Estimated ventricle size using Evans index: reference values from a population-based sample.

BACKGROUND AND PURPOSE: Evans index is an estimate of ventricular size used in the diagnosis of idiopathic normal-pressure hydrocephalus (iNPH). Values >0.3 are considered pathological and are required by guidelines for the diagnosis of iNPH. However, there are no previous epidemiological studies on Evans index, and normal values in adults are thus not precisely known. We examined a representative sample to obtain reference values and descriptive data on Evans index. METHODS: A population-based sample (n = 1235) of men and women aged ≥70 years was examined. The sample comprised people living in private households and residential care, systematically selected from the Swedish population register. Neuropsychiatric examinations, including head computed tomography, were performed between 1986 and 2000. RESULTS: Evans index ranged from 0.11 to 0.46. The mean value in the total sample was 0.28 (SD, 0.04) and 20.6% (n = 255) had values >0.3. Among men aged ≥80 years, the mean value of Evans index was 0.3 (SD, 0.03). Individuals with dementia had a mean value of Evans index of 0.31 (SD, 0.05) and those with radiological signs of iNPH had a mean value of 0.36 (SD, 0.04). CONCLUSIONS: A substantial number of subjects had ventricular enlargement according to current criteria. Clinicians and researchers need to be aware of the range of values among older individuals.

Plasma and cerebrospinal fluid concentrations of neurofilament light protein correlate in patients with idiopathic normal pressure hydrocephalus.

BACKGROUND: Neurofilament light chain protein (NFL), a marker of neuronal axonal degeneration, is increased in cerebrospinal fluid (CSF) of patients with idiopathic normal pressure hydrocephalus (iNPH). Assays for analysis of NFL in plasma are now widely available but plasma NFL has not been reported in iNPH patients. Our aim was to examine plasma NFL in iNPH patients and to evaluate the correlation between plasma and CSF levels, and whether NFL levels are associated with clinical symptoms and outcome after shunt surgery. METHODS: Fifty iNPH patients with median age 73 who had their symptoms assessed with the iNPH scale and plasma and CSF NFL sampled pre- and median 9 months post-operatively. CSF plasma was compared with 50 healthy controls (HC) matched for age and gender. Concentrations of NFL were determined in plasma using an in-house Simoa method and in CSF using a commercially available ELISA method. RESULTS: Plasma NFL was elevated in patients with iNPH compared to HC (iNPH: 45 (30-64) pg/mL; HC: 33 (26-50) (median; Q1-Q3), p = 0.029). Plasma and CSF NFL concentrations correlated in iNPH patients both pre- and postoperatively (r = 0.67 and 0.72, p < 0.001). We found only weak correlations between plasma or CSF NFL and clinical symptoms and no associations with outcome. A postoperative NFL increase was seen in CSF but not in plasma. CONCLUSIONS: Plasma NFL is increased in iNPH patients and concentrations correlate with CSF NFL implying that plasma NFL can be used to assess evidence of axonal degeneration in iNPH. This finding opens a window for plasma samples to be used in future studies of other biomarkers in iNPH. NFL is probably not a very useful marker of symptomatology or for prediction of outcome in iNPH.

A new scale for assessment of severity and outcome in iNPH.

OBJECTIVE: To present a new, continuous, calibrated and norm-based scale for the grading of severity and assessment of treatment outcome in idiopathic normal pressure hydrocephalus (iNPH). PATIENTS AND METHODS: A scale designed for the assessment of the four domains, gait, neuropsychology, balance and continence, using ordinal ratings and continuous measures, was developed. Data from a series of 181 consecutive iNPH patients were used to calibrate the continuous parts of the scale and to describe the distributional properties of the ordinal ratings. Data from normative studies were used to determine the limits for normal scores. RESULTS: The construction of the scale made it well equipped to separate iNPH patients at baseline, and the total scores assumed a bell-shaped, approximately normal distribution. All four domain scores correlated significantly with each other, underscoring the well-known syndromatic nature of iNPH, and justifying the use of a total score to describe the patients. Reliability [Cronbach's α for the total score = 0.74, and for the domains of gait and neuropsychology, 0.86 and 0.89, respectively) and validity estimates (convergent validity evaluated by Spearman rank correlations for the scale and the modified Rankin scale (ρ = -0.61) and the mini mental state examination (ρ = 0.57)] are satisfying. CONCLUSION: The iNPH scale covers the four most important symptom domains and the full range of severity of the iNPH syndrome. The scale is sensitive, reliable, valid and feasible. We recommend that it should be used in future iNPH research.

One-year outcome in the European multicentre study on iNPH.

OBJECTIVES: To assess the 1-year outcome after shunt surgery in patients with idiopathic normal pressure hydrocephalus (iNPH). METHODS: Patients (n = 142) were prospectively included in the European multicentre study by 13 centres. Diagnoses were based solely on clinical and radiological findings. All received a programmable ventriculoperitoneal shunt. Re-examinations, 12 months after surgery, were performed in 115 patients, and the outcome was assessed by the modified Rankin scale (mRs) and a new iNPH grading scale. Improvement was defined as ≥1 step on the mRs and ≥5 points on the iNPH scale. RESULTS: The scores on both scales were significantly improved after 1 year of shunt treatment (Ps < 0.001). Sixty-nine per cent of the patients were improved according to the mRs and 84% according to the iNPH scale. The proportion able to live independently (scores 0-2 on the mRs) was increased from 53% before to 82% 12 months after surgery (P < 0.001). Neither classification (typical or questionable) nor comorbidity affected the level of improvement. Patients not completing the study were worse off with regard to their clinical condition at entry than completers. Twenty-eight per cent of the patients experienced complications and were either conservatively (13%) or surgically (15%) treated. CONCLUSION: The results of this prospective multicentre study on patients with iNPH diagnosed solely on clinical and radiological criteria support shunt surgery in patients presenting with symptoms and signs and MRI findings suggestive of iNPH.

Reduced thalamic N-acetylaspartate in idiopathic normal pressure hydrocephalus: a controlled 1H-magnetic resonance spectroscopy study of frontal deep white matter and the thalamus using absolute quantification.

INTRODUCTION: Patients with idiopathic normal pressure hydrocephalus (INPH) frequently have a reduction in cerebral blood flow in the subcortical frontal lobe/basal ganglia/thalamic areas. With magnetic resonance spectroscopy, the metabolism in the brain can be examined. The aim of this study was to investigate if there was a compromised metabolism in the thalamus and in the subcortical frontal areas in INPH patients. This was done by measuring total creatine, myo-inositol, total choline, N-acetylaspartate (NAA), total N-acetylaspartate (tNA), glutamate and lactate levels. A comparison was made with healthy individuals (HI). SUBJECTS AND METHODS: 16 patients (nine males, seven females, mean age 74 years, range 49-83) diagnosed as INPH and 15 HI (nine males, six females, mean age 74 years, range 62-89) were examined. (1)H magnetic resonance spectroscopy (1.5 T, point-resolved spectroscopy, echo time/relaxation time 30/3000 ms, volume of interest 2.5-3 ml) was performed in frontal deep white matter and in the thalamus. Absolute quantification with internal water as a reference was used. RESULTS: INPH patients had lower NAA (p=0.02) and lower tNA (p=0.05) concentrations in the thalamus compared with HI. NAA and tNA in the frontal deep white matter did not differ between patients and HI. The absolute metabolic concentrations of total creatine, myo-inositol total choline, tNA, lactate and Cr ratios in frontal deep white matter and in the thalamus were similar in INPH patients and HI. CONCLUSION: Reduced thalamic NAA and tNA in INPH patients suggest a compromised metabolic neuronal function in these regions. Thus, the thalamus might have an important role in the pathogenesis of INPH.

Spinal cerebrospinal fluid volume in healthy elderly individuals.

The amount of spinal cerebrospinal fluid (CSF) could be of importance for the understanding of CSF dynamics, CSF biomarker analyses as well as for the amount and effect of anaesthesia using intrathecally administered drugs. However, knowledge of spinal CSF volumes is scarce. The main purpose of this article is to present data on spinal CSF volumes. In total, 22 healthy individuals aged between 64 and 76 years underwent MR imaging with a 3D balanced turbo field echo pulse sequence, which provided high contrast between spinal cord, CSF and the extradural surroundings. The entire spinal CSF volume, the cervical, thoracic, and lumbosacral CSF volumes and the spinal cord volume were calculated. The total spinal CSF volume was 81 ± 13 ml (range 52-103 ml). The amount of CSF in the cervical region was 19 ± 4 ml, in the thoracic region 38 ± 8 and in the lumbosacral region 25 ± 7 ml. There was no difference between genders nor was there any correlation with height. The volume of the spinal cord was 20 ± 3 ml. The results present new magnetic resonance imaging-based data on the spinal CSF volume in healthy elderly individuals.

Absence of Disproportionately Enlarged Subarachnoid Space Hydrocephalus, a Sharp Callosal Angle, or Other Morphologic MRI Markers Should Not Be Used to Exclude Patients with Idiopathic Normal Pressure Hydrocephalus from Shunt Surgery.

BACKGROUND AND PURPOSE: Several studies have evaluated the use of MR imaging markers for the prediction of outcome after shunt surgery in idiopathic normal pressure hydrocephalus with conflicting results. Our aim was to investigate the predictive value of a number of earlier proposed morphologic MR imaging markers in a large group of patients with idiopathic normal pressure hydrocephalus. MATERIALS AND METHODS: One hundred sixty-eight patients (mean age, 70 ± 9.3 years) with idiopathic normal pressure hydrocephalus, subjected to standardized quantification of clinical symptoms before and after shunt surgery, were included in the study. Outcome was calculated using a composite score. Preoperative T1, FLAIR, and flow-sensitive images were analyzed regarding the presence of 13 different morphologic MR imaging markers. RESULTS: The median Evans index was 0.41 (interquartile range, 0.37-0.44). All patients had an aqueductal flow void sign present and white matter hyperintensities. The median callosal angle was 68.8° (interquartile range, 57.7°-80.8°). Dilated Sylvian fissures were found in 69%; focally dilated sulci, in 25%; and widening of the interhemispheric fissure, in 55%. Obliteration of the sulci at the convexity was found in 36%, and 36% of patients were characterized as having disproportionately enlarged subarachnoid space hydrocephalus. Sixty-eight percent of patients improved after surgery. None of the investigated MR imaging markers were significant predictors of improvement after shunt surgery. CONCLUSIONS: Disproportionately enlarged subarachnoid space hydrocephalus, a small callosal angle, and the other MR imaging markers evaluated in this study should not be used to exclude patients from shunt surgery. These markers, though they may be indicative of idiopathic normal pressure hydrocephalus, do not seem to be a part of the mechanisms connected to the reversibility of the syndrome.

Ventricular cerebrospinal fluid neurofilament protein levels decrease in parallel with white matter pathology after shunt surgery in normal pressure hydrocephalus.

Normal pressure hydrocephalus (NPH) is characterized by disturbed cerebrospinal fluid (CSF) dynamics and white matter lesions (WML). Although the morphology of these lesions is described, little is known about the biochemistry. Our aim was to explore the relationship between ventricular CSF markers, periventricular WML and postoperative clinical outcome in patients with NPH. We analysed lumbar and ventricular concentrations of 10 CSF markers, 12 clinical symptoms and signs, magnetic resonance imaging (MRI) periventricular white matter hyperintensities (PVH) and ventricular size before and 3 months after shunt surgery in 35 patients with NPH. Higher ventricular CSF neurofilament protein (NFL), an axonal marker, correlated with more extensive PVH. A larger postoperative reduction in NFL correlated with larger reduction in PVH and a more pronounced overall improvement. Albumin ratio, HMPG, NPY, VIP and GD3 increased postoperatively whereas NFL, tau and HVA decreased. Variations in ventricular size were not associated with CSF concentrations of any marker. We conclude that NPH is characterized by an ongoing periventricular neuronal dysfunction seen on MRI as PVH. Clinical improvement after shunt surgery is associated with CSF changes indicating a restitution of axonal function. Other biochemical effects of shunting may include increased monoaminergic and peptidergic neurotransmission, breakdown of blood brain barrier function, and gliosis.

Amyloid mis-metabolism in idiopathic normal pressure hydrocephalus.

BACKGROUND: Patients with idiopathic normal pressure hydrocephalus (iNPH) have reduced cerebrospinal fluid (CSF) concentrations of amyloid-ß (Aß) and α- and ß-cleaved soluble forms of amyloid precursor protein (sAPPα and sAPPß). The aims of this study were to examine if changes could also be seen in the CSF for secreted metabolites of APP-like protein 1 (APLP1) and to explore the prognostic value of amyloid-related CSF biomarkers, as well as markers of neuronal injury and astroglial activation, as regards to clinical outcome after shunt surgery. METHODS: Twenty patients diagnosed with iNPH, 10 improved and 10 unchanged by shunt surgery, and 20 neurologically healthy controls were included. All patients were examined clinically prior to surgery and at 6-month follow-up after surgery using the iNPH scale. Lumbar puncture was performed pre-operatively. CSF samples were analyzed for neurofilament light (NFL), Aß isoforms Aß38, Aß40 and Aß42, sAPPα, sAPPß, APLP1 ß-derived peptides APL1ß25, APL1ß 27 and APL1ß 28 and YKL40 by immunochemical methods. RESULTS: The concentrations of all soluble forms of APP, all Aß isoforms and APL1ß28 were lower, whilst APL1ß25 and APL1ß27 were higher in the CSF of iNPH patients compared to controls. There was no difference in biomarker concentrations between patients who improved after surgery and those who remained unchanged. CONCLUSIONS: The reduced CSF concentrations of Aß38, Aß40, Aß42, sAPPα and sAPPß suggest that APP expression could be downregulated in iNPH. In contrast, APLP1 concentration in the CSF seems relatively unchanged. The increase of APL1ß25 and APL1ß27 in combination with a slight decreased APL1ß28 could be caused by more available γ-secretase due to reduced availability of its primary substrate, APP. The data did not support the use of these markers as indicators of shunt responsiveness.

Serum IGF-1 is higher in patients with idiopathic normal pressure hydrocephalus than in the population.

BACKGROUND: Hypopituitarism has been reported in patients with idiopathic normal pressure hydrocephalus (iNPH), which could enhance characteristic symptoms like impaired wakefulness, gait, body balance, and subcortical cognitive deterioration. PURPOSE: To compare basal serum levels of pituitary and sex hormones and serum insulin-like growth factor-1 (S-IGF-1) in patients with iNPH and an age-matched control population, and to correlate the preoperative hormone levels with symptoms and signs pre-operatively and three months after surgery. METHODS: A cross-sectional case control design was used. Patients diagnosed with iNPH, n=108 (65 men and 43 women, mean age 72.3 years), were consecutively included during 2006-2011 at Sahlgrenska University Hospital, Gothenburg, Sweden. S-TSH, S-free T4, S-FSH, S-LH, S-prolactin, plasma ACTH, S-testosterone, S-oestradiol and S-IGF-1 were examined. Symptoms and signs were scored using the iNPH scale score. Population controls, n=146, were recruited from the WHO MONICA project, Gothenburg in 2008. RESULTS: Men and women with iNPH had higher S-IGF-1 than controls (p<0.001). Women with iNPH had lower S-TSH (p=0.016) than controls, but the frequency of levothyroxine substitution was similar. Among men, a higher level of S-IGF-1 was associated with milder symptoms, while higher levels of S-FSH and S-LH were associated with more severe symptoms. CONCLUSIONS: Patients with iNPH did not have lower levels of pituitary or sex hormones but presented with higher levels of S-IGF-1, compared with healthy, age-matched controls. Higher S-IGF-1 in men was related to milder mental and physical symptoms and signs.

Cerebrospinal fluid proteins and cells in men subjected to long-term exposure to organic solvents.

Cerebrospinal fluid (CSF) was obtained from 17 men occupationally exposed to organic solvents and diagnosed as having a psycho-organic syndrome. Healthy volunteers and patients without neurological disorders were used as controls. The albumin ratio was increased in three heavily exposed men, indicating an increased passage of albumin over the blood-brain barrier. A slight monocytoid reaction was present in three of the subjects in the exposed group. Myelin basic protein and enolase activity were within normal limits. Isoelectric focusing of CSF-enriched proteins obtained by absorption chromatography showed alterations in nine out of 17 exposed individuals: The most prominent change was a relative increase of the protein band with Ip 4.7.

Normal pressure hydrocephalus triggers intrathecal production of TNF-alpha.

Normal pressure hydrocephalus (NPH) is associated with periventricular white matter lesions and demyelination. The aim of the present study was to examine the cerebrospinal fluid (CSF) levels of tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine mediating myelin damage, in patients with NPH. TNF-alpha levels were analyzed by ELISA and measured before and after shunt operation in 35 patients with NPH. The levels of this cytokine were related to the symptomatology and to magnetic resonance imaging (MRI) verified white matter lesions. They were also related to intrathecal levels of sulfatide, a marker for white matter degradation and to levels of neurofilament, a marker for neuronal degeneration. The preoperative levels of TNF-alpha were increased in the CSF of NPH patients compared to controls, and correlated to the levels of sulfatide. The intrathecal TNF-alpha levels were higher in NPH patients with impairment of wakefulness than in those without this symptom. The preoperative TNF-alpha levels were significantly correlated to the improvement of psychometrical test scores, and of wakefulness and to the overall improvement of the patients following shunt operation. Importantly, shunt operation led to complete disappearance of intrathecal TNF-alpha. We conclude that NPH is correlated with intrathecal TNF-alpha production being reversed following shunt operation in parallel with the clinical improvement. The positive correlation between preoperative TNF-alpha and sulfatide levels in the CSF suggest that intrathecal TNF-alpha may contribute to the damage of the white matter known to occur in patients with NPH.

Posttraumatic seesaw nystagmus abolished by ethanol ingestion.

We describe a patient who was left with a midchiasmal injury and bitemporal hemianopia after head trauma. Four months later, she developed typical seesaw nystagmus and moderate hydrocephalus. Lumbar punctures did not affect the nystagmus, but a temporary cessation was documented after ingestion of ethanol.

CSF neurofilament and glial fibrillary acidic protein in normal pressure hydrocephalus.

We examined CSF levels of markers of neuronal degeneration and astrogliosis-the light subunit of the neurofilament triplet protein (NFL) and the glial fibrillary acidic protein (GFAP)-in 65 patients with normal pressure hydrocephalus (NPH). NFL was increased sixfold (864 +/- 1,538 [mean +/- SD] versus 156 +/- 81 ng/L; p < or = 0.001) and GFAP twofold (1,116 +/- 1,085 versus 637 +/- 295 ng/L; p < or = 0.01) in NPH patients compared with neurologically healthy age-matched controls. No correlation was found between any particular symptom or sign and GFAP levels in CSF. The levels of NFL, on the other hand, were higher in patients with severe symptoms compared with those with moderate or no symptoms. Furthermore, there was a correlation between a high level of NFL and gait disturbance, incontinence, psychometric incapability, and social dysfunction. A high preoperative NFL level was associated with favorable outcome after shunt surgery. This indicates that NFL is a marker of ongoing and possibly still-reversible axonal damage in NPH.

Dementia of different etiologies: vasoactive intestinal polypeptide in CSF.

Patients with normal-pressure hydrocephalus, multi-infarct dementia, and recent cerebral infarction had significantly lower vasoactive intestinal polypeptide (VIP) levels than age-matched controls (11 +/- 3 pmol/l, 17 +/- 4 pmol/l, 21 +/- 4 pmol/l, and 33 +/- 4 pmol/l, respectively). Three months after a shunt operation, the VIP levels had increased significantly in patients with hydrocephalus (54 +/- 13 pmol/l). VIP concentration in patients with senile dementia did not differ from that of controls.

Hypotension induced by prostacyclin treatment during cardiopulmonary bypass does not increase the risk of cerebral complications.

High-dose prostacyclin treatment during cardiopulmonary bypass reduces platelet activation and possibly postoperative blood loss. A side-effect is arterial hypotension. We studied the incidence of cerebral complications in 79 patients requiring coronary bypass. Only patients without known cerebrovascular disease were studied. Thirty-nine patients received prostacyclin 50 ng/kg/min during cardiopulmonary bypass and 40 patients served as controls. Mean arterial blood pressure in the group given prostacyclin was below 30 mm Hg during the first 30 minutes of bypass but remained above 60 mm Hg in the control group. Postoperative neurological examination revealed transient cerebral dysfunction in six control patients and two prostacyclin-treated patients. Investigation of cerebrospinal fluid showed signs of blood-brain barrier damage in 12 control and seven prostacyclin-treated patients. Cytologic changes in cerebrospinal fluid consistent with brain tissue damage occurred in two control patients but in no patient given prostacyclin. Myelin basic protein and adenylate kinase in cerebrospinal fluid were assayed as being markers of brain damage. Myelin basic protein was within the normal range in all patients. Adenylate kinase was moderately increased (greater than 0.035 U/L) in five of 15 control patients and six of 13 prostacyclin-treated patients. We conclude that treatment with prostacyclin 50 ng/kg/min during cardiopulmonary bypass does not increase the risk of postoperative cerebral damage.

A technique for simultaneous sampling of cerebrospinal and brain extracellular fluid in unanaesthetized rabbits.

The continuous sampling of cerebrospinal fluid (CSF) from unanaesthetized rabbits was combined with dialysis-perfusion of the hippocampus in order to simultaneously sample the extracellular fluid (ECF) and the CSF. Implantation of the CSF-drainage into the subarachnoid space caused a transient increase of blood cells and serum-derived proteins in the CSF. Essentially normal values were restored within 4 days. The subsequent implantation of a dialysis probe also induced an increase in CSF cells and proteins which returned to preoperative values within 2 days. The protein pattern of the ECF was dominated by proteins with isoelectric points of 4.4, 4.5, 4.6 and 5.0 and molecular weights of 14, 30 and 45 kDa. Bands with similar mobility were seen in CSF and serum, however at relatively lower concentrations, as compared to the total protein content.

VIP in cerebrospinal fluid of patients with multiple sclerosis.

The concentration of VIP was measured radioimmunochemically in cerebrospinal fluid (CSF) from 14 healthy volunteers and from 22 patients with multiple sclerosis. Significantly lower levels of VIP was obtained in the patients (18 +/- 3 pmol/l) than in controls (37 +/- 4 pmol/l). There was no correlation between the level of VIP in CSF and other CSF parameters such as albumin. IgG or cell content; nor between VIP concentration and the physical handicap or neuropsychiatric symptoms. There was a trend towards lower values of VIP in patients with steadily progressing rather than intermittent course of the disease but the difference between the groups was not significant.

A sensitive ELISA for glial fibrillary acidic protein: application in CSF of adults.

The present study concerns an ELISA for glial fibrillary acidic protein (GFAP) in cerebrospinal fluid (CSF). The application of the method in CSF of children has previously been described in this journal. We have now adapted the technique to allow determination of the much higher GFAP concentrations found in normal and pathological CSF of adults. The assay range was extended to 16,000 pg/ml. CSF levels as high as 170,000 pg/ml could be assayed since dilution experiments indicated immunological identity between purified GFAP and GFAP in CSF. In normal controls the concentrations correlated significantly with age (P < 0.001, Spearman rank correlation test). The concentrations were less than 200 pg/ml before 20 years of age and increased to between 500 and 1300 pg/ml at approximately 75 years of age. This increase of CSF GFAP probably reflects formation of astroglial filaments in the CNS and it must be taken into consideration when determining the pathological CSF GFAP level. The method was validated using CSF samples from patients with either astrogliosis or acute tissue destruction in the CNS. Although augmented levels were observed in both groups it is quite clear that patients with acute tissue destruction may display very high CSF GFAP concentrations, whereas levels in patients with astrogliosis were only modestly increased if at all.

Cerebrospinal fluid proteins and cells in normal-pressure hydrocephalus.

A total of 21 patients with normal-pressure hydrocephalus were examined. Cerebrospinal fluid (CSF) was collected before and after operation with a ventriculoperitoneal shunt. A slight plasma-like protein pattern indicating a blood-brain barrier (BBB) dysfunction was seen in 38% of the patients before operation. No characteristic changes could be found in the "CSF-specific" protein fraction. After the shunt operation 65% of the patients had a BBB dysfunction to macromolecules and 70% had two additional acidic protein bands in the CSF-specific fraction. Ventricular CSF protein content was 73% of lumbar CSF content when shunts were patent. Isotope encephalography showed a radionuclide accumulation at the intracranial part of the shunt system, indicating that the BBB damage might be located round the shunt catheter.