Abstract
Background and Purpose
Diffusion-weighted imaging can depict secondary signal change of the substantia nigra of patients with ipsilateral striatal infarction via a decrease in the apparent diffusion coefficient (ADC). Clinical predictors of this phenomenon remain unclear.
Methods
We assessed 98 stroke patients with acute ischemic lesions in the hemilateral basal ganglia, external capsule, or internal capsule. The ADC values of the bilateral substantia nigra obtained from a follow-up MRI, various clinical factors, and patients’ outcome were analyzed. Nineteen patients who underwent a follow-up MRI within 3 days were excluded from analysis because none of them demonstrated a significant ADC change of substantia nigra.
Results
Of 79 patients, 21 (26.6%) revealed a decreased ADC in the substantia nigra. Ischemic lesions in the globus pallidus (odds ratio 12.90) and the presence of emboligenic diseases (odds ratio 6.95) were independent predictors for an ADC decrease in the substantia nigra. The clinical outcome 3 months after stroke onset was not different between patients with an ADC decrease and patients without.
Conclusions
A reduction of ADC in the substantia nigra after acute striatal infarction was more frequently observed when the globus pallidus was affected or when the patient had emboligenic diseases, however, did not necessarily relate to the patient's clinical outcome.
Keywords: acute stroke, apparent diffusion coefficient, secondary degeneration, striatal infarction, substantia nigra
Secondary signal change (SSC) of the substantia nigra (SN) after ipsilateral striatal infarction, detected by MRI, is one of the most well-known remote effects after focal brain damage.1–4 Diffusion-weighted imaging is capable of depicting this SSC as a hyperintense signal with a decreased apparent diffusion coefficient (ADC) more sensitively and earlier than other techniques.5–8
SSC of the SN is not always observed in patients with striatal infarction, and clinical predictors for this phenomenon have not yet been resolved. In previous reports, some clinical factors were suspected to have a relationship with the SSC of the SN.7,8 However, there have been no large-scale studies performed capable of elucidating the relationship between these factors and the SSC of the SN by analyses, including multivariate analysis. Additionally, the prognosis of patients who presented with SSC of the SN is unclear.4
The purpose of this study is to investigate the clinical characteristics and outcome of acute stroke patients who reveal an ADC decrease of the SN.
Methods
We prospectively collected consecutive stroke patients with acute ischemic lesions in the hemilateral basal ganglia on diffusion- weighted imaging performed at admission and who underwent follow-up MRI within 3 weeks.7,8 The basal ganglia included cau-date head, putamen, globus pallidus, external capsule, and internal capsule. We excluded patients with any brainstem lesions or bilateral basal ganglia lesions. A total of 168 patients fulfilled the inclusion criteria, and 70 patients whose complete assessment by MRI was not obtained were excluded: pacemaker implantation (n=2), old lesions on the basal ganglia (n=7), no follow-up MRI (n=39), and a motion artifact or other technical issues (n=22). An informed consent was obtained from all of them or their family members.
We used a 1.5 T unit MRI system. In evaluation of secondary degeneration of the SN, we used an absolute ADC value on an ADC mapping image. A region of interest was manually drawn in the SN, at the level of the superior colliculus in all subjects (Figure).9 We defined the normal ADC range of the SN from analysis of images of control subjects. We calculated the ADC ratio of the SN (ADC contralateral to the symptom side/ADC ipsilateral to the symptom side) in each subject. When the ADC ratio is <−2 SD (<0.78), the patient was regarded as having a significant decrease of ADC of the SN.
Figure.
Diffusion-weighted imaging (DWI) of a 76-year-old female 6 days after onset (A, B). Apparent diffusion coefficient (ADC) map (C) and its schema (D) at the level of the mesencephalus. Hyperintense lesions are observed in the right basal ganglia, internal capsule, and subcortical white matter in the right cerebral hemisphere. The right substantia nigra demonstrates vague hyperintensity on DWI. When the region of interest is located at the center (dotted circle in D) of the bilateral wing-shaped region (grey-colored regions in D) and is divided into 9 segments in the midbrain, the ADC of the right side was 0.62×10–3 mm2/s and the left side was 0.89×10–3 mm2/s.
We preliminarily investigated the relationship between the time interval from the onset of stroke to the MRI and the change of the ADC of the SN. Of 98 patients, none of the 19 patients who underwent follow-up MRI within 3 days of onset demonstrated a significantly decreased ADC ratio of <0.78. Therefore, we decided to analyze the ADC of the SN on MRI performed 3 days from onset. In 4 patients who underwent MRI twice 3 days after onset, we used a lower ADC ratio.
We divided the patients into 2 groups: those with a decreased ADC of the SN and those without a decreased ADC. The clinical factors were compared between the 2 groups. Additionally, we investigated the patients’ outcome in each group: the ΔNIHSS (National Institutes of Health Stroke Scale [NIHSS] score day 10−NIHSS score on day 0), functional outcome on discharge, and 3 months after onset (by a mailed questionnaire).
The Mann–Whitney U test, the χ2 test, or Fisher exact test was used for univariate analysis. Then, we performed logistic regression analysis with the step-up procedure. P values <0.05 were considered significant.
Results
Of 79 patients, 21 (26.6%) showed a decreased ADC of the SN. On univariate analysis, the recanalization of the MCA, emboligenic diseases, globus pallidus lesions, and caudate nucleus lesions were most frequently observed in patients with an ADC decrease of the SN (Table 1). Based on logistic regression analysis, globus pallidus lesions and the presence of emboligenic diseases were independent predictors of an ADC decrease of the SN (Table 2). These results did not change after adjustment by NIHSS score on admission or ischemic lesion volume.
Table 1.
Clinical Characteristics in Patients With and Without an ADC Decrease of the Substantia Nigra
| ADC Decrease n=21 | Normal n=58 | P Value | |
|---|---|---|---|
| Age, y, median (IQR) | 78 (71–85) | 79 (74–83) | 0.427 |
| Male sex, n (%) | 11 (52) | 27 (47) | 0.647 |
| Hypertension, n (%) | 17 (81) | 48 (83) | 1.000* |
| Diabetes mellitus, n (%) | 2 (10) | 11 (19) | 0.496* |
| Hypercholesterolemia, n (%) | 4 (19) | 14 (24) | 0.767* |
| Current smoking, n (%) | 2 (10) | 5 (9) | 1.000* |
| IHD, n (%) | 4 (19) | 7 (12) | 0.429 |
| Previous CVD or TIA, n (%) | 6 (29) | 6 (10) | 0.073* |
| Interval between onset and follow-up MRI | 7 (5–9) | 7 (5–9) | 0.929 |
| NIHSS score on admission, median (IQR) | 17 (10–29) | 12 (6–21) | 0.055 |
| ADC, ipsilateral (χ10-3), mm2/s, median (IQR) | 0.61 (0.54–0.65) | 0.75 (0.72–0.82) | <0.001 |
| ADC, contralateral (χ10-3), mm2/s, median (IQR) | 0.89 (0.81–0.91) | 0.82 (0.77–0.88) | 0.038 |
| MCA recanalization, n (%) | 14 (67) | 14 (24) | <0.001 |
| MCA trunk occlusion on admission, n (%) | 17 (81) | 23 (40) | 0.001 |
| MCA trunk occlusion on follow-up, n (%) | 3 (14) | 9 (16) | 1.000* |
| Hemorrhagic change of the basal ganglia, n (%) Site of lesion | 10 (48) | 15 (26) | 0.066 |
| Putamen, n (%) | 20 (95) | 47 (81) | 0.166* |
| Globus pallidus, n (%) | 19 (90) | 24 (41) | <0.001 |
| Caudate nucleus | 12 (57) | 18 (31) | 0.035 |
| External capsule | 12 (57) | 35 (60) | 0.798 |
| Internal capsule, n (%) | 11 (52) | 25 (43) | 0.465 |
| Ischemic lesion volume, cm3, median (IQR) | 43.6 (20.7–102.9) | 19.6 (4.7–60.5) | 0.031 |
| Stroke subtype | 0.040 | ||
| Large artery atherosclerosis, n (%) | 2 (10) | 16 (28) | |
| Cardioembolism, n (%) | 15 (71) | 21 (36) | |
| Small vessel occlusion, n (%) | 0 | 7 (12) | |
| Other determined/undetermined pathogenesis, n (%) | 3 (14) | 13 (22) | |
| Transient ischemic attack, n (%) | 1 (5) | 1 (2) | |
| Presence of emboligenic diseases, n (%) | 18 (86) | 29 (50) | 0.004 |
| Extracranial carotid stenosis >50%, n | 2 | 2 | |
| Complicated lesions in aortic arch, n | 1 | 3 | |
| Atrial fibrillation, n | 17 | 15 | |
| Severe congestive heart failure, n | 0 | 2 | |
| Nonbacterial thromboendocarditis, n | 0 | 1 | |
| Patent foramen ovale, n | 2 | 0 | |
| Broad OMI, n | 0 | 2 |
ADC indicates apparent diffusion coefficient; CVD, cerebrovascular disease; IHD, ischemic heart disease; IQR, interquartile range; MCA, middle cerebral artery; NIHSS, National Institutes of Health Stroke Scale; OMI, old myocardial infarction; and TIA, transient ischemic attack. P values were assessed by Mann-Whitney U test, χ2 test, or
Fisher exact test.
Table 2.
Multivariate Analysis for Decreased ADC
| Odds Ratio | 95% CI | P Value | |
|---|---|---|---|
| Globus pallidus lesions | 12.90 | 2.91–92.61 | <0.001 |
| Presence of emboligenic diseases | 6.95 | 1.75–36.15 | 0.005 |
| MCA recanalization | 2.97 | 0.84–10.89 | 0.091 |
ADC indicates apparent diffusion coefficient; CI, confidence interval; MCA, middle cerebral artery.
No statistically significant difference was observed between median NIHSS score at day 10 in patients with an ADC decrease of the SN and in those without (15 versus 11; P=0.23). However, median ΔNIHSS scores indicated a preferable trend to patients with an ADC decrease of the SN (−3 versus −1; P=0.06). The modified Rankin Scale score (5 versus 5; P=0.49) and Barthel index (5 versus 20; P=0.23) on discharge, and the modified Rankin Scale score 3 months were not different between the 2 groups (5 versus 4; P=0.10).
Discussion
In this study, we provided 3 major findings about the ADC values of the SN after acute ipsilateral striatal infarction. First, globus pallidus lesions and the embolic mechanism have an independent relationship with an ADC decrease of the SN. Second, an ADC decrease of the SN begins 3 days after the index stroke. Third, an ADC decrease of the SN was not related to the patients’ clinical outcome.
The relationship between the globus pallidus ischemic lesions and the ADC decrease of the SN was an intriguing finding. Putaminal lesions did not reveal an independent relationship, unlike a previous report using T2-weighted imaging.2 In human beings, unlike in rats,10 the GABAergic inhibitory pathway from the neostriatum, including the caudate head and putamen, mainly projects into the pars reticulata, whereas the pathway from the paleostriatum, including the globus pallidus, projects into the pars compacta.11 Therefore, the relationship between the globus pallidus lesions and an ADC decrease of the SN in our study was consistent with previous reports that the neuropatho-logic changes in the SN mainly occurs in the pars compacta.1,2,12
The presence of emboligenic diseases was related to an ADC decrease of the SN in the study, which confirmed the validity of our hypothesis that sudden, destructive damage to the striatum may be related to SSC of the SN.7,8
In this study, we could not find any patients who presented a significant ADC decrease of SN within 3 days after stroke onset. Because the MRI results were not assessed on any successive days in this observational study, we cannot conclude that an ADC decrease of the SN begins approximately at 4 days.
An ADC decrease of the SN was not related to the short-term and long-term clinical outcomes. Because striatal lesions do not cause any severe neurologic deficits, clinical symptoms of the participants were presumably attributed to cortical or other subcortical lesions, including those of the pyramidal tract.
Footnotes
Disclosures
None.
References
- 1.Tamura A, Kirino T, Sano K, Takagi K, Oka H. Atrophy of the ipsilateral substantia nigra following middle cerebral artery occlusion in the rat. Brain Res. 1990;510:154–157. doi: 10.1016/0006-8993(90)90744-v. [DOI] [PubMed] [Google Scholar]
- 2.Nakane M, Teraoka A, Asato R, Tamura A. Degeneration of the ipsilateral substantia nigra following cerebral infarction in the striatum. Stroke. 1992;23:328–332. doi: 10.1161/01.str.23.3.328. [DOI] [PubMed] [Google Scholar]
- 3.Ogawa T, Okudera T, Inugami A, Noguchi K, Kado H, Yoshida Y, et al. Degeneration of the ipsilateral substantia nigra after striatal infarction: evaluation with MR imaging. Radiology. 1997;204:847–851. doi: 10.1148/radiology.204.3.9280270. [DOI] [PubMed] [Google Scholar]
- 4.Zhang J, Zhang Y, Xing S, Liang Z, Zeng J. Secondary neurodegeneration in remote regions after focal cerebral infarction: a new target for stroke management? Stroke. 2012;43:1700–1705. doi: 10.1161/STROKEAHA.111.632448. [DOI] [PubMed] [Google Scholar]
- 5.Kinoshita T, Moritani T, Shrier DA, Wang HZ, Hiwatashi A, Numaguchi Y, et al. Secondary degeneration of the substantia nigra and corticospinal tract after hemorrhagic middle cerebral artery infarction: diffusion-weighted MR findings. Magn Reson Med Sci. 2002;1:175–178. doi: 10.2463/mrms.1.175. [DOI] [PubMed] [Google Scholar]
- 6.Moritani T, Smoker WR, Sato Y, Numaguchi Y, Westesson PL. Diffusion-weighted imaging of acute excitotoxic brain injury. AJNR. Am J Neuroradiol. 2005;26:216–228. [PMC free article] [PubMed] [Google Scholar]
- 7.Nakajima M, Hirano T, Terasaki T, Uchino M. Signal change of the substantia nigra on diffusion-weighted imaging following striatal infarction. Intern Med. 2010;49:65–68. doi: 10.2169/internalmedicine.49.2694. [DOI] [PubMed] [Google Scholar]
- 8.Ohe Y, Uchino A, Horiuchi Y, Maruyama H, Deguchi I, Fukuoka T, et al. Magnetic resonance imaging investigation of secondary degeneration of the mesencephalic substantia nigra after cerebral infarction. J Stroke Cerebrovasc Dis. doi: 10.1016/j.jstrokecerebrovasdis.2011.06.006. Published ahead of print July 22, 2011. [DOI] [PubMed] [Google Scholar]
- 9.Chan LL, Rumpel H, Yap K, Lee E, Loo HV, Ho GL, Fook-Chong S, Yuen Y, Tan EK. Case control study of diffusion tensor imaging in Parkinson's disease. J Neurol Neurosurg Psychiatr. 2007;78:1383–1386. doi: 10.1136/jnnp.2007.121525. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Zhao F, Kuroiwa T, Miyasaka N, Nagaoka T, Nakane M, Tamura A, et al. Characteristic changes in T(2)-value, apparent diffusion coefficient, and ultrastructure of substantia nigra evolving exofocal postischemic neuronal death in rats. Brain Res. 2001;895:238–244. doi: 10.1016/s0006-8993(00)03281-9. [DOI] [PubMed] [Google Scholar]
- 11.Carpenter MB, Sutin J. Human Neuroanatomy. Williams & Willkins Co; Baltimore, MD: 1983. pp. 587–599. [Google Scholar]
- 12.Oo TF, Henchcliffe C, Burke RE. Apoptosis in substantia nigra following developmental hypoxic-ischemic injury. Neuroscience. 1995;69:893–901. doi: 10.1016/0306-4522(95)00282-n. [DOI] [PubMed] [Google Scholar]