|Year : 2014 | Volume
| Issue : 6 | Page : 267-271
Human immunodeficiency virus-associated mania and mild neurocognitive disorder
Shang-Lun Lin1, Chi-Hung Lin1, Wei-Tsung Kao1, Jen-Lin Chang1, Dong-Sheng Tzeng2
1 Department of Psychiatry, Kaohsiung Armed Forces General Hospital, Taiwan, China
2 Department of Psychiatry, Kaohsiung Armed Forces General Hospital; Faculty in Hyperbaric and Undersea Institute, National Defence Medical Center; School of Nursing, Fooyin University, Kaohsiung, Taiwan, China
|Date of Submission||17-Mar-2014|
|Date of Decision||15-Jul-2014|
|Date of Acceptance||15-Aug-2014|
|Date of Web Publication||19-Dec-2014|
Dr. Dong-Sheng Tzeng
Department Psychiatry, Kaohsiung Armed Forces General Hospital, No. 2, Chung Cheng 1st Road, Kaohsiung 802, Taiwan
Source of Support: None, Conflict of Interest: None
In the present work, we report a case of Taiwanese male who developed flu-like seroconversion illness initially. Then early-onset human immunodeficiency virus-related mania was found 4 weeks later. In the case, sepsis-induced delirium complicated the treatment course. Quetiapine and topiramate were used for short-term stabilization and long-term treatment. Mild neurocognitive disorder, the hint of worse prognosis, was proved by intact psycho-cognitive evaluation.
Keywords: Acquired immune deficiency syndrome, human immunodeficiency virus, human immunodeficiency virus-associated mild neurocognitive disorder, mania, quetiapine, topiramate
|How to cite this article:|
Lin SL, Lin CH, Kao WT, Chang JL, Tzeng DS. Human immunodeficiency virus-associated mania and mild neurocognitive disorder. J Med Sci 2014;34:267-71
| Introduction|| |
The incidence of mania in human immunodeficiency virus (HIV)-infected patients has been reported to be higher than that of the general population. About 1-2% of patients with early HIV infection experienced manic episodes. And coincident mild neurocognitive disorder (MND)  often predict inferior prognosis. The rate of mania increases as four folds after the onset of acquired immune deficiency syndrome (AIDS). 
| Case Report|| |
Mr. A is a 33-year-old single man with no psychiatric history or substance abuse. He was initially admitted with 3 days history of febrile (temperature of 38°C), generalized erythematous papules, arthralgia, and malaise in April, 2008. His full blood count showed hemoglobin: 14.6 g/dL, hematocrit: 42%, white blood cells: 10.9 × 10 9 /L (58% PMN, 30% LYMP, 9% M); platelet count: 86 × 10 9 /L. A clinical diagnosis of dengue fever was made. He was given fluid support, and his fever subsided 3 days later. Seven days later, the fever returned. Physical examination revealed generalized maculopapular rash. He did not have a recent history of traveling or jungle trekking.
With further inquiry, he admitted to have had unprotected sexual contact with a male partner about 2 months before the onset of his symptoms. At this time, his AxSYM HIV antibody screening test was positive (signal-to-cut-off ratio 9.1). Then the Western blot analysis confirmed the HIV infection (presence of antibodies against gp41, p17, and p31). In view of his recent unprotected sexual exposure and his laboratory results, the diagnosis of acute HIV seroconversion illness was made. The CD4 cell count was 439 cells/mm 3 , and his HIV-1 viral load was >100,000 copies/ml.
The patient developed manic symptoms inclusive of an elevated mood, psychomotor agitation, decreased need for sleep, irritability, grandiose delusion, pressured speech on June 15, 2008. These symptoms persisted for 7 days. The patient was, therefore, enforced to take sick leave. One week later, the manic episode spontaneously remitted without any treatment. These symptoms improved without treatment after 1 week. His manic symptoms recurred in June 2011 for lack of any treatment. In addition to previous symptoms, he had disorientation, flight of idea, buying spress, undressing in public, fever and mild dry cough. Then he presented delirium 1 day later. The laboratory data showed a CD4 lymphocyte count of 38 cells/mm 3 , HIV-1 viral load of 161,000 copies/ml. The patient developed opportunistic infections including oral candidiasis, and anal herpes, which were observed in physical assessment. Pneumocystis carnii pneumonia was highly suspected [Figure 1] thought the lung tissue and sputum for polymerase chain reaction were not available. The brain computed tomography revealed no evidence of abscess or tumors. Multiple antibiotics (sulfamethoxazole, trimethoprim, acyclovir, and ceftazidime) cured his multiple infections. Initially, we choosed quetiapine for his manic symptoms. We did this because the patient had poor adherence to drug level monitoring. Taken into account that mania-associated violence tendency frightens health care workers, it was urgent to rapidly control his mania. Initially, we choosed quetiapine for his manic symptoms. The manic symtpoms became much resolved after starting adjunctive of topiramate therapy 3 days later. The manic symptoms responded well to quetiapine (gradually increased to 1000 mg/day within 7 days) and topiramate (300 mg/day). No extrapyramidal symptoms or side effects were found. On hospital day 47 the patient's insight, manic symptoms, opportunistic infection revealed much improvement and highly active antiretroviral therapy (HAART) was triggered.
|Figure 1: High-resolution chest computed tomography (arranged for refractory cough and normal chest radiograph): Diffuse and geographic ground-glass opacities (thin arrow) with interstitial septal thickening (thick arrow) in both peri-hilar and lower lobes|
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The patient went back to work after his physical illness and manic symptoms fully remitted. However, he was criticized by his company for inefficiency. HAART started immediately after his mania partially remitted (Young Mania Rating Scale [YMRS] = 9) and his drug adherence improved. The temporal relationship between HIV-1 activity and the mania severity (YMRS) was illustrated in [Figure 2].
|Figure 2: CD4 count: cells/mm3, Virus load: copies/mm3, OPD: out-patient department. It demonstrated that each mania episode accompanied with the surged human immunodeficiency virus load, vice versa. The patient experienced two manic episodes which Young Mania Rating Scale were 31 (short, thin arrow) and 46 (long thin arrow)|
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The patient went back to work after his physical illness and manic symptoms fully rem`itted. However, he was criticized by his company for inefficiency. We, therefore, arranged neuropsychological and occupational assessment for him in September, 2011. The comprehensive occupational therapy evaluation (COTE) scale was 28 and the Chu's Hand Dexterity Test (CHDT) revealed moderate decline in daily functioning. The patient had impairment in at least two cognitive areas. For one, the Wechsler Adult Intelligence Scale-III showed borderline intelligence (inferior to previous full intelligence 102 at age of 20). Second, significantly defective results in Wisconsin Card Sorting Test (WCST) were observed. The patient was, therefore, diagnosed of HIV-associated MND.  During March 2012, the patient's WCST performance remained poor but his COTE scale was decreased to 13. And his CHDT revealed approximately normal function.
| Discussion|| |
This case of HIV-associated mania illustrates three important implications. First, reduced HIV-associated morbidity and mortality led to a reduced index of suspicion and likely, missed diagnosis, especially in seroconversion illness. Second, central nervous system (CNS) HIV, now more completely understood, continues to be prevalent and is a modern "great imitator" of psychiatric illness, including mania and MND. Finally, combination therapy of quetiapine and topiramate can be effectively treated HIV-associated secondary mania. Our limitation in this case is the deficiency of cerebrospinal fluid (CSF) reports which can exclude other CNS illness.
Index of suspicion
Studies suggested that early and continuous HAART improve HIV patients' chance of surviving 5 years at least 90%.  Because of reduced HIV hospitalization rates, physicians may be less familiar with HIV CNS complications, particularly among young, homosexual men and drug abuse. HIV infection was present in 1.2% of the psychiatric outpatients, approximately 4 times the occurrence of HIV infection in the general adult population of the United States. 
Acute HIV infection (also called HIV seroconversion illness or acute retroviral syndrome) is frequently misdiagnosed or under-diagnosed. The development of acute retroviral syndrome typically coincides with high levels of viraemia and the host's initial immunological response. Symptoms typically occur 2-6 weeks after exposure and last for 14 days but may persist for as long as 10 weeks.  The formation of HIV-1-specific antibodies marks the completion of seroconversion; antibodies are generally detectable by 3-12 weeks of infection but may take up to 6-12 months to form.  The interval between acute HIV infection and AIDS (defined by an absolute CD4 cell count of <200 cells/mm 3 ) is highly variable, with a median time of approximately 10 years.  As for this case, it is possible that the lack of antiretroviral therapy shortens the interval between acute HIV infection and AIDS. In a cohort of 46 patients with primary HIV infection, more than 85% sought medical attention, but only 25% received the correct diagnosis.  Acute retroviral syndrome has been reported to be confused with a variety of other illnesses, including infectious mononucleosis, secondary syphilis and other common and important tropical and subtropical infections such as typhus, dengue and leptospirosis.  This confusion is of particular concern because the disease burden of dengue, typhus and leptospirosis is high in the Asian and Pacific regions, and many patients are treated presumptively for those conditions on clinical grounds.
Mania as a manifestation of central nervous system human immunodeficiency virus infection
Simultaneous plasma and CSF HIV-1 viral load monitoring have demonstrated that the CNS is an independent site of viral replication, especially in the later stages of AIDS.  It means the virus may replicate separately in the CNS and plasma. According to Ellen et al., , secondary mania was diagnosed if the patient was HIV positive and had no clear personal or family history of mood disorders. This patient presented with HIV-associated mania that has been described in the literature as an early-onset mania by the definition of CD4 counts >200 cells/mm 3 during first mania episode on 2008.  HIV positive patients with bipolar mania might have more cognitive impairment and more immune suppression than patients with HIV-related secondary mania.  The patient's undressing in public on 2011 proved the literature's findings that more manic symptom in HIV-related secondary mania. 
human immunodeficiency virus-associated mild neurocognitive disorder
The HIV-infected individuals with neuropsychologically impairment had a higher risk of dying than those without impairment. This was particularly true for those meeting syndromic diagnostic criteria of MND.  In a population-based study, the mortality rate was significant higher in HIV-positive patients with neurologic disorders (compared with those without neurologic disorders), e.g., MND, HIV-associated dementia, distal sensory polyneuropathy, CNS opportunistic infections, seizure, headache, and myopathy.  As a result, further image studies (brain or spinal magnetic resonance imaging) and neuromuscular tests should be arranged early for differentiate neurologic disorders.
Treatment for human immunodeficiency virus related secondary mania
A research have suggested psychiatric comorbidity rates of 50% and more.  The Organization of AIDS Psychiatry (OAP) was established as a Special Interest Group of the Academy of Psychosomatic Medicine in 2004. The American Psychiatric Association established an office of HIV psychiatry as well as an AIDS Committee at the beginning of the AIDS pandemic and has been at the forefront of education and training in AIDS psychiatry. Insufficiency of placebo-controlled trials clearly indicates significant knowledge gaps in almost all treatment areas of HIV psychiatry, particularly in the areas of cognition, psychosis, mania, and anxiety disorders. The OAP recommended quetiapine as the first-line treatment for secondary mania in a web-based HIV Psychiatry Treatment Consensus Survey in 2010,  presumably because of its benign effects with regard to extrapyramidal symptoms for diseases prominently affecting the basal ganglia, such as Parkinson's disease  or HIV illness.  Prescribing quetiapine in critical ill patients with delirium results in a faster delirium resolution, less agitation, and a greater rate of transfer to home or rehabilitation.  Topiramate, despite the lack of Food and Drug Administration -approved indication for acute mania,  is often utilized as second-line treatments in acute bipolar mania.  The combination of quetiapine (metabolized by CYP3A4 to an active metabolite) and topiramate, an inducer of CYP3A4, has possible synergistic effects and the risk of increased body temperature and decreased sweating.  This therapy has been reported to induce heat stroke among bipolar children.  Our patient was an adult and did not develop heat stroke. However, we still suggest that if such patients need concomitant topiramate treatment in addition to their quetiapine, the recommended dosing guideline should be followed strictly. During maintenance phase, the dosage of quetiapine and topiramate should be tapered because etravirine, part of HAART, has weak inducing effect on CYP 3A4.  While the underlying mechanism for HIV-associated secondary mania is unknown, an organic insult to the brain plays an important role. It is conceivable that antiretroviral medications that penetrate across the blood-brain barrier into CNS tissues can potentially protect HIV-infected individuals from incident mania.  Inconsistent with this model, the incidence of HIV-associated secondary mania declined after the introduction of HAART. 
| Conclusion|| |
This case had a manic-like episode before flu-like seroconversion illness. Without any treatment, he developed AIDS 3 years later. Then he developed sepsis, manic symptoms and delirium. Ultimately he was successfully treated with antibiotics, HAART, quetiapine and topiramate. The possibility of HIV-associated mania should be highly considered in a healthy young adults presenting extreme manic episode after a recent history of febrile and other systematic illness. The case report also reminds psychiatrists to consider HIV-associated MND in such cases after their psychiatric symptoms remitted.
| Funding|| |
The authors have no sources of funding to disclose.
| Disclosure|| |
The authors declare this study has no conflict of interest.
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[Figure 1], [Figure 2]