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J Neurol (2005) 252:958–963 DOI 10.1007/s00415-005-0791-2 ORIGINAL COMMUNICATION

Phil Hyu Lee Correlation of diameter and gait Suk Woo Yong Yo ung Hwan Ahn disturbance in patients with idiopathic Kyoon Huh normal pressure hydrocephalus

■ Received: 13 July 2004 Abstract Background and pur- significantly smaller in the NPH Received in revised form: pose Although gait disturbance is group than in the controls 19 November 2004 an important feature of idiopathic (14.8 ± 0.9 vs. 17.1 ± 0.7 mm, Accepted: 13 December 2004 normal pressure hydrocephalus p < 0.001). There were inverse cor- Published online: 19 April 2005 (NPH), only tentative theories have relations between the midbrain di- been offered to explain its patho- ameter and the widths of the two physiology. It has been suggested ventricles (r = –0.562, p = 0.008 for that the mesencephalic locomotor the third ventricle, and r = –0.510, region is the anatomical substrate p = 0.018 for the lateral ventricle). for the development of the hypoki- The severity of gait disturbance netic NPH gait. To investigate this was negatively correlated with the possibility, we evaluated the corre- midbrain diameter (r = –0.598, lation between gait disturbance p = 0.004), but the degree of cogni- and midbrain diameter. Methods tive dysfunction and incontinence We enrolled 21 patients with NPH showed no significant correlation P. H . Le e, M.D., Ph.D. () · S. W.Yong, M.D. · and 20 age-matched control sub- with midbrain diameter or ventric- K. Huh, M.D. jects for the study. The maximal di- ular width. Conclusions This study Dept. of Neurology, College of Medicine Ajou University ameter of the midbrain and pons, suggests that midbrain atrophy is Woncheon-dong San 5, Paldal-ku and the width of the lateral and significantly associated with gait Suwon, Kyungki-do, 442–749, South Korea third ventricles were measured us- disturbance in NPH. Tel.: +82-31/219-5174 ing midsagittal T1-weighted MRI Fax: +82-31/219-5178 ■ E-Mail: [email protected] and axial T2-weighted MRI, respec- Key words normal pressure tively. Gait disturbance, cognitive hydrocephalus · midbrain · gait Y. H. Ahn, M.D., Ph.D. Dept. of Neurosurgery dysfunction, and incontinence disturbance · mesencephalic Ajou University School of Medicine were semiquantified. Results The locomotor region Suwon, Korea maximal midbrain diameter was

The clinical elements of the NPH gait can be summa- Introduction rized as a hypokinetic gait which is characterized by di- minished gait velocity, reduced stride length, reduced Idiopathic normal pressure hydrocephalus (NPH) is step height, and dynamic disequilibrium [17, 28, 31, 34]. characterized by the clinical triad of gait disturbance, Patients with many other neurodegenerative diseases, progressive cognitive dysfunction, and urinary inconti- such as Parkinson’s disease, subcortical arteriosclerotic nence. Radiological investigations typically reveal en- encephalopathy, progressive supranuclear palsy (PSP), largement of the ventricles without cortical atrophy [2, and corticobasal degeneration, may develop hypoki- 10].Gait disturbance is the first clinical manifestation in netic gait during the disease progression [4, 35, 37]. The most cases of NPH and is one of the most important question of how gait disturbances develop in NPH pa-

JON 1791 symptoms [5, 9, 24]. tients remains unresolved. Some researchers have pos- 0958_0963_Lee_JON_1791 08.08.2005 07:34 Uhr Seite 959

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tulated that frontal lobe dysfunction plays a major role, tio of the greatest distance between the lateral walls in the frontal horns of the first and second ventricles, and the diameter of the inner while others have suggested that hydrocephalus con- table of the skull, both in the transverse plane) was calculated on T1- tributes to the interruption of the subcortical circuit weighted imaging. The maximal diameter of the midbrain and pons connecting the frontal lobe and basal ganglia [3, 19, 28]. was measured on T1-weighted imaging of the midsagittal plane with Based on recent animal studies, the mesencephalic the scanners’internal measurement device [39],using the PiView sys- locomotor region, which plays a major role in locomo- tem program (Fig. 1A). Since maximal ventricular width is known to be well correlated with ventricular volume [38], we measured the tion, has been suggested as the anatomical substrate for width of the lateral ventricle (horizontal distance at the midpoint of the development of gait freezing in idiopathic Parkin- the anteroposterior ventricular scan at the level of the septum pellu- son’s disease and other parkinsonisms [7, 23, 30]. In hu- cidum) on T2-weighted axial images (Fig. 1B). The diameter of the mans, the mesencephalic locomotor region is located in third ventricle was determined by the maximum transverse diameter on axial scans (Fig. 1C). Two neurologists (L. P.H and Y.S.U) mea- the dorsolateral portion of the midbrain [8]. sured the widths of each image in a blinded fashion, and the average In the present study, we assessed the midbrain diam- value was obtained. eter in patients with NPH and analyzed the relationship between the midbrain diameter and gait disturbance to ■ evaluate the contribution of midbrain to NPH gait. Rating scales of NPH symptoms The degree of gait disturbance was semiquantified according to the scale developed by Larsson et al. [22]: 1, normal; 2, insecure; 3, inse- Patients and methods cure with cane; 4, bimanual support; 5, aided; 6, wheelchair. The de- gree of urinary incontinence was recorded semiquantitatively, based ■ Patient population and controls on the scale developed by Krauss et al. [18]: 0, none; 1, sporadic in- continence or urge phenomena; 2,frequent incontinence; 3,only min- Twenty-one NPH patients who were inpatients in the Department of imal control.The degree of cognitive impairment was also semiquan- Neurology and Neurosurgery at Ajou University Hospital from Janu- tified according to the scale of Krauss et al.[20,22]: 0,none; 1,minimal ary, 2001, to April, 2004, were enrolled in the study. The diagnosis of attention or memory deficits; 2, considerable deficits, but oriented to NPH was based on the presence of the following symptoms and signs: situational context; 3, not or only marginally oriented. (1) gait disturbance, (2) cognitive dysfunction, urinary disturbance, or both, (3) ventricular enlargement (Evans ratio > 0.31) without cor- ■ tical atrophy on brain magnetic resonance imaging (MRI) [31],(4) in- Statistical Analysis tracranial pressure below 20 CmH20, as measured by lumbar punc- ture, (5) ventricular filling and block of convexity flow on Statistical analyses were performed with the use of a commercially radionuclide cisternography, (6) absence of other neurological dis- available software package (SPSS, version 10.0). The diameters of the eases that could explain the symptoms, such as progressive supranu- pons and midbrain of patients with NPH and controls were compared clear palsy (PSP) or corticobasal degeneration, or ventricular en- using the Mann-Whitney U test. The Spearman’s correlation test was largement described above [10, 21]. The control group consisted of used to test for associations between the midbrain size and the degree age- and sex-matched healthy volunteers who were free of neurolog- of clinical symptoms of NPH. To determine the interobserver relia- ical disease and whose neurological examinations were normal. bility of the rating, a Cronbach’s alpha coefficient was calculated. P values less than 0.05 were considered statistically significant.

■ Brain MRI and measurements

Routine MRI images of the brain were obtained for all subjects on a 1.5-T Signa Scanner (GE, Signa, Advantage). The Evans ratio (the ra-

ABC

Fig. 1 (A) Measurement of the midsagittal maximal anteroposterior diameter of the midbrain (solid line) and pons (dotted line) on sagittal T1-weighted MR images using the internal measurement device. (B) Maximum lateral ventricle width (solid line) determined where the septum pellucidum remains thin. (C) The maximal third ventricle width (solid line) 0958_0963_Lee_JON_1791 08.08.2005 07:34 Uhr Seite 960

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Results the diameter of the third ventricle and the diameter of the midbrain (r = –0.562, p = 0.008; Fig. 3A). In addition, The mean age of the patients with NPH was 70.5 years the diameter of the lateral ventricle was inversely corre- (SD 5.6),and 9 (42.8%) were female.The mean age of the lated with the diameter of the midbrain (r = –0.510, healthy control subjects (73.5 years, SD 4.9) was not sta- p = 0.018; Fig. 3B). tistically different from that of patients with NPH, and 9 Among the major symptoms of NPH, only the sever- (45%) were female. All patients with NPH had under- ity of gait disturbance showed an inverse correlation gone radionuclide cisternography that had confirmed with the midbrain diameter (r = –0.598,p = 0.004; Fig. 4); communicating hydrocephalus. All patients with NPH no association was found between urinary incontinence performed the CSF drainage, which subjectively im- or cognitive dysfunction and the midbrain diameter. No proved gait in all patients. The mean of the Evans ratio significant correlation was found between gait disturb- in patients with NPH was 0.39 (SD 0.03). The reliability ance, urinary incontinence, or cognitive dysfunction coefficients for the width of ventricle and maximal mid- with the diameters of the lateral or third ventricle. sagittal diameter of midbrain and pons were as follows: the lateral ventricle, 0.98; the third ventricle, 0.982; the midbrain, 0.975; the pons, 0.979. A The degree of gait disturbance was rated at level 1 in four patients, level 2 in nine patients, level 3 in three pa- tients, level 4 in two patients, level 5 in one patient, and level 6 in two patients.Urinary incontinence was present at level 0 in eight patients, level 1 in six patients, level 2 in five patients,and level 3 in two patients.The degree of cognitive impairment was level 0 in ten patients, level 1 in four patients, level 2 in seven patients, and level 3 in no patients. The midbrain diameter, measured on the midsagittal image, was markedly decreased in patients with NPH, compared with the healthy control subjects (14.8 ± 0.9 mm vs. 17.1 ± 0.6 mm, p < 0.001; Fig. 2). In contrast,there was no significant difference between the two groups in the diameter of the pons (22.8 ± 0.9 mm vs. 23.4 ± 0.7 mm, p > 0.05). There was a significant inverse correlation between

B

Fig. 2 Scatterplot of the maximal anteroposterior midbrain diameter for patients Fig. 3 Relationship between the midbrain diameter and the width of the third with idiopathic normal pressure hydrocephalus (NPH) and control subjects. The ventricle (A) or the lateral ventricle (B), showing inverse correlations between the mean value of the midbrain diameter in patients with NPH is significantly lower midbrain diameter and the ventricular widths than in controls 0958_0963_Lee_JON_1791 08.08.2005 07:34 Uhr Seite 961

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was clearly distinguishable from the gait of patients with Parkinson’s disease [19, 32]. Furthermore, the equilib- rium-related gait variables, such as the step width and the foot rotation angles, remained unaffected by thera- peutic tapping of the CSF [33], although the gait veloc- ity and stride length were markedly improved following the CSF drainage. Based on these results, Stolze et al. speculated that the disturbance of equilibrium in NPH patients cannot be explained by defects in the basal gan- glia and suggested that the subsystems for motor pro- gramming and balance may be differently involved [33]. However, the anatomical substrate for the balance sys- tem is not yet known. It could be frontal lobe, basal gan- glia, or related posture center [33, 36]. The results of the present study raise the possibility that midbrain atrophy may be the pathological substrate for the disturbance of gait equilibrium in patients with Fig. 4 Relationship between the midbrain diameter and gait disturbance, show- NPH. There is a large body of evidence indicating that ing a significant inverse correlation between the midbrain diameter and the degree the pedunculopontine nucleus (PPN) plays an impor- of gait disturbance tant role in locomotion, although the anatomical sub- strates for gait and postural disturbances remain poorly understood [23, 30]. The PPN is a part of the mesen- cephalic locomotor region, a functionally defined area Discussion based on induction of locomotor activity by either elec- trical or chemical stimulation of the tegmental region The present study demonstrated that the midbrain di- [7, 11]. In the , the anterior aspect of the ameter was markedly decreased in patients with NPH. PPN rostrally contacts the dorsomedial aspect of the Furthermore, the decrement of the midbrain diameter posterolateral , while the retrorubral in patients with NPH was inversely correlated with the field borders it dorsally. The most dorsal aspect of the semiquantitative score for severity of gait disturbance. PPN is bounded caudally by the pontine cuneiform and However, no relationship between the severity of any of subcuneiform nuclei and ventrally by the pontine retic- the clinical symptoms of NPH and ventricular size was ular formation [30]. Pathological studies in humans found. have reported that 60–70% and 40–50% of cholinergic Although gait disturbance is an important feature of neurons in the PPN degenerated in PSP and Parkinson’s NPH, only tentative theories have been offered to ex- disease, respectively [6, 15, 16, 41, 42]. This degeneration plain its pathophysiology.It has been postulated that hy- appeared to be responsible for gait freezing,gait ignition drocephalus may directly compress and therefore im- failure, and postural instability in patients with PSP or pede the corticospinal fibers controlling the leg advanced Parkinson’s disease [23, 30]. In addition, the movements and/or frontopontocerebellar fibers as they involvement of the PPN in human locomotion is sup- descend close to the lateral ventricle [12, 36]. Others ported by the report of Masdeu et al., which demon- have suggested that ventricular enlargement interrupts strated that a focal lesion in the midbrain the cortical-subcortical basal ganglia loop, which con- was associated with severe gait disturbance and postural nects the frontal cortex and basal ganglia, thus resulting instability [25, 26]. Although not extensively studied, in frontal lobe-like gait disturbance with marked dise- gait disturbances in patients with PSP are usually related quilibrium [1, 3, 28]. Recently, Owler et al. [29] reported to balance impairment,as a result of which patients have that the baseline cerebral blood flow was decreased in a stiff and wide-based gait,with a tendency to keep their the basal ganglia and the thalamus but not in white mat- knees extended, as well as a dysfunction in the postural ter regions, and the thalamic blood flow was correlated reflex and a loss of balance [14].These features may bear with NPH score.They suggest that the basal ganglia may similarities to the dynamic disequilibrium seen in gait have an important role in the gait disorder of NPH. disturbance of NPH patients; however,whether gait pat- The locomotion pattern in NPH is characterized by terns between NPH and PSP share similar underlying reduced gait velocity, mostly due to a diminished stride pathophysiology remains to be determined by future length,reduced foot-to-floor clearance during the swing gait analyzing study. phase, and slow movement of the lower extremities. De- It is not clear how hydrocephalus may result in atro- tailed gait analysis in NPH patients has revealed a phy of the midbrain structures.There are reports of sec- prominent disturbance of dynamic equilibrium, which ondary parkinsonism caused by aqueductal stenosis or 0958_0963_Lee_JON_1791 08.08.2005 07:34 Uhr Seite 962

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secondary hydrocephalus, presumably by dysfunction midbrain after CSF drainage.Likewise,we did not inves- of the nigrostriatal dopaminergic system (and conse- tigate the correlation of the midbrain diameter and quent decrease in dopamine) induced by hydrocephalus equilibrium-related gait variables that are unresponsive [27] or by direct compression of the rostral midbrain by to CSF drainage, as was suggested by Stolze and col- the expanding third or fourth ventricles [3, 13, 40]. The leagues [33], because detailed analyses of gait patterns correlations between the diameters of the lateral and in all patients with NPF were not available. third ventricle and the midbrain diameter would sup- In summary, the present study demonstrates that port the possibility of a compressive effect of the ventri- midbrain atrophy is significantly associated with gait cles on the midbrain. disturbance in NPH. We cautiously postulate that the Some limitations of our study should be mentioned. brainstem-related posture center, including the mid- Since the study was designed retrospectively, it is possi- brain, may be the anatomical substrate for the disturb- ble that a selection bias was introduced. Also, we were ance of the balance system in NPH. not able to assess possible changes in the diameter of the

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