extremity

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dexterity was used to assess fine motor skills that may reflect deficits in writing ability and

speech.(24,25)

Each evaluation takes approximately 2 hours to complete. Post-operative neurocognitive

evaluations (n=13) using the same battery with alternate forms for memory and phonemic and

semantic fluency were completed during patient follow-up at least 6-18 months after shunt

placement.

The Z scores for each subtest score for every patient were calculated and assessed

using normative data from published reports or test manuals, taking into account age, gender

and education. Impairment was defined as a Z score > -1.5 standard deviations (SD) below the

mean.(26,27) Subsequently, improvement after shunt placement was assessed using the

Reliable Change Index for each neurocognitive variable.(28) This measures whether the change

(increased or decreased) in the individual’s score is statistically significant (P<0.05).

Additionally, we identified a significant change in scores by defining “improvement” as an

absolute change greater than 1 SD.(29)

Ventriculoperitoneal Shunt Surgery

Patients for whom a trial of CSF drainage supported a diagnosis of probable iNPH

underwent surgical implantation of a ventriculoperitoneal shunt as treatment for their symptoms.

The shunts generally contained programmable valves (Codman, Inc.) programmed initially to a

setting of 120 mm of water. Valve settings were adjusted post-operatively as needed to

maximize symptom improvement and minimize signs or symptoms of overdrainage such as

positional headaches or subdural hematomas.

Statistical Analysis

The SAS statistical software program (SAS Inc, NC, version 9.3) and Microsoft Excel

2011(Microsoft Office, version 14.0.0) was used for all database analyses. The Reliable Change

Index for each neurocognitive test score was calculated using pre-programmed score change

calculators on Microsoft Excel spreadsheets. Statistical significance was set at the P<0.05 level.

All statistical analyses were performed by T.H., E.C., and M.M.

Outcomes Assessment

Patients were evaluated by a group of board certified neurosurgeons and/or neurologists

before and after CSF drainage trials and shunt placement. Patients who showed signs of

improvement in gait, incontinence or cognition after a trial of CSF drainage were offered

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ventriculoperitoneal shunt placement. Patients were evaluated post-operatively at 2 weeks and

at 6 weeks, and were then followed with periodic monthly or annual clinic visits as needed for a

period of up to 11 years. Changes in gait were based upon assessments of Timed Up and Go

test times, gait speed, step height, cadence, balance, the need for gait assistive devices and the

number of falls.(30) Changes in urinary/fecal incontinence or urgency were assessed in

collaboration with nursing staff, caregivers and patients. Changes in cognitive function were

assessed using neurological examinations, formal neurocognitive evaluations, statements by

caregivers and patient self-reports. These criteria were collectively used to categorize the

overall degree of improvement as improved or not improved.

For the retrospective cohort of 529 patients, the mean duration of follow up after shunt

placement was 32.3 ± 30.8 months, with a range of 1 to 132 months. The median duration of

follow up was 22 months. Based on the aforementioned criteria, the overall rate of positive

shunt-response was found to be 79%. Approximately 78% of patients who presented with the

classic iNPH triad improved after shunt placement.

Section 4: Results

Retrospective study on language, speech, and writing deficits in iNPH

Prevalence and characterization of deficits in iNPH

Of the 529 patients who underwent shunt placement for iNPH at the Brigham and

Women’s Hospital between July 2001 and March 2015, 23.1% presented with language

difficulties, 12.9% presented with motor-related speech difficulties, and 4% presented with

motor-related writing deficits (Figure 2A).

Of those patients who presented with deficits in language (Figure 2B), 75.4% specifically

demonstrated deficits in expressive language, while 10.7% exhibited difficulties in receptive

language. An additional 10.7% presented with difficulties in both expressive and receptive

language, while 3.3% displayed difficulties with reading and writing complete, grammatically

correct sentences. Among the subset of patients who presented with expressive language

deficits, word-finding difficulties were notably prevalent at 43.9%. Word-finding difficulty was

commonly self-reported by patients and their families during history taking, as well as noted by

healthcare providers during their respective examinations. Deficits in overall verbal fluency were

also prevalent, affecting 29.0% of the subgroup of patients with expressive language difficulties.

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Here, verbal fluency was defined as difficulty in accessing proper grammar structure, sound

forms and/or vocabulary in order to communicate with ease.

Among patients who presented with deficits in motor-related speech (Figure 2C), the

most common difficulties included dysarthria (25.0%), overall slowness of speech (27.9%), and

stuttering/shakiness (10.3%).

Prospective study of neurocognitive dysfunctions in iNPH

Quantitative characterization of neurocognitive dysfunctions in iNPH

Prior to shunt placement for iNPH, 71 patients underwent formal pre-operative

neurocognitive evaluations. The pre-surgical battery for iNPH included a variety of cognitive

tests as detailed above in the Methods section.

We defined impairment as a Z score > -1.5 SD below the mean, standardized for patient

age, sex, and level of education. Data analysis revealed that at least half of the iNPH patient

population demonstrated impairments across the selected neurocognitive evaluations (Figure

3). Baseline testing of premorbid intelligence (IQ) of this patient pool was tested using the

WTAR, which assess abilities usually unaffected by cognitive decline associated with

neurological damage. Nearly three-quarters of patients tested above average on this measure

(Z score > 0). In contrast, patient scores were skewed toward below average in the MMSE and

Trails A test, which account for overall cognitive deficits and attention/processing speed,

respectively. Additionally, the distributions of Z scores on the FAS and Animals verbal fluency

tests, and on the Grooved Pegboard fine motor skill test, were spread predominantly below the

quantitative level of impairment. Approximately two-thirds of patients scored below average on

the MMSE and Trails A tests, which primarily test subcortical functions, while more than 75%

ranged below average on the Animals, Trails B and Grooved Pegboard tests, which primarily

assess cortical functions. Prospectively collected formal pre-operative neurocognitive

evaluations indicate that cortical dementia (i.e. declines in language ability, fine motor skills and

executive function) is indeed characteristic of the neurocognitive profile of patients with iNPH.

Prevalence of neurocognitive dysfunctions in iNPH

Analysis of the 71 prospectively performed pre-operative neurocognitive evaluations

revealed the presence of a variety of language deficits (Figure 4). Assessment of cortical

functions indicated that semantic verbal fluency was impaired in 67.6% of iNPH patients, and

phonemic verbal fluency was impaired in 53.5% of these patients. When upper extremity

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dexterity associated with writing and left cortex-controlled motor speech functions were

examined, fine motor coordination on the Grooved Pegboard test was found to be impaired in

67.6% of patients. Executive function, as determined by set switching in the Trails B test, was

impaired in 69.0% of patients. Looking next at “subcortical” functions, 42.2% of patients

demonstrated impaired cognitive processing speed, as measured by the Trails A test, and

35.2% of patients had impaired attention in the context of overall cognitive status as assessed in

the MMSE. Overall, cortical dysfunction, specifically in semantic verbal fluency, executive

function and fine motor skills, was more prevalent among the iNPH population than subcortical

dysfunction.

Focused analysis of pre- and post-operative cognitive evaluations

Analysis of 13 iNPH patients who received neurocognitive evaluations before and after

shunt placement revealed that 12 out of 13 experienced overall improvements in gait, urinary

incontinence and/or cognition. To identify post-operative changes in cognitive function,

significant improvement or decline (P<0.05) after shunt placement was assessed using the

Reliable Change Index for each neurocognitive subtest.

On the FAS and Animals test, 31.0% demonstrated significant improvement in semantic

or phonemic verbal fluency, while 7.7% declined. On the Trails A test, 23.1% demonstrated

significant improvement in processing speed, while 15.0% declined. Notably, in the Trails B set

switching test, 38.5% improved in executive function, while 23.1% declined. On the Grooved

Pegboard test of the dominant hand, 30.8% demonstrated significant improvement in fine motor

dexterity, while 7.7% declined. In HVLT-R Total Recall, 23.1% of patients showed significant

improvement in verbal learning, while 7.7% declined. In HVLT-R Delayed Recall, 38.5% of

patients demonstrated significant improvement in verbal retrieval and verbal memory, while

7.7% declined.

Considering significant improvements in language and executive function together,

84.6% of these patients (11 out of 13) improved in overall cortical function, with significant

improvements seen in language and executive function. Of these patients whose cortical

dementia improved (n=11), nearly two-thirds (63.6%) improved specifically in language-related

functions, including verbal fluency, verbal learning, and/or verbal memory. Looking at language-

related functions in isolation, 53.8% (7 out of 13) of patients improved. There was also

improvement seen in subcortical functioning, as assessed by increased processing speed in

23.1% (3 out of 13) of patients. Fine motor coordination skills were improved as well in 30.8% of

patients (4 out of 13). Two patients, one of whom did not show overall improvement in

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symptoms post-operatively, were reported to be co-morbid for Alzheimer’s disease. However,

both patients’ gait and subsequent quality of life were documented to have improved over time.

Section 5: Discussion

In this study, we present data both from a retrospective medical record review of 529

iNPH patients as well as prospectively performed pre-operative neurocognitive evaluations of 71

iNPH patients that reveal the prevalence and nature of speech and language difficulties in iNPH.

Whereas the retrospective analysis suggested a prevalence of 23.1% (122 out of 529), the more

rigorous prospective analysis using formal neurocognitive battery measures revealed a

prevalence of language-related deficits of 70.4% (50 out of 71) among patients with shunt-

responsive iNPH. Our study is the first to demonstrate language difficulties in a majority of

shunt-responsive iNPH patients. Analysis of the 71 neurocognitive evaluations completed prior

to shunt placement revealed impairments specifically in verbal fluency, supporting our findings

from a retrospective analysis of a larger iNPH cohort (n=529) that language and speech deficits

occur commonly in this disorder. We also prospectively identified fine motor deficits in

approximately 71.0% of patients with iNPH, indicating that such deficits are not limited to lower

extremity function.

Contrary to the current dogma, we find that the presence of language or speech

difficulties is not a negative predictor of iNPH. A comparison of data from our retrospective and

prospective studies suggests that the estimate of 23.1% of iNPH patients who reported

“language difficulty” in the retrospective study is an underestimate of the true prevalence of

deficits in language in iNPH. Difficulties with speech and writing may also be more prevalent

than were noted in hospital records. Formal assessment of impairments in speech and

language are needed to more consistently identify deficits in these areas in patients with

possible iNPH. While the symptoms of gait disturbance and urinary incontinence are easier to

identify and are more commonly reported by patients and caregivers, the third symptom of

“subcortical dementia” is neither well-defined nor comprehensive. Along with accurate gait

analyses, patients with potential iNPH would benefit from careful neurological assessments of

cognition and language both before and after shunt placement surgery.

Current research recommends supplemental tests, including prolonged CSF drainage, to

increase diagnostic accuracy in iNPH.(13) However, tailored neuropsychological assessments

may also help to differentiate iNPH from other diseases that can mimic this disorder. For

example, our study demonstrates that patients with iNPH do not display the baseline decline in

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premorbid IQ or intellectual function seen in patients with progressing AD.(31) In support of the

notion that iNPH is primarily characterized by a decline in subcortical functions of the brain, past

studies have focused on significant differences between iNPH patients and age-, sex- and

MMSE-matched probable AD patients in terms of their performance on various tests of attention

and psychomotor speed.(15,16,31) In contrast, our study has revealed that patients with iNPH

demonstrate significant cortical impairment, including deficits in language, fine motor skills, and

executive function. These findings indicate that patients with iNPH may present with more of a

“mixed dementia” characterized by declining subcortical and cortical function.

Until now, there has been no general agreement concerning which cognitive functions

are more likely to be restored after shunt placement.(10) In this study, pre- and post-operative

neurocognitive evaluations revealed that 84.6% of iNPH patients (11 out of 13) experienced

improvement in one or more areas of cortical function after shunt surgery, with two-thirds

demonstrating significant improvement in language functions. Overall, more than half of patients

scored significantly higher on tests of language-related functions after shunt placement.

Improvement was also seen in subcortical functions and fine motor skills. These post-shunt

improvements not only affirm the profile of a mixed cortical and subcortical dementia in this

disease, but they also reveal the existence of pathophysiological mechanisms underlying

language processing and production that can be reversed by CSF drainage in iNPH patients.

Pathologic changes in iNPH are widespread and include cortical thinning of white matter in most

areas of the brain, including inferior and posterior regions.(15,32,33) Previous studies on

cognitive dysfunction in iNPH have delved focally into frontal lobe functions of attention,

executive function and memory,(34–36) but our findings indicate that a more comprehensive

characterization of iNPH dementia is warranted.

There are several strengths and limitations of the current study. The large number of

iNPH patients included in this study (n = 529) allowed us to unambiguously document the

presence of speech and language dysfunctions in iNPH, as well as other deficits (e.g. writing

deficits) that occur less commonly in this disorder. As always, studies involving the retrospective

review of medical records raises concerns of potential selection bias or recall bias that could

lead to inaccurate estimates of incidence or prevalence. Indeed, our analysis of prospectively

collected data from formal neurocognitive evaluations in a subset of 71 patients who were later

proven to have shunt-responsive iNPH revealed a much higher prevalence language deficits

among iNPH patients than was observed in the retrospective analysis. This analysis thus serves

as a valuable addition to the larger retrospective analysis.

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We obtained pre-operative and post-operative neurocognitive evaluations in a small

group (n = 13) of iNPH patients. Our analysis demonstrated clear improvements in language

and speech functions in a majority of affected iNPH patients. These data provide a rational

basis for a similar study involving a larger group of iNPH patients to replicate these findings.

Given the high prevalence of deficits in language and speech in patients with iNPH, our

findings endorse the integration of a standardized iNPH neurocognitive assessment battery into

the clinical diagnosis and management of iNPH. Limiting factors include both the lengthy

duration and inherently strenuous nature of multiple neurocognitive tests for iNPH patients,

given their advanced age and the impairments associated with this disorder. However, future

streamlining of the neurocognitive battery and strategic scheduling of post-operative

appointments with both neurosurgery and neurology will facilitate the accrual of additional post-

shunt placement data and allow us to more clearly define the cognitive deficits in iNPH.

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Section 6: Acknowledgments

This work was supported by a generous gift from Susan and Frederick B. Sontag.

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References

1. Graff-Radford NR. Normal Pressure Hydrocephalus. Vol. 25, Neurologic Clinics. 2007. p.

809–32.

2. Miller BH. Symptomatic occult hydrocephalus with “normal cerebrospinal fluid pressure”.

Va Med Mon (1918). 1970;97(11):693–5.

3. Virhammar J, Laurell K, Cesarini KG, Larsson E-M. Preoperative Prognostic Value of MRI

Findings in 108 Patients with Idiopathic Normal Pressure Hydrocephalus. AJNR Am J

Neuroradiol. 2014;58:1–8.

4. Tanaka N, Yamaguchi S, Ishikawa H, Ishii H, Meguro K. Prevalence of possible idiopathic

normal-pressure hydrocephalus in Japan: The Osaki-Tajiri project. Neuroepidemiology.

2009;32(3):171–5.

5. Iseki C, Takahashi Y, Wada M, Kawanami T, Adachi M, Kato T. Incidence of idiopathic

normal pressure hydrocephalus (iNPH): A 10-year follow-up study of a rural community in

Japan. J Neurol Sci. 2014;339(1-2):108–12.

6. Marmarou A, Young HF, Aygok G a. Estimated incidence of normal pressure

hydrocephalus and shunt outcome in patients residing in assisted-living and extended-

care facilities. Neurosurg Focus. 2007;22(4):E1.

7. Kazui H, Miyajima M, Mori E, Ishikawa M, Hirai O, Kuwana N, et al. Lumboperitoneal

shunt surgery for idiopathic normal pressure hydrocephalus (SINPHONI-2): An open-

label randomised trial. Lancet Neurol. 2015;14(6):585–94.

8. Golz L, Ruppert F-H, Meier U, Lemcke J. Outcome of modern shunt therapy in patients

with idiopathic normal pressure hydrocephalus 6 years postoperatively. J Neurosurg.

2014;121(4):771–5.

9. Koivisto AM, Alafuzoff I, Savolainen S, Sutela A, Rummukainen J, Kurki M, et al. Poor

cognitive outcome in shunt-responsive idiopathic normal pressure hydrocephalus.

Neurosurgery. 2013;72(1):1–8.

10. Picascia M, Zangaglia R, Bernini S, Minafra B, Sinforiani E, Pacchetti C. A review of

cognitive impairment and differential diagnosis in idiopathic normal pressure

hydrocephalus. Funct Neurol. CIC Edizioni Internationali; 2015 Jan;30(4):217–28.

11. McGirt MJ, Woodworth G, Coon AL, Thomas G, Williams MA, Rigamonti D, et al.

Diagnosis, Treatment, and Analysis of Long-term Outcomes in Idiopathic Normal-

Pressure Hydrocephalus. Neurosurgery. 2005;57(4):699–705.

12. Relkin N, Marmarou A, Klinge P, Bergsneider M, Black PM. Diagnosing idiopathic

  17

normal-pressure hydrocephalus. Vol. 57, Neurosurgery. 2005. p. S4–16; discussion ii – v.

13. Marmarou A, Bergsneider M, Klinge P, Relkin N, Black PML. INPH guidelines, part III:

The value of supplemental prognostic tests for the preoperative assessment of idiopathic

normal-pressure hydrocephalus. Vol. 57, Neurosurgery. 2005.

14. Malm J, Graff-Radford NR, Ishikawa M, Kristensen B, Leinonen V, Mori E, et al. Influence

of comorbidities in idiopathic normal pressure hydrocephalus - research and clinical care.

A report of the ISHCSF task force on comorbidities in INPH. Fluids Barriers CNS.

2013;10(1):22.

15. Saito M, Nishio Y, Kanno S, Uchiyama M, Hayashi A, Takagi M, et al. Cognitive profile of

idiopathic normal pressure hydrocephalus. Dement Geriatr Cogn Dis Extra.

2011;1(1):202–11.

16. Whitehouse PJ, Lerner A, Hedera P, Heilman KM, Valenstein E. Dementia. Clinical

neuropsychology (3rd ed.). 1993. 603-645 p.

17. Green RE a, Melo B, Christensen B, Ngo L-A, Monette G, Bradbury C. Measuring

premorbid IQ in traumatic brain injury: an examination of the validity of the Wechsler Test

of Adult Reading (WTAR). J Clin Exp Neuropsychol. 2008;30(2):163–72.

18. Wallace M, Kurlowicz L. The Mini Mental State Examination (MMSE). try this Best Pract

Nurs Care to Older Adults from Hartford Inst Geriatr Nurs. 1999;(3).

19. Tombaugh TN, Kozak J, Rees L. Normative data stratified by age and education for two

measures of verbal fluency: FAS and animal naming. Arch Clin Neuropsychol.

1999;14(2):167–77.

20. Tombaugh TN. Trail Making Test A and B: Normative data stratified by age and

education. Arch Clin Neuropsychol. 2004;19(2):203–14.

21. Ruff RM, Parker SB. Gender- and age-specific changes in motor speed and eye-hand

coordination in adults: normative values for the Finger Tapping and Grooved Pegboard

Tests. Percept Mot Skills. 1993;76(3 Pt 2):1219–30.

22. Benedict RHB, Schretlen D, Groninger L, Brandt J. Hopkins Verbal Learning Test –

Revised: Normative Data and Analysis of Inter-Form and Test-Retest Reliability. Clin

Neuropsychol. 1998;12(1):43–55.

23. Grogan A, Green DW, Ali N, Crinion JT, Price CJ. Structural correlates of semantic and

phonemic fluency ability in first and second languages. Cereb Cortex. 2009;19(11):2690–

8.

24. Kornse DD, Manni JL, Rubenstein H, Graziani LJ. Developmental apraxia of speech and

manual dexterity. J Commun Disord. 1981;14(4):321–30.

  18

25. Puente AE, McCaffrey RJ. Handbook of neuropsychological assessment: A

biopsychosocial perspective. Neuropsychologia. 1994.

26. Jak AJ, Bondi MW, Delano-Wood L, Wierenga C, Corey-Bloom J, Salmon DP, et al.

Quantification of five neuropsychological approaches to defining mild cognitive

impairment. Am J Geriatr Psychiatry. 2009;17(5):368–75.

27. Tuokko HA, McDowell I. An overview of mild cognitive impairment. Mild cognitive

impairment: International perspectives. 2006. p. 3–28.

28. Jacobson NS, Truax P. Clinical significance: A statistical approach to defining meaningful

change in psychotherapy research. J Consult Clin Psychol. 1991;59(1):12–9.

29. Thomas G, McGirt MJ, Woodworth GF, Heidler J, Rigamonti D, Hillis AE, et al. Baseline

neuropsychological profile and cognitive response to cerebrospinal fluid shunting for

idiopathic normal pressure hydrocephalus. Dement Geriatr Cogn Disord. 2005;20(2-

3):163–8.

30. Beauchet O, Fantino B, Allali G, Muir SW, Montero-Odasso M, Annweiler C. Timed up

and go test and risk of falls in older adults  : a systematic review. J Nutr Heal Aging.

2011;15(10):6–11.

31. McFarlane J, Welch J, Rodgers J. Severity of Alzheimer’s disease and effect on

premorbid measures of intelligence. Br J Clin Psychol. 2006;45(Pt 4):453–63.

32. Kang K, Ko PW, Jin M, Suk K, Lee HW. Idiopathic normal-pressure hydrocephalus,

cerebrospinal fluid biomarkers, and the cerebrospinal fluid tap test. J Clin Neurosci.

2014;21(8):1398–403.

33. Sasaki H, Ishii K, Kono AK, Miyamoto N, Fukuda T, Shimada K, et al. Cerebral perfusion

pattern of idiopathic normal pressure hydrocephalus studied by SPECT and statistical

brain mapping. Ann Nucl Med. 2007;21(1):39–45.

34. Iddon JL, Pickard JD, Cross JJ, Griffiths PD, Czosnyka M, Sahakian BJ. Specific patterns

of cognitive impairment in patients with idiopathic normal pressure hydrocephalus and

Alzheimer’s disease: a pilot study. J Neurol Neurosurg Psychiatry. 1999;723–32.

35. Ogino A, Kazui H, Miyoshi N, Hashimoto M, Ohkawa S, Tokunaga H, et al. Cognitive

impairment in patients with idiopathic normal pressure hydrocephalus. Dement Geriatr

Cogn Disord. 2006;21(2):113–9.

36. Walchenbach R, Geiger E, Thomeer RTWM, Vanneste J a L. The value of temporary

external lumbar CSF drainage in predicting the outcome of shunting on normal pressure

hydrocephalus. J Neurol Neurosurg Psychiatry. 2002;72(4):503–6.

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Figures

Figure 1. Retrospective study design. Flow diagram depicting the stratification of deficits in language, speech and writing among iNPH patients.

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Figure 2. Retrospective analysis of the prevalence and characterization of language and speech deficits in iNPH (n=529). A) Prevalence of language difficulties, motor-related speech difficulties and motor-related writing difficulties prior to shunt placement. B) Stratification of the 122 patients with language deficits into those demonstrating deficits in expressive versus receptive language, those who display both, and those with more complex manifestations of language function. Expressive language difficulties include symptoms of word-finding difficulty and verbal fluency in conversation. Receptive language difficulties include inability to comprehend simple and multistep statements or commands during hospital visits. C) Categorization of the 68 patients with motor-related speech deficits into those with dysarthria, overall slowness, stuttering and combinations/other.

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Figure 3. Boxplots depicting the distribution of pre-operative neurocognitive battery Z scores of shunt-responsive iNPH patients (n=71). Raw data were obtained from prospective formal neurocognitive evaluations of 71 possible iNPH patients prior to lumbar CSF drainage trials and shunt placement for iNPH. Impairment on the various neuropsychiatric assessment tools was defined as a Z score greater than 1.5 SD below the mean (standardized for age, sex, and education level). Descriptions of the tests included in the iNPH battery can be found in the Methods section. A majority of patients demonstrated above average premorbid IQ, but nearly three-quarters of patients attained scores below average or at the level of impairment across a number of neurocognitive tests.

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Figure 4. Analysis of prospectively collected data on the prevalence of language and speech dysfunction in 71 iNPH patients. Impairments in cortical functions (including language, fine motor, executive function) and subcortical functions (including processing speed and attention) were assessed using formal neurocognitive evaluations completed prior to shunt placement. Deficits in semantic verbal fluency and executive function, as well as fine motor skills, are prevalent among the iNPH population.

iNPH

pat

ient

s(n

=71)

0% 10% 20% 30% 40% 50% 60% 70% 80%

0.35

0.42

0.69

0.68

0.54

0.68

Impaired verbal fluency - semanticImpaired verbal fluency - phonemicImpaired fine motor coordinationImpaired executive function - set switchingImpaired cognitive processing speedImpaired attention / concentration

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Figure 5. Focused analysis of pre- and post-operative cognitive evaluations reveal improved outcomes in various cognitive functions. Thirteen iNPH patients received neurocognitive evaluations before and after shunt placement. Significant improvement or decline (P<0.05) post-surgery was assessed using the Reliable Change Index for each neurocognitive subtest.