Acta Neurochirurgica

, Volume 158, Issue 12, pp 2311–2319

Multimodal analysis to predict shunt surgery outcome of 284 patients with suspected idiopathic normal pressure hydrocephalus

  • Antti J. Luikku
  • Anette Hall
  • Ossi Nerg
  • Anne M. Koivisto
  • Mikko Hiltunen
  • Seppo Helisalmi
  • Sanna-Kaisa Herukka
  • Anna Sutela
  • Maria Kojoukhova
  • Jussi Mattila
  • Jyrki Lötjönen
  • Jaana Rummukainen
  • Irina Alafuzoff
  • Juha E. Jääskeläinen
  • Anne M. Remes
  • Hilkka Soininen
  • Ville Leinonen
Clinical Article - Abstract



Optimal selection of idiopathic normal pressure hydrocephalus (iNPH) patients for shunt surgery is challenging. Disease State Index (DSI) is a statistical method that merges multimodal data to assist clinical decision-making. It has previously been shown to be useful in predicting progression in mild cognitive impairment and differentiating Alzheimer’s disease (AD) and frontotemporal dementia. In this study, we use the DSI method to predict shunt surgery response for patients with iNPH.


In this retrospective cohort study, a total of 284 patients (230 shunt responders and 54 non-responders) from the Kuopio NPH registry were analyzed with the DSI. Analysis included data from patients’ memory disorder assessments, age, clinical symptoms, comorbidities, medications, frontal cortical biopsy, CT/MRI imaging (visual scoring of disproportion between Sylvian and suprasylvian subarachnoid spaces, atrophy of medial temporal lobe, superior medial subarachnoid spaces), APOE genotyping, CSF AD biomarkers, and intracranial pressure.


Our analysis showed that shunt responders cannot be differentiated from non-responders reliably even with the large dataset available (AUC = 0.58).


Prediction of the treatment response in iNPH is challenging even with our extensive dataset and refined analysis. Further research of biomarkers and indicators predicting shunt responsiveness is still needed.


Idiopathic normal pressure hydrocephalus Shunt response Computer-assisted diagnosis Prognosis Cognitive decline 





Alzheimer’s disease


Area under the receiver-operator curve



Amyloid-beta 42


Body mass index


Clinical dementia rating


Computed tomography


Cerebrospinal fluid


Disease state index


Hyperphosphorylated tau


Intracranial pressure


Idiopathic normal pressure hydrocephalus


Kuopio University Hospital


Mini-Mental State Examination


Normal pressure hydrocephalus


Ventriculoperitoneal shunt

Supplementary material

701_2016_2980_MOESM1_ESM.pdf (232 kb)
ESM 1(PDF 231 kb)


  1. 1.
    Alafuzoff I, Pikkarainen M, Arzberger T, Thal DR, Al-Sarraj S, Bell J, Bodi I, Budka H, Capetillo-Zarate E, Ferrer I, Gelpi E, Gentleman S, Giaccone G, Kavantzas N, King A, Korkolopoulou P, Kovács GG, Meyronet D, Monoranu C, Parchi P, Patsouris E, Roggendorf W, Stadelmann C, Streichenberger N, Tagliavini F, Kretzschmar H (2008) Inter-laboratory comparison of neuropathological assessments of β-amyloid protein: a study of the BrainNet Europe consortium. Acta Neuropathol 115(5):533–546CrossRefPubMedGoogle Scholar
  2. 2.
    Brean A, Eide PK (2008) Assessment of idiopathic normal pressure patients in neurological practice: the role of lumbar infusion testing for referral of patients to neurosurgery. Eur J Neurol 15(6):605–612CrossRefPubMedGoogle Scholar
  3. 3.
    Delwel EJ, de Jong DA, Avezaat CJJ (2005) The prognostic value of clinical characteristics and parameters of cerebrospinal fluid hydrodynamics in shunting for idiopathic normal pressure hydrocephalus. Acta Neurochir (Wien) 147(10):1037–1043CrossRefGoogle Scholar
  4. 4.
    Eide PK, Brean A (2006) Intracranial pulse pressure amplitude levels determined during preoperative assessment of subjects with possible idiopathic normal pressure hydrocephalus. Acta Neurochir (Wien) 148(11):1151–1156CrossRefGoogle Scholar
  5. 5.
    Eide P, Pripp A (2014) Increased prevalence of cardiovascular disease in idiopathic normal pressure hydrocephalus patients compared to a population-based cohort from the HUNT3 survey. Fluids Barriers CNS 11(1):19CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Eide PK, Sorteberg W (2010) Diagnostic intracranial pressure monitoring and surgical management in idiopathic normal pressure hydrocephalus. Neurosurgery 66(1):80–91CrossRefPubMedGoogle Scholar
  7. 7.
    Elobeid A, Laurell K, Cesarini KG, Alafuzoff I (2015) Correlations between mini-mental state examination score, cerebrospinal fluid biomarkers, and pathology observed in brain biopsies of patients with normal-pressure hydrocephalus. J Neuropathol Exp Neurol 74(5):470–479CrossRefPubMedGoogle Scholar
  8. 8.
    Folstein MF, Folstein SE, McHugh PR (1975) “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12(3):189–198CrossRefPubMedGoogle Scholar
  9. 9.
    Foss T, Eide PK, Finset A (2007) Intracranial pressure parameters in idiopathic normal pressure hydrocephalus patients with or without improvement of cognitive function after shunt treatment. Dement Geriatr Cogn Disord 23(1):47–54CrossRefPubMedGoogle Scholar
  10. 10.
    Gölz L, Ruppert F-H, Meier U, Lemcke J (2014) Outcome of modern shunt therapy in patients with idiopathic normal pressure hydrocephalus 6 years postoperatively. J Neurosurg 121(4):771–775CrossRefPubMedGoogle Scholar
  11. 11.
    Hall A, Mattila J, Koikkalainen J, Lotjonen J, Wolz R, Scheltens P, Frisoni G, Tsolaki M, Nobili F, Freund-Levi Y, Minthon L, Frolich L, Hampel H, Visser P, Soininen H (2015) Predicting progression from cognitive impairment to Alzheimer’s disease with the Disease State Index. Curr Alzheimer Res 12(1):69–79CrossRefPubMedGoogle Scholar
  12. 12.
    Hall A, Muñoz-Ruiz M, Mattila J, Koikkalainen J, Tsolaki M, Mecocci P, Kloszewska I, Vellas B, Lovestone S, Visser PJ, Lötjonen J, Soininen H, Alzheimer Disease Neuroimaging Initiative, AddNeuroMed consortium, DESCRIPA and Kuopio L-MCI (2015) Generalizability of the disease state index prediction model for identifying patients progressing from mild cognitive impairment to Alzheimer’s disease. J Alzheimers Dis 44(1):79–92PubMedGoogle Scholar
  13. 13.
    Hamilton R, Patel S, Lee EB, Jackson EM, Lopinto J, Arnold SE, Clark CM, Basil A, Shaw LM, Xie SX, Grady MS, Trojanowski JQ (2010) Lack of shunt response in suspected idiopathic normal pressure hydrocephalus with Alzheimer disease pathology. Ann Neurol 68(4):535–540CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Hashimoto M, Ishikawa M, Mori E, Kuwana N (2010) Diagnosis of idiopathic normal pressure hydrocephalus is supported by MRI-based scheme: a prospective cohort study. Cerebrospinal Fluid Res 7(1):18PubMedPubMedCentralGoogle Scholar
  15. 15.
    Hulstaert F, Blennow K, Ivanoiu A, Schoonderwaldt HC, Riemenschneider M, Deyn PPD, Bancher C, Cras P, Wiltfang J, Mehta PD, Iqbal K, Pottel H, Vanmechelen E, Vanderstichele H (1999) Improved discrimination of AD patients using -amyloid(1–42) and tau levels in CSF. Neurology 52(8):1555–1555CrossRefPubMedGoogle Scholar
  16. 16.
    Ishikawa M, Hashimoto M, Mori E, Kuwana N, Kazui H (2012) The value of the cerebrospinal fluid tap test for predicting shunt effectiveness in idiopathic normal pressure hydrocephalus. Fluids Barriers CNS 9(1):1CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Junkkari A, Sintonen H, Nerg O, Koivisto AM, Roine RP, Viinamäki H, Soininen H, Jääskeläinen JE, Leinonen V (2015) Health-related quality of life in patients with idiopathic normal pressure hydrocephalus. Eur J Neurol 22(10):1391–1399CrossRefPubMedGoogle Scholar
  18. 18.
    Kazui H, Mori E, Ohkawa S, Okada T, Kondo T, Sakakibara R, Ueki O, Nishio Y, Ishii K, Kawaguchi T, Ishikawa M, Takeda M (2013) Predictors of the disappearance of triad symptoms in patients with idiopathic normal pressure hydrocephalus after shunt surgery. J Neurol Sci 328(1–2):64–69CrossRefPubMedGoogle Scholar
  19. 19.
    Kitagaki H, Mori E, Ishii K, Yamaji S, Hirono N, Imamura T (1998) CSF spaces in idiopathic normal pressure hydrocephalus: morphology and volumetry. AJNR Am J Neuroradiol 19(7):1277–1284PubMedGoogle Scholar
  20. 20.
    Klinge P, Marmarou A, Bergsneider M, Relkin N, Black PM (2005) Outcome of shunting in idiopathic normal-pressure hydrocephalus and the value of outcome assessment in shunted patients. Neurosurgery 57(3):S2–40–S2–52Google Scholar
  21. 21.
    Koivisto AM, Alafuzoff I, Savolainen S, Sutela A, Rummukainen J, Kurki M, Jääskeläinen JE, Soininen H, Rinne J, Leinonen V (2013) Poor cognitive outcome in shunt-responsive idiopathic normal pressure hydrocephalus. Neurosurgery 72(1):1–8CrossRefPubMedGoogle Scholar
  22. 22.
    Kojoukhova M, Koivisto AM, Korhonen R, Remes AM, Vanninen R, Soininen H, Jääskeläinen JE, Sutela A, Leinonen V (2015) Feasibility of radiological markers in idiopathic normal pressure hydrocephalus. Acta Neurochir (Wien) 157(10):1709–1719CrossRefGoogle Scholar
  23. 23.
    Leinonen V, Koivisto AM, Savolainen S, Rummukainen J, Sutela A, Vanninen R, Jääskeläinen JE, Soininen H, Alafuzoff I (2012) Post-mortem findings in 10 patients with presumed normal-pressure hydrocephalus and review of the literature. Neuropathol Appl Neurobiol 38(1):72–86CrossRefPubMedGoogle Scholar
  24. 24.
    Malm J, Graff-Radford NR, Ishikawa M, Kristensen B, Leinonen V, Mori E, Owler BK, Tullberg M, Williams M a, Relkin NR (2013) 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 10(1):22Google Scholar
  25. 25.
    Marmarou A, Bergsneider M, Klinge P, Relkin N, Black PM (2005) The value of supplemental prognostic tests for the preoperative assessment of idiopathic normal-pressure hydrocephalus. Neurosurgery 57(3 Suppl):S2–17–S2–28Google Scholar
  26. 26.
    Mattila J, Koikkalainen J, Virkki A, Simonsen A, van Gils M, Waldemar G, Soininen H, Lötjönen J, Alzheimer’s Disease Neuroimaging Initiative (2011) A disease state fingerprint for evaluation of Alzheimer’s disease. J Alzheimers Dis 27(1):163–176PubMedGoogle Scholar
  27. 27.
    Mattila J, Soininen H, Koikkalainen J, Rueckert D, Wolz R, Waldemar G, Lötjönen J (2012) Optimizing the diagnosis of early Alzheimer’s disease in mild cognitive impairment subjects. J Alzheimers Dis 32(4):969–979PubMedGoogle Scholar
  28. 28.
    McGirt MJ, Woodworth G, Coon AL, Thomas G, Williams MA, Rigamonti D (2005) Diagnosis, treatment, and analysis of long-term outcomes in idiopathic normal-pressure hydrocephalus. Neurosurgery 57(4):699–705CrossRefPubMedGoogle Scholar
  29. 29.
    Morris JC (1993) The Clinical Dementia Rating (CDR): Current version and scoring rules. Neurology 43(11):2412–2412CrossRefPubMedGoogle Scholar
  30. 30.
    Morris JC, Heyman A, Mohs RC, Hughes JP, van Belle G, Fillenbaum G, Mellits ED, Clark C (1989) The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part I. Clinical and neuropsychological assessment of Alzheimer’s disease. Neurology 39(9):1159–1165CrossRefPubMedGoogle Scholar
  31. 31.
    Muñoz-Ruiz MÁ, Hartikainen P, Hall A, Mattila J, Koikkalainen J, Herukka S-K, Julkunen V, Vanninen R, Liu Y, Lötjönen J, Soininen H (2013) Disease state fingerprint in frontotemporal degeneration with reference to Alzheimer’s disease and mild cognitive impairment. J Alzheimers Dis 35(4):727–739PubMedGoogle Scholar
  32. 32.
    Pyykko OT, Helisalmi S, Koivisto AM, Molsa JAA, Rummukainen J, Nerg O, Alafuzoff I, Savolainen S, Soininen H, Jaaskelainen JE, Rinne J, Leinonen V, Hiltunen M (2012) APOE4 predicts amyloid- in cortical brain biopsy but not idiopathic normal pressure hydrocephalus. J Neurol Neurosurg Psychiatry 83(11):1119–1124CrossRefPubMedGoogle Scholar
  33. 33.
    Pyykkö OT, Lumela M, Rummukainen J, Nerg O, Seppälä TT, Herukka S-K, Koivisto AM, Alafuzoff I, Puli L, Savolainen S, Soininen H, Jääskeläinen JE, Hiltunen M, Zetterberg H, Leinonen V (2014) Cerebrospinal fluid biomarker and brain biopsy findings in idiopathic normal pressure hydrocephalus. PLoS One 9(3):e91974CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Relkin N, Marmarou A, Klinge P, Bergsneider M, Black PM (2005) Diagnosing idiopathic normal-pressure hydrocephalus. Neurosurgery 57(3):S2–4–S2–16Google Scholar
  35. 35.
    Savolainen S, Hurskainen H, Paljärvi L, Alafuzoff I, Vapalahti M (2002) Five-year outcome of normal pressure hydrocephalus with or without a shunt: predictive value of the clinical signs, neuropsychological evaluation and infusion test. Acta Neurochir (Wien) 144(6):515–523CrossRefGoogle Scholar
  36. 36.
    Seppala TT, Nerg O, Koivisto AM, Rummukainen J, Puli L, Zetterberg H, Pyykko OT, Helisalmi S, Alafuzoff I, Hiltunen M, Jaaskelainen JE, Rinne J, Soininen H, Leinonen V, Herukka SK (2012) CSF biomarkers for Alzheimer disease correlate with cortical brain biopsy findings. Neurology 78(20):1568–1575CrossRefPubMedGoogle Scholar
  37. 37.
    Tarnaris A, Kitchen ND, Watkins LD (2009) Noninvasive biomarkers in normal pressure hydrocephalus: evidence for the role of neuroimaging. J Neurosurg 110(5):837–851CrossRefPubMedGoogle Scholar
  38. 38.
    Thomas G, McGirt MJ, Woodworth G, Heidler J, Rigamonti D, Hillis AE, Williams MA (2005) Baseline neuropsychological profile and cognitive response to cerebrospinal fluid shunting for idiopathic normal pressure hydrocephalus. Dement Geriatr Cogn Disord 20(2–3):163–168CrossRefPubMedGoogle Scholar
  39. 39.
    Tisell M, Tullberg M, Hellström P, Edsbagge M, Högfeldt M, Wikkelsö C (2011) Shunt surgery in patients with hydrocephalus and white matter changes. J Neurosurg 114(5):1–7CrossRefGoogle Scholar
  40. 40.
    Virhammar J, Laurell K, Cesarini KG, Larsson E-M (2014) Preoperative prognostic value of MRI findings in 108 patients with idiopathic normal pressure hydrocephalus. Am J Neuroradiol 35(12):2311–2318CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Wien 2016

Authors and Affiliations

  • Antti J. Luikku
    • 1
    • 2
  • Anette Hall
    • 1
  • Ossi Nerg
    • 1
    • 3
  • Anne M. Koivisto
    • 1
    • 3
  • Mikko Hiltunen
    • 1
    • 3
    • 4
  • Seppo Helisalmi
    • 1
  • Sanna-Kaisa Herukka
    • 1
    • 3
  • Anna Sutela
    • 5
  • Maria Kojoukhova
    • 2
    • 5
  • Jussi Mattila
    • 6
    • 7
  • Jyrki Lötjönen
    • 6
    • 7
  • Jaana Rummukainen
    • 8
  • Irina Alafuzoff
    • 1
    • 9
  • Juha E. Jääskeläinen
    • 2
  • Anne M. Remes
    • 1
    • 3
  • Hilkka Soininen
    • 1
    • 3
  • Ville Leinonen
    • 2
  1. 1.Institute of Clinical Medicine–NeurologyUniversity of Eastern FinlandKuopioFinland
  2. 2.Neurosurgery of Neuro CenterKuopio University HospitalKuopioFinland
  3. 3.Neurology of NeuroCenterKuopio University HospitalKuopioFinland
  4. 4.Institute of BiomedicineUniversity of Eastern FinlandKuopioFinland
  5. 5.Department of RadiologyKuopio University HospitalKuopioFinland
  6. 6.VTT Technical Research Centre of FinlandTampereFinland
  7. 7.Combinostics LtdTampereFinland
  8. 8.Department of PathologyKuopio University HospitalKuopioFinland
  9. 9.Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University and Department of Pathology and CytologyUppsala University HospitalUppsalaSweden

Personalised recommendations