A case of mania due to cryptococcal meningitis, successfully treated with adjunctive olanzapine, in a patient with acquired immunodeficiency syndrome

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General Hospital Psychiatry 33 (2011) 301.e3 – 301.e6

Case Report

A case of mania due to cryptococcal meningitis, successfully treated with adjunctive olanzapine, in a patient with acquired immunodeficiency syndrome David R. Spiegel, M.D.⁎, Christopher E. Bayne, M.D., Lyndy Wilcox, M.D., Margarita Somova, M.D. Department of Psychiatry and Behavioral Sciences, Eastern Virginia Medical School, Norfolk, VA 23507, USA Received 5 August 2010; accepted 5 November 2010

Abstract We report on the case of a patient with acquired immune deficiency syndrome- and Cryptococcus neoformans meningitis-related mania in which olanzapine was successfully used adjunctively and transiently to antifungal therapy. © 2011 Elsevier Inc. All rights reserved. Keywords: Olanzapine; Mania; Acquired immunodeficiency syndrome; Meningitis

1. Introduction Cryptococcus neoformans meningitis (CNM) has emerged as a leading cause of infectious morbidity and mortality in patients with acquired immune deficiency syndrome (AIDS). Among human immunodeficiency virus (HIV)-seropositive subjects, CNM is the second most common cause of opportunistic neuroinfection [1]. A retrospective analysis of 142 patients fulfilling the diagnostic criteria for CNM and severe immune suppression (CD4, b100 cells/mm3) identified neuropsychiatric manifestations of the illness. Manic episodes occurred in 33% of these patients [2]. (Mania due to AIDS is discussed elsewhere [3–6].) It has been suggested that the intravascular C. neoformans pathogen crosses into brain parenchyma by breaching the blood–brain barrier through weaknesses in the Virchow– Robin spaces. Furthermore, intracerebral C. neoformans distribution is global, with a relatively higher distribution in the region of the caudate and hippocampus and possibly

⁎ Corresponding author. Department of Psychiatry and Behavioral Sciences, Eastern Virginia Medical School, 825 Fairfax Ave., Norfolk, VA 23507, USA. Tel.: +1 757 446 5888. E-mail address: [email protected] (D.R. Spiegel). 0163-8343/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.genhosppsych.2010.11.004

delineating a structural explanation for the development of neuropsychiatric symptoms in CNM [7]. We report on the case of a patient with AIDS- and CNMrelated mania in which psychiatric treatment goals were to treat acute mania for efficient integration of fungemia resolution and initiation of highly active antiretroviral therapy (HAART).

2. Case report Our patient is a 53-year-old man who presented to the emergency department complaining of conjunctiva discharge. His medical history is remarkable for HIV-1. Unfortunately, the patient is nonadherent to HAART, a finding in up to 45% of North American patients with HIV-1 [8]. His workup revealed a CD4 count of 3 cells/mm3 (1.2 %) with pancytopenia and an HIV-1 viral load of 226,841 copies/ml; computed topography of the patient's head showed diffuse cortical atrophy, and blood and cerebrospinal fluid cultures grew C. neoformans. His neurological examination and the remainder of his substance abuse workup, including blood alcohol level and urine drug screen, were unremarkable on admission. The patient had no premorbid psychiatric or substance abuse history, and as best we were able to determine, he was able to perform all

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activities of daily living without assistance. The medicine service began 14 days of azole treatment for probable CNM, and HAART was withheld pending resolution of meningitis. For several days following hospital admission, our patient became “increasingly agitated and restless”; he was yelling at the staff and refusing various medical workups and treatments. On Hospital Day 9, he refused all medical treatment and developed acute renal failure. We were asked to assess his decision-making capacity. Upon interview, our patient refused to elaborate on personal or familial psychiatric history because, “he is wellknown throughout the land.” However, on chart review, there is no reported personal or familial psychiatric history. The patient admitted to refusing treatment because “important people do not need treatment,” and he has a Young Mania Rating Scale (YMRS) [9] score of 30 (Irritability=6, Speech=6, Content=6, Increased Motor Activity–Energy=4, Language–Thought Disorder=2, Disruptive–Aggressive Behavior=2, Insight=2, Appearance=1, Sleep=1, Elevated Mood=0, Sexual Interest=0), with symptoms present for about 12 days. Cognitively, he was oriented ×3, without waxing or waning of alertness and with a Mini Mental Status Examination (MMSE) score of 26 [10]. On the MMSE, the patient's short-term memory was intact, but he lost the last two points on attention and concentration. Although we could not effectively rule out dementia secondary to AIDS, other than his irritability and inadequacies on the attention and concentration section of the MMSE, the patient displayed no signs or symptoms of HIV-associated dementia, including memory loss, mental slowing, reading and comprehension difficulties and apathy [11]. Thus, olanzapine 10 mg orally bid was started; it was increased to 10 mg tid after 3 days with no improvement in his YMRS score, although he scored a zero on both the Simpson Angus Scale (SAS) [12] and the Barnes Akathisia Scale (BARS) [13]. After 3 more days, our patient's YMRS score decreased to 16 and his BARS and SAS scores remained unremarkable; he agreed to therapy for CNM and to begin HAART on discharge. As our patient continued treatment for CNM, we were able to decrease olanzapine to 5 mg bid after 7 days (YMRS score of 5, SAS and BARS scores of 0). Ultimately, after he completed treatment, we discontinued olanzapine, as his YMRS score was 1. On discharge, treatment with HAART was initiated.

3. Discussion Priority was placed on treating the patient's meningitis first before restarting him on combined antiretroviral treatment for HIV; however, once an AIDS patient not taking HAART develops CNM, long-term survival requires HAART, but timing of initiation remains controversial. Early introduction may potentiate immune reconstitution inflammatory syndrome, but delayed therapy in the developing world is associated with significant mortality [14].

Others contend that it is not necessarily this timing of HAART initiation but organism load that is associated with the development of immune reconstitution inflammatory syndrome [15]. Further studies regarding timing of initiating HAART in AIDS patients with CNM are essential. The literature cites several cases of CNM-induced manic disorders [16–18]. Symptoms of mania that have been identified in CNM include elated and irritable mood, a decreased need for sleep, pressured speech, increased libido, racing thoughts or flights of ideas, clear evidence of distractibility, reckless behavior (excessive pleasurable activities) without regard for consequences, grandiosity, severe thought disturbances, grandiose and paranoid delusions and auditory and visual hallucinations [2,18]. The psychiatric manifestations of CNM have been reported to usually respond to psychotropic drugs even before antifungal treatment has commenced; therefore, a favorable response to treatment does not necessarily exclude the existence of an underlying infection. Weeks of delay in diagnosis are common, and establishing the diagnosis may require repeated LPs. Although the psychiatric symptoms usually remit with treatment, the underlying infection can run a relapsing and lethal course [18]. In one case series, about 25% of women and 20% of men with CNM presented with mania, second only to delirium as the most common neuropsychiatric manifestation of cryptococcal meningitis [2]. It has been postulated that these symptoms may be due to meningeal cryptococcosis [19]. With limited evidence base for the treatment of mania due to CNM (or AIDS) available, our decision to initiate treatment with olanzapine was based on limitations of traditional mood stabilizers in HIV-infected patients (see Table 1) [3,20–31] and our patient's unique medical conditions. Atypical antipsychotics (AAPs) may present another viable treatment option [3]. As HIV induces neuronal damage at the basal ganglia [32], treating HIV-infected patients with dopamine receptor-2 antagonists increases the risk of extrapyramidal symptoms (EPSs). In prior case reports and series, the AAPs risperidone, ziprasidone and olanzapine have been safely used to effectively treat MAIDS [3,33,34]; however, in a head-to-head comparison in patients with schizophrenia, both risperidone and ziprasidone had a greater risk of developing EPSs than olanzapine [35]. Additionally, save clozaril, similar studies reported increased efficacy with olanzapine (vs. other AAPs) [36]. Thus, we chose to treat our patient with olanzapine, which, while not devoid of EPS risks, did not develop in our patient. Nonetheless, as olanzapine is known to cause significant metabolic side effects, several reports have shown HAART to contribute to worsening metabolic parameters (such as weight gain) as well [37,38]. How long-term olanzapine would interact with HAART in terms of metabolic complications is currently unknown; however, olanzapine's effect on metabolic parameters may be less of a concern since new, “lipid-friendly” antiretrovirals have been shown to contribute to increased levels of high-density lipoprotein

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Table 1 Limitations of traditional mood stabilizers in AIDS patients Medication

Potential enhancement of HIV replication

Blood dyscrasia

Drug–drug interactions (specifically, HAART)

Others

Lithium carbonate

−

−

−

Valproic acid

+

+, thrombocytopenia

Lopinavir/ritonavir may lower level

Carbamazepine

+

+, aplastic anemia; agranulocytosis

May induce level of certain antiretrovirals

Gastrointestinal pain, tremor, polyuria, nocturnal urination, weight gain, edema, exacerbation of psoriasis May inhibit thyroid hormone release, and the prevalence of hypothyroidism is increased; statistically significant negative effect on memory, vigilance and reaction time With long-term therapy: nephrogenic diabetes insipidus and progressive renal insufficiency; possible persistent hyperparathyroidism and hypercalcemia. Gastrointestinal disturbances, tremor and body weight gain Other notable adverse effects include encephalopathy symptoms (at times associated with hyperammonemia), pancreatitis, liver toxicity (with an overall incidence of 1 in 20,000) and teratogenicity. Some studies have also suggested manifestations of polycystic ovary syndrome. Somnolence, dizziness, headache. Rash and leukopenia (∼10% of patients), albeit benign and transient in most cases Rare serious adverse effects: Stevens–Johnson syndrome and toxic epidermal necrolysis; changes in lipid profiles have been noted, but hyperglycemia and clinically significant weight gain are uncommon.

Sources: Refs. [1–5] and [22–32]. (−) None known or reported. (+) Reported, either in vivo or in vitro.

and overall favorable lipid profiles [39,40]. We were able to discontinue olanzapine in our patient, and at 1-month follow-up and with compliance to HAART, our patient had not had a relapse of manic phenomenology. Several limitations in our case report include that while olanzapine can treat mania, our patient was also being treated with fluconazole for CNM, and the resolution of the latter could also have attenuated our patient's symptoms of mania. Additionally, we could not definitively procure that our patient's phenomenology was due to cryptococcal meningitis, AIDS or both. Thus, while we advocate for double-blind studies using AAPs for treatment of HIV- and opportunistic infection-induced mania, this would be adjunctive to antimicrobial treatment.

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