The clinical presentations of CM are variable [1, 19] and the pathophysiology of its neurologic sequelae is also complex [1, 19]. Although many factors including positive cryptococcal antigenemia detection may influence the appearance and presentations of clinical CM [20, 21], in patients with HIV-negative CM, little is known about the duration between the contact with C. neoformans and the occurrence of clinical symptoms as well as the duration between the initial onset of symptoms and the first consultation with a physician. In this study, all the seven CM patients with ASCI had altered consciousness and other focal neurologic signs for a varying period of time (1 week-2 months) before they came to our hospital for treatment. As shown in this study, the initial presentations of ASCI may be masked by or mixed with other clinical features, but they were detected by an early MRI study. CT study can show the various appearance of intracranial cryptococcosis , but the superiority of cranial MRI study to CT study in detecting the intracranial lesions of CM has been well demonstrated in the study of Charlier et al. . Therefore, for thorough clinical evaluation, early MRI study using specific imaging sequences such as DWI and ADC maps should be mandatory for early detection of ASCI in HIV-negative CM patients.
It has been postulated that CM rarely results in cerebral infarction when compared with other fungal diseases [24, 25] and that cerebral infarction is common in HIV-infected patients with CM [26, 27], but these assumptions were not based on a thorough MRI study. Qureshi et al.  demonstrated an increased likelihood of cerebral infarction in HIV-infected patients compared with HIV-seronegative young individuals. Tjia et al.  found a 4% incidence of cerebral infarction secondary to CM in HIV-seronegative patients. In this MRI-based study, ASCI was found in 18.9% (7/37) of the HIV-negative CM patients.
We examined the risks factors of ASCI in HIV-negative CM patients, and the significant findings were as follows: First, altered consciousness on admission and DM and previous stroke as the underlying conditions are risk factors for ASCI. Second, a higher mean age at infection was a risk factor associated with cerebral infarction in HIV-negative CM patients. Therefore, in CM patients with the above-mentioned significant factors, the clinician should pay attention to the high possibility of ASIC occurrence in this group of patients.
With serial transcranial color-coded sonography (TCCS) and magnetic resonance angiography (MRA) studies, cerebral hemodynamic change was found to be last longer in CM than in acute bacterial meningitis [6, 29], but a mismatch of the findings between TCCS and MRA studies in CM were also demonstrated . Cerebrovascular complications are reported to be more common in chronic meningitis than in promptly treated acute symptomatic bacterial infections [29, 30]. In the seven cases of this study, MRI detected ASCI within 1 week to 2 months of the development of clinical symptoms, and ASCI can recur during the therapeutic course, as shown in Case 5. This finding regarding the timing of the onset of ASCI is consistent with those reported in the case of chronic meningitis [12, 31, 32], which indicate that cerebral infarction can occur in both the acute and late stages during treatment for chronic meningitis.
There are several types of CM-related cerebrovascular events reported in the literature [8–12, 25, 33]. This study revealed that multiple cerebral infarctions were the most common type (86%; 6/7; Cases 1, 2, and 4-7)), and single infarction accounted for only 14% (1/7; Case 3). With regard to the distribution of the cerebral infarctions, both anterior and posterior cerebrovascular territories were involved in most patients. All the infarctions were lacunar, and no large cerebral infarction was noted. Hemorrhagic transformation was noted in only one patient (Case 2). In chronic meningitis, the inflammatory reaction is most intense in the basal meninges [6, 12, 34]. Because of this, basal exudates are usually most severe at the circle of Willis, and most cerebral infarcts are located in the territory of middle cerebral artery (MCA), particularly in the territories of the medial lenticulostriate and thalamoperforating arteries. In one murine model study of CM conducted by Charlier et al. , they showed that the primary event leading to CM was the parenchyma invasion after crossing the blood-brain-barrier at the cortical capillaries level surrounded by the Virchow-Robin space which may explain the high occurrence of brain lesions including ischemic events in this territory. However, actually, the stem and/or cortical branches of the MCA in the sylvian fissure, the supraclinoid portion of the internal carotid artery, and the vertebrobasilar system may also be involved [36–38]. This pathophysiological characteristic may explain why in our seven CM patients, ASCI was widely distributed, and almost all cerebrovascular territories were involved. Brainstem and/or cerebellum involvement were noted in 57% (4/7) of the HIV-negative CM adults with ASCI; this relatively high incidence of posterior fossa involvement in previously reported studies [8, 9, 12, 13] were not MRI-based study. MRA for our seven CM cases showed varying degrees of arterial stenosis. Many mechanisms have been proposed for the cerebral vasculopathy in CM, including strangulation of vessels at the skull base, vasculitis, spasm, contraction, and thrombotic occlusion [6, 9, 39].
The therapeutic results of these seven patients showed a mortality rate of 43% (3/7), and all the survivors had serious neurologic deficits. This result is consistent with the previous belief that CM is a serious infectious disease of the CNS [1–3]. The CM patients with ASCI had a significant incidence of altered consciousness, as shown in Table 2, at the early stage of CM and had a poor prognosis of statistical significance when compared with those CM patients without ASCI. The prognostic influence of cerebral infarction on patients with chronic meningitis was also mentioned before .