In 2018, more than 14% of the 23 million people in Taiwan were ≥ 65 years of age, and more people were aged ≥65 years than < 15 years, meaning that Taiwan has become an aged society [
14]. In this study, 38.4% (38/99) of the adult patients with CM were elderly (≥ 65 years), indicating that this age group were more vulnerable to CM. This epidemiologic significance has not been reported in other Asian countries with an aged society or Western countries such as the United States [
15‐
19].
In the current study, headache, fever and altered consciousness were the main clinical presentations of the 38 elderly patients with CM. These clinical presentations were similar to those of the non-elderly adults with CM (Table
1), and to both elderly and non-elderly adults with acute bacterial meningitis [
5,
20]. Therefore, it is difficult to differentiate the exact type of meningitis if only the clinical presentations are considered. To avoid a missed or delayed diagnosis of CM in the elderly, keeping this specific infectious syndrome in mind and conducting appropriate studies for CNS infections are needed, especially in elderly patients with altered consciousness and/or headache and/or fever.
In this study, gender, altered consciousness and recent cerebral infarction were significantly different between the elderly and non-elderly groups. Although the sample size was not large and few variables were considered for the multivariate logistic regression analysis, based on the stepwise procedures, only three variables were selected as important predictive variables. Therefore, the maximum likelihood estimates of the coefficients were valid in the analysis.
In Taiwan, the retirement age is 65 years [
21]. Previous studies have reported that more males are affected by cryptococcosis than females, and this disparity is seen in both HIV-positive and HIV-negative patients with cryptococcal infections [
22]. We also reported the same male predominance in CM patients in our previous study [
8], and a study from China also reported similar findings [
15]. However, in the present study, there was a significant difference in gender between the elderly and non-elderly groups, with more females in the elderly group (57.9%, 22/38) and more males in the non-elderly group (78.7%, 48/61). Although a sex difference in the genetic architecture of susceptibility to
C. neoformans infection was reported in an animal study [
23], this difference has not been reported in clinical studies of elderly patients with CM. Altered consciousness as the initial presentation in CM is known to be an important prognostic factor for this serious infectious disease [
11]. In the current study, significantly more of the elderly group had altered consciousness as the initial presentation compared to the non-elderly group (
p < 0.001) and the patients with CM overall in our previous study [
8]. Cerebral infarction is an important but frequently ignored finding in CM [
8,
24], and it is also a significant prognostic factor of this serious infectious disease. In this study, the presence of cerebral infarction was a significant clinical feature in the elderly group. With the increasing size of the elderly population and evolving neuroimaging technology, silent cerebral infarction has garnered a lot of attention [
25].The prevalence of cerebral infarction in the elderly population is known to increase steadily with age, and well-known cardiovascular risk factors and the metabolic syndrome are also important risk factors for the development of cerebral infarction in the elderly [
25]. Our previous study revealed that old age was a significant factor for the development of cerebral infarction in CM patients [
26]. In addition to age, many other factors may also play a role in the disturbance of cerebral hemodynamics and the subsequent development of cerebral infarction in patients with CM [
24,
26], in which obvious basal meningeal enhancement as shown in brain MRI may play a significant role [
8,
24,
26]. Increased basal meningeal enhancement is an important finding in brain MRI and confirms that inflammatory reactions are most intense in the basal meninges of patients with CM [
8,
24,
26], and that local lenticulostriate and thalamoperforating arterioles are affected by such inflammatory processes with the subsequent development of cerebral infarction.
Among the 38 elderly patients with CM, 14 died during the therapeutic course, for a high mortality rate of 36.8%. As shown in Table
2, the presence of cryptococcemia was a significant prognostic factor for this specific group of patients, and it was present in 50% (7/14) of the non-survivors and 8.3% (2/24) of the survivors. The presence of cryptococcemia is a serious infectious condition, and patients with cryptococcemia have been reported to have a grave prognosis [
27‐
29]. Therefore, CM patients with concomitant
C. neoformans bloodstream infections should receive more aggressive and adequate treatment [
28,
29].