CRYPTOCOCCAL meningitis in a HIV negative newly diagnosed diabetic patient: a CASE report

Cryptococcus neoformans is an opportunistic fungus that causes infection of the central nervous system in those who are immunocompromised, particularly in human immunodeficiency virus (HIV) patients [1]. It infrequently infects HIV-negative persons such as post-organ transplant patients and those with diabetes mellitus, liver cirrhosis and alcoholism [1]. Inadequate glucose control in diabetic patients increases their risk to infections due to numerous factors especially the glucose-rich blood which is media for micro-organism growth [2‐4]. Remarkably, diabetic patients mount dramatic immune responses to cryptococcus that are paradoxical to their immunosuppressive state. Studies have shown that optimal control of blood sugar levels in diabetic patients in Sub-Saharan Africa is very low [5‐7]. This case report emphasizes the need to recognize cryptococcus as a possible cause of meningitis in non-HIV patients in Sub-Saharan Africa and to highlight the possibility of grave outcomes due to the paradoxical immune response in diabetic patients with cryptococcal meningitis. The case report also highlights the need for widespread availability of amphotericin-B and flucytosine in hospitals in Sub-Saharan Africa.

A 27 year old African lady, from Bungoma County in Western Kenya, was admitted with generalized tonic clonic seizures lasting 5 to 10 min. This was associated with loss of consciousness for 10–20 min and left sided hemiparesis that lasted nearly 30 min after the convulsion. These symptoms had lasted one day but had been preceded by severe frontal headache radiating to the occiput and neck, chills, and photophobia for three days. Her past medical history was significant for peptic ulcer disease and allergic rhino-sinusitis for which she uses omeprazole, antacid and celestamine intermittently. Social history is notable for a diabetic twin sister who had been on insulin. The twin sister had died of pneumonia three days to the patient’s admission. The patient’s mother died ten years ago due to complications associated with diabetes. She is separated from her husband but she stays with her six year old daughter. The patient runs a small pharmacy business. She had travelled with her twin sister to a funeral before they fell sick.

Cryptococcus neoformans is an opportunistic fungus that causes infection of the central nervous system in those who are immunocompromised, particularly in human immunodeficiency virus (HIV) patients [1]. It is rarely reported as a cause of meningitis in HIV seronegative patients in Sub-Saharan Africa. However, it may infect persons with other immunosuppressed systems like patients on chronic glucocorticoid use, malignancy, sarcoidosis and liver failure [1]. Sub-Saharan Africa is experiencing an increasing prevalence of diabetes [2]. Of note is that low levels of adequate glucose control are achieved in diabetic patients who are on any form of treatment [3, 4]. This is bound to increase the occurrence of cryptococcal meningitis in non HIV non transplant patients, who are predominantly diabetic patients.

C. neoformans is acquired through inhalation. From the respiratory tract it causes disseminated disease with a propensity for the central nervous system (neourotopism). Sometimes it may spread to the bone, prostate, skin, eyes and liver [1, 8]. Cryptococcal meningitis can present as fever, malaise, headache, vomiting, meningeal signs, seizures and cranial nerve palsies [8, 9]. These features tend to be sub-acute with the headache evolving over 2–4 weeks [10].

Diabetic patients with poorly controlled blood sugars are more prone to infections since the glucose-rich blood serves as an excellent media for growth. Cryptococcal infections in these patients are severe. Hyperglycemia causes impaired granulocyte chemotaxis, phagocytosis and deficient cell-mediated immunity, which is the most important host response to cryptococcal infection. Elevated serum levels of TNF-α and interleukin-6 in patients with diabetes let them mount an exaggerated immune response to C. neoformans [5‐7]. This milieu is a recipe for infections to lead to fatal outcomes as reported by Kushawaha and colleagues in their case report [1].

This lady was on the alternative regimen for treating cryptococcal meningitis in adults [11]. In the induction phase, she was given fluconazole 1200 mg od for two weeks. This was followed by 800 mg of fluconazole for the consolidation phase of 8 weeks and 400 mg for the maintenance phase. CSF sterilization was confirmed in the fourth week and the patient has remained asymptomatic. This is in contrast to the recommended combination of amphotericin B and flucytosine for the induction phase that provides greater fungicidal activity, early CSF sterilization, lower rates of treatment failure and lower mortality [12‐15].

Due to the exaggerated immune response, some scholars offer that anti-inflammatory medication like corticosteroids may have an adjunctive role in the management of cryptococcal meningitis in diabetic patients [1, 16]. Lack of a CT scan, and inability to estimate serum cryptococcal antigen or to do a CSF culture limited the work up of this patient.

In conclusion, this case demonstrates that with the rising prevalence of diabetes in Sub-Saharan Africa, just like in China, cryptococcal meningitis should be considered in the differential diagnosis for diabetic patients presenting with chronic headache accompanied with fever and neurologic deficits [17]. It is important to note that presentations may be dramatic and the outcomes grave due to the paradoxically exaggerated immune response to C. neoformans [18]. The response to fluconazole was satisfactory in this patient. However, effort should be made to avail the more effective combination of amphotericin B and flucytosine in resource poor setting. Modalities like laboratory services to monitor any toxicities should also be availed. Otherwise researchers should endeavor to come up with cheaper, effective but less toxic formulations. A co-positive state with malarial parasites may not preclude the diagnosis, and treatment thereof, of cryptococcal meningitis especially in a malaria-endemic zone. A high index of suspicion may be extremely rewarding in such a presentation.