Psychosomatics 2013:]:]]]–]]]
& 2013 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.
Case Report Secondary Mania as a Possible Neuropsychiatric Complication of Dengue Fever Jessica Harder, M.D., Samata Sharma, M.D., M.P.H., David Gitlin, M.D.
Introduction Dengue fever is an arboviral illness transmitted by the Aedes mosquito and caused by a flavivirus. Endemic to Southeast Asia, the South Pacific, Central America, and the Caribbean, it is a potentially lethal infection on the rise, both in these endemic areas and in regions previously minimally affected by it. Climate change and rapid urbanization are thought to be partly responsible for the increases.1 Moreover, travelers from the United States and Canada who go abroad are increasingly bringing the infection back to their home cities.2 Although rarely diagnosed in most US hospitals, it is likely more prevalent than formally acknowledged. Some estimates suggest between 110,000 and 200,000 new infections annually in this country.3 Dengue is increasingly acknowledged as the cause of significant neurologic sequelae, at least in the acute phase. It has recently been demonstrated to be a neurotrophic virus with possible neurologic sequelae including Guillain-Barre syndrome, intracranial hemorrhage, ischemic stroke, isolated nerve palsies, and encephalopathy.19,20 However, it is little known to be a cause of neuropsychiatric symptoms and typically goes unrecognized by psychiatrists seeing patients in acute care settings or consultation-liaison services. This lack of familiarity may result in misdiagnosis as a primary bipolar disorder, psychotic disorder, or nonspecific delirium and consequently to inappropriate treatment. We present a case of apparent manic reaction after dengue fever and conduct a literature review for similar cases. This is the first case of mania following dengue documented in the American literature and the first in the literature to Psychosomatics ]:], ] 2013
present a follow-up of disease course well after the initial episode. Case Report Mr. M, a 48-year-old man with a history of tuberculosis infection for which he received 6 months of antibiotic treatment, dengue fever, sensorineural hearing loss, depression, and anxiety presented to the outpatient psychiatry department of a teaching hospital for management of anxious ruminations and angry outbursts. He had no history of traumatic brain injury or seizures. He gave a history of dengue virus infection two years before presentation while working in Indonesia, and noted that it was followed by mood changes and mood lability. In particular, he described feeling “elated” and “ecstatic,” being extremely talkative and energetic, thinking more quickly and writing more, to the point where his wife told him to “slow down.” He also recalled asking his wife to take dictation for him because his ideas were coming so quickly he could not write them down, and he felt they were very important. He believed that he had been given mood stabilizers for a brief time while abroad, although there were no known mood stabilizing agents amongst his leftover medications. He was prescribed hydroxyzine for sleep during this episode. (Sulbutiamine 200 mg, a dimer of vitamin B1, which Received September 16, 2013; revised November 12, 2013; accepted November 19, 2013. From Brigham and Women's Hospital, Boston, MA. Send correspondence and reprint requests to Jessica Harder, 221 Longwood Avenue, Boston 02115, MA; e-mail: [email protected]. edu & 2013 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.
www.psychosomaticsjournal.org
1
Case Report he thought was prescribed for his mood being “too up,” is not used as a mood stabilizer in this country but is used for asthenia in other parts of the world.15 There is at least 1 case of manic activation associated with massive sulbutiamine overuse,16 but as this was concurrent with mood stabilizer discontinuation in a patient with known bipolar disorder, it is difficult to draw conclusions from this case.) Mr. M reported that the episode resolved after about 6 months without further treatment. However, about 1 year before presentation he began to experience worsening depression with suicidal ideation, with a plan to asphyxiate himself using the CO emissions from his car. Despite rehearsing this plan, the patient did not make any suicide attempts and his suicidality abated. At the time of this evaluation, he was noted to have depressive symptoms associated with increased irritability and some impulsive outbursts. Although Mr. M had a long history of depression for which he had had numerous unsuccessful antidepressant trials, the episode of manic or hypomanic symptoms following dengue viral infection was the only one of its kind in his history. He had been maintained on low-dose citalopram (10 mg) for the preceding 4 years without any reported adverse consequences. He did report a family history of mood disorder with possible suicidality in his father. Citalopram administration was continued and lamotrigine was started for irritability, impulsivity, and depressed mood with a history of mania. Lamotrigine was gradually titrated up with subsequent improvement in mood, irritability, and impulsive outbursts. However, while abroad, shortly after a dose increase to 175 mg, rash accompanied by fever, neck stiffness, and oral ulcerations developed in Mr. M and lamotrigine was discontinued. He tolerated a 10-day course of oral steroids without overt manic symptoms, though he did complain of feeling “hyper.” At this time, his initial mania was reconsidered and thought to be plausibly secondary to dengue, given his mood stability in the face of known promanic agents. He was then maintained off a mood stabilizer without ill effects for over a year even after successive increases in his antidepressant. He did continue 1 mg of lorazepam at HS for sleep for over a year before tapering it to off. At last follow-up, Mr. M was stable while on 40 mg of citalopram for mood with some residual depressive symptoms but no evidence of mania. 2
www.psychosomaticsjournal.org
Discussion
Dengue is endemic in many tropical and subtropical parts of the world (http://www.healthmap.org/dengue/ index.php) and seasonal variations in infection rates are common, with the highest rates occurring after the rainy season.17 The disease dengue is caused by 4 distinct but related viruses (DENV-1 through 4), for which viral typing helps to better characterize clinical patterns. Dengue fever should be suspected when a patient with exposure to an endemic area has high fever accompanied by 2 or more of the following: myalgia, arthralgia, headache, ocular or retro-orbital pain, rash, leukopenia, or hemorrhagic manifestations not meeting the criteria for dengue hemorrhagic fever. Nausea, vomiting, anorexia, or abdominal pain may occur. Further hemorrhagic manifestation, thrombocytopenia, or signs of plasma leakage would characterize dengue hemorrhagic fever, and these along with evidence of circulatory failure would describe dengue shock syndrome.13 Dengue infection can be confirmed by virus or viral genome detection or by detection of immune response (IgM and IgG) with utility of the specific test varying by time since infection.14 Neurologic sequelae of dengue virus infection are not common but have been described in the literature. They include intracranial hemorrhage, ischemic stroke, vascular thrombosis, myelitis, Guillain-Barre syndrome, encephalitis, encephalopathy,19and isolated nerve palsy.20 It appears that neurologic manifestations are most common with serotypes DENV-2 and DENV-3.18 We investigated the existing literature on specifically neuropsychiatric sequelae of dengue infection by performing a PubMed search using the keyword “dengue fever” and keywords for neuropsychiatric mood disruption (mania, bipolar, bipolar disorder, manic, manic depressive, mood, mood AND sequelae, neurologic, case study AND neurologic, psychiatric) in humans published in English, French, German, or Spanish. The reference lists of all relevant articles were also searched for relevant publications. Studies were considered relevant if they pertained to known or suspected cases of dengue fever with subsequently noted neuropsychiatric disturbance involving symptoms of a manic state, including but not limited to elevated or expansive mood, irritable or expansive affect, new psychosis, increased goaldirected activity, and decreased need for sleep. The Psychosomatics ]:], ] 2013
Harder et al. literature review revealed 5 previous cases of mania documented after dengue fever. Of the previously documented cases, 3 occurred in young men for whom the manic episode, although occurring in close temporal association with the dengue infection, could theoretically have represented a first episode of mania as a manifestation of primary bipolar disorder. In a case report, Rapp et al.4 described a 21-year-old man returning to Paris after a year in Djibouti with a history of a self-resolving flulike illness with associated thrombocytopenia who was found to have dengue-specific IgM reactivity. He presented with agitation, pressured speech, and flight of ideas, consistent with a manic state. Evaluation revealed no other likely etiologies, and the syndrome, which was felt to be a consequence of dengue fever, resolved without sequelae after 2 months. In this case, the rapid resolution and self-limited nature of the illness would argue against a diagnosis of bipolar disorder. A similar case was that of a 21-year-old man resident of India who contracted IgM antibody– confirmed dengue fever in whom pressured speech, irritability, increased psychomotor activity, grandiose delusions, and decreased need for sleep developed on the sixth day of his illness.5 He was noted to have no personal or family history of bipolar illness, and his symptoms responded to treatment with haloperidol and carbamazepine, with resolution by day 14. A lack of family history of affective illness decreases the likelihood that this was a first presentation of bipolar disorder. Additional information on his course over time would clarify whether this was a first manifestation of bipolar illness. A more complicated case was described by Rittmannsberger et al.6 They report the case of a 21-yearold man who had traveled to India to study abroad, and developed a high fever, followed 1 week after its resolution by impairments in concentration and memory, sleep disturbances, social withdrawal, and signs of confusion followed by seizure. He developed grandiose delusions and became acutely suicidal. Tests for IgG and IgM antibodies were positive for dengue virus and the hemagglutination inhibition assay showed titers positive for the presence of dengue virus type 2. In his case, although there was a family history of affective disorders, he was thought to be having a response to his dengue infection. His psychotic symptoms responded to olanzapine and resolved by Psychosomatics ]:], ] 2013
hospital discharge, but anxiety persisted even with sertraline treatment for a year. Fluorodeoxyglucosepositron emission tomography, interestingly, showed diminished tracer uptake in the mesial temporal and parietal cortical areas; the ubiquitous nonuniform speckled enhancement pattern was thought to corroborate the clinical diagnosis of encephalopathy. In this case, despite a probable genetic predisposition to affective illness, the presentation is more suggestive of psychotic break in the context of encephalopathy given the abnormal glucose metabolism seen on positron emission tomography scan, the impairments in attention, and the accompanying neurologic signs (seizure). Jhanjee et al.7 reported the case of a 28-year-old Indian man with IgM enzyme-linked immunosorbent assay-confirmed dengue infection and associated thrombocytopenia, who presented with elevated mood and self-confidence, decreased need for sleep, increased goal-directed activity and speech production, irritability, grandiosity, delusions, and aggressive outbursts that developed 3 days after onset of his febrile illness. There were no signs of encephalitis or encephalopathy, and workup revealed no other probable cause for his symptoms. There was no family history of mood disorder. He responded to divalproex and risperidone, and he had no recurrence of mania after 3 months of outpatient follow-up. Although this man was older at the time of his illness, he might still be considered to be within the range for a first episode of bipolar mania. A case of later-onset first episode mania in a patient with no predisposing family history provides additional support for the possibility that dengue fever may result in mania. Blum et al.8 described a 52-yearold female patient with no previous psychiatric history and no family history of psychosis in whom headache, fever, diarrhea, and dizziness developed during a 2-month stay in Haiti. On day 2 of a hospital admission for evaluation of syncope, auditory and visual hallucinations, delusional thinking with fears that hospital staff were trying to harm her, agitation, ideas of reference, and labile mood developed. There was no somnolence, seizure, or neurologic deficit. Workup demonstrated highly elevated levels of IgG and IgM antibodies against dengue virus with other causes ruled out with appropriate tests. Her psychosis resolved rapidly with antipsychotic medications, which were continued for 6 weeks. The authors note www.psychosomaticsjournal.org
3
Case Report the uniqueness in the medical literature of psychosis as the primary symptom associated with dengue fever and advocate for consideration of a diagnosis of dengue in any new neuropsychiatric syndrome occurring after exposure in an endemic area. Conclusion Our case highlights a possible relationship between dengue virus infection and neuropsychiatric sequelae. Mr. M, who had never before had hypomanic symptoms despite multiple trials of unopposed antidepressant medications, experienced new-onset symptoms of a manic episode following dengue infection, followed by a severe depressive episode with suicidality. On presentation to our clinic he remained in a somewhat depressed state with possible mixed symptoms (irritability and decreased need for sleep). His condition ultimately stabilized with treatment for his depressive symptoms without the need for mood stabilizers, thus supporting a diagnosis of a unipolar depressive disorder and suggesting that his brief manic symptoms could be attributed to a reaction to dengue virus infection. Our review of the literature provided further support for a neuropsychiatric response to dengue fever that closely resembles the manic state of idiopathic bipolar disorder. This case adds to the body of literature establishing a link between dengue and mania, illustrates the importance of distinguishing between idiopathic and dengue-related mania, and provides data on successful long-term psychiatric management of such patients. It is unclear precisely how dengue directly or indirectly produces its neurologic or neuropsychiatric effects; any discussion of putative mechanisms must
account for the paucity of existing evidence. Rapp et al. suggested 3 possible mechanisms, including encephalopathy precipitated by metabolic or hemodynamic derangements, viral encephalitis, and postviral autoimmune-mediated encephalitis. Puccioni-Sohler et al.9 similarly suggested several possible mechanisms, including metabolic disturbance, direct viral invasion of the central nervous system, intracerebral hemorrhage, and autoimmune reaction secondary to infection. A prospective study of dengue infection in 8 Thai children found encephalitis in the absence of metabolic disturbance in all cases, arguing against that etiology.10 Ramos et al.11 reported isolating dengue virus from cerebral tissue (medulla and cerebellum) in a case of fatal dengue, but also described more generalized immunoreactivity, which might explain a manic reaction and would support an autoimmune etiology. Perhaps, as in some postinfectious autoimmune encephalitides, an antibody to a neural surface antigen is the source of the psychiatric changes.12 More needs to be understood about this emerging disease, particularly as it becomes increasingly common in the United States. Given the pleomorphic neurologic manifestations of dengue virus infection, it is not surprising that neuropsychiatric manifestations should occur as well. Increasing awareness of the possible neuropsychiatric profile of dengue would enable medical and psychiatric providers to identify and manage this condition and would pave the way for better understanding of the mechanisms underlying mania after neuroinflammatory disease. Recognizing manic symptoms secondary to dengue infection as a clinical entity would allow further study of this phenomenon and clarification of best practices for psychiatric management.
References 1. Yacoub S, Kotit S, Yacoub MH: Disease appearance and evolution against a backdrop of climate change and reduced resources. Phil Trans R Soc A 2011; 369(1942):1719–1729 2. Pinheiro FP, Corber SJ: Global situation of dengue and dengue haemorrhagic fever, and its emergence in the Americas. World Health Stat 1997; 50(3–4):161–169 3. Hotez P: Neglected infections of poverty in the United States of America. PLoS One 2008; 2(6):e256 4. Rapp C, Debord T, Imbert P, Roué R: A psychiatric form of dengue after a visit to Djibouti. Presse Med 2002; 31(36):1704 [French] 5. Mendhekar DN, Aggarwal P, Aggarwal A: Classical mania associated with dengue infection. Indian J Med Sci 2006; 60(3):115–116
4
www.psychosomaticsjournal.org
6. Rittmannsberger H, Foff C, Doppler S, Pichler R: Psychiatric manifestation of a dengue-encephalopathy. Wien KlinWochenschr 2010; 122(3 Suppl):87–90 [German] 7. Jhanjee A, Srivastava S: Mania in dengue fever. Indian J Psychiatry 2011; 20:56–57 8. Blum JA, Pfeifer S, Hatz CF: Psychiatric manifestations as the leading symptom in an expatriate with dengue fever. Infection 2010; 38(4):341–343 9. Puccioni-Sohler M, Soares CN, Papaiz-Alvarenga R, Castro MJ, Faria LC, Peralta JM: Neurologic dengue manifestations associated with intrathecal specific immune response. Neurology 2009; 73(17):1413–1417 10. Kankirawatana P, Chokephaibulkit K, Puthavathana P, Yoksan S, Apintanapong S, Pongthapisit V: Dengue
Psychosomatics ]:], ] 2013
Harder et al.
11.
12. 13. 14. 15. 16.
infection presenting with central nervous system manifestation. J Child Neurol 2000; 15(8):544–547 Ramos C, Sánchez G, Pando RH, et al: Dengue virus in the brain of a fatal case of hemorrhagic dengue fever. J Neurovirol 1998; 4(4):465–468 Wilson MR, Tyler KL: Issues and updates in emerging neurologic viral infections. Semin Neurol 2011; 31(3):245–253 http://wwwn.cdc.gov/nndss/document/2012_case%20defini tions.pdf http://apps.who.int/iris/bitstream/10665/76887/1/97892415 04713_eng.pdf Van Reeth O: Pharmacologic and therapeutic features of sulbutiamine. Drugs Today (Barc) 1999; 35:187–192 Douzenis A, Michopoulos I, Lykouras L: Sulbutiamine, an innocent over the counter drug, interferes with therapeutic
Psychosomatics ]:], ] 2013
17. 18.
19. 20.
outcome of bipolar disorder. World J Biol Psychiatry 2006; 7(3):183–185 Rajapakse S, Rodrigo C, Rajapakse A: Treatment of dengue fever. Infect Drug Resist 2012; 5:103–112 Gupta M, Nayak R, Khwaja GA, Chowdhury D: Acute disseminated encephalomyelitis associated with dengue infection: a case report with literature review. J Neurol Sci 2013; 335:216–218, http://dx.doi.org/10.1016/j.jns.2013. 08.029 [pii: S0022-510X(13)02878-5] Murthy JM: Neurological complication of dengue infection. Neurol India 2010; 58(4):581–584 Shivanthan MC, Ratnayake EC, Wijesiriwardena BC, Somaratna KC, Gamagedara LK: Paralytic squint due to abducens nerve palsy: a rare consequence of dengue fever. BMC Infect Dis 2012; 12:156
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5
& 2013 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.
Case Report Secondary Mania as a Possible Neuropsychiatric Complication of Dengue Fever Jessica Harder, M.D., Samata Sharma, M.D., M.P.H., David Gitlin, M.D.
Introduction Dengue fever is an arboviral illness transmitted by the Aedes mosquito and caused by a flavivirus. Endemic to Southeast Asia, the South Pacific, Central America, and the Caribbean, it is a potentially lethal infection on the rise, both in these endemic areas and in regions previously minimally affected by it. Climate change and rapid urbanization are thought to be partly responsible for the increases.1 Moreover, travelers from the United States and Canada who go abroad are increasingly bringing the infection back to their home cities.2 Although rarely diagnosed in most US hospitals, it is likely more prevalent than formally acknowledged. Some estimates suggest between 110,000 and 200,000 new infections annually in this country.3 Dengue is increasingly acknowledged as the cause of significant neurologic sequelae, at least in the acute phase. It has recently been demonstrated to be a neurotrophic virus with possible neurologic sequelae including Guillain-Barre syndrome, intracranial hemorrhage, ischemic stroke, isolated nerve palsies, and encephalopathy.19,20 However, it is little known to be a cause of neuropsychiatric symptoms and typically goes unrecognized by psychiatrists seeing patients in acute care settings or consultation-liaison services. This lack of familiarity may result in misdiagnosis as a primary bipolar disorder, psychotic disorder, or nonspecific delirium and consequently to inappropriate treatment. We present a case of apparent manic reaction after dengue fever and conduct a literature review for similar cases. This is the first case of mania following dengue documented in the American literature and the first in the literature to Psychosomatics ]:], ] 2013
present a follow-up of disease course well after the initial episode. Case Report Mr. M, a 48-year-old man with a history of tuberculosis infection for which he received 6 months of antibiotic treatment, dengue fever, sensorineural hearing loss, depression, and anxiety presented to the outpatient psychiatry department of a teaching hospital for management of anxious ruminations and angry outbursts. He had no history of traumatic brain injury or seizures. He gave a history of dengue virus infection two years before presentation while working in Indonesia, and noted that it was followed by mood changes and mood lability. In particular, he described feeling “elated” and “ecstatic,” being extremely talkative and energetic, thinking more quickly and writing more, to the point where his wife told him to “slow down.” He also recalled asking his wife to take dictation for him because his ideas were coming so quickly he could not write them down, and he felt they were very important. He believed that he had been given mood stabilizers for a brief time while abroad, although there were no known mood stabilizing agents amongst his leftover medications. He was prescribed hydroxyzine for sleep during this episode. (Sulbutiamine 200 mg, a dimer of vitamin B1, which Received September 16, 2013; revised November 12, 2013; accepted November 19, 2013. From Brigham and Women's Hospital, Boston, MA. Send correspondence and reprint requests to Jessica Harder, 221 Longwood Avenue, Boston 02115, MA; e-mail: [email protected]. edu & 2013 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.
www.psychosomaticsjournal.org
1
Case Report he thought was prescribed for his mood being “too up,” is not used as a mood stabilizer in this country but is used for asthenia in other parts of the world.15 There is at least 1 case of manic activation associated with massive sulbutiamine overuse,16 but as this was concurrent with mood stabilizer discontinuation in a patient with known bipolar disorder, it is difficult to draw conclusions from this case.) Mr. M reported that the episode resolved after about 6 months without further treatment. However, about 1 year before presentation he began to experience worsening depression with suicidal ideation, with a plan to asphyxiate himself using the CO emissions from his car. Despite rehearsing this plan, the patient did not make any suicide attempts and his suicidality abated. At the time of this evaluation, he was noted to have depressive symptoms associated with increased irritability and some impulsive outbursts. Although Mr. M had a long history of depression for which he had had numerous unsuccessful antidepressant trials, the episode of manic or hypomanic symptoms following dengue viral infection was the only one of its kind in his history. He had been maintained on low-dose citalopram (10 mg) for the preceding 4 years without any reported adverse consequences. He did report a family history of mood disorder with possible suicidality in his father. Citalopram administration was continued and lamotrigine was started for irritability, impulsivity, and depressed mood with a history of mania. Lamotrigine was gradually titrated up with subsequent improvement in mood, irritability, and impulsive outbursts. However, while abroad, shortly after a dose increase to 175 mg, rash accompanied by fever, neck stiffness, and oral ulcerations developed in Mr. M and lamotrigine was discontinued. He tolerated a 10-day course of oral steroids without overt manic symptoms, though he did complain of feeling “hyper.” At this time, his initial mania was reconsidered and thought to be plausibly secondary to dengue, given his mood stability in the face of known promanic agents. He was then maintained off a mood stabilizer without ill effects for over a year even after successive increases in his antidepressant. He did continue 1 mg of lorazepam at HS for sleep for over a year before tapering it to off. At last follow-up, Mr. M was stable while on 40 mg of citalopram for mood with some residual depressive symptoms but no evidence of mania. 2
www.psychosomaticsjournal.org
Discussion
Dengue is endemic in many tropical and subtropical parts of the world (http://www.healthmap.org/dengue/ index.php) and seasonal variations in infection rates are common, with the highest rates occurring after the rainy season.17 The disease dengue is caused by 4 distinct but related viruses (DENV-1 through 4), for which viral typing helps to better characterize clinical patterns. Dengue fever should be suspected when a patient with exposure to an endemic area has high fever accompanied by 2 or more of the following: myalgia, arthralgia, headache, ocular or retro-orbital pain, rash, leukopenia, or hemorrhagic manifestations not meeting the criteria for dengue hemorrhagic fever. Nausea, vomiting, anorexia, or abdominal pain may occur. Further hemorrhagic manifestation, thrombocytopenia, or signs of plasma leakage would characterize dengue hemorrhagic fever, and these along with evidence of circulatory failure would describe dengue shock syndrome.13 Dengue infection can be confirmed by virus or viral genome detection or by detection of immune response (IgM and IgG) with utility of the specific test varying by time since infection.14 Neurologic sequelae of dengue virus infection are not common but have been described in the literature. They include intracranial hemorrhage, ischemic stroke, vascular thrombosis, myelitis, Guillain-Barre syndrome, encephalitis, encephalopathy,19and isolated nerve palsy.20 It appears that neurologic manifestations are most common with serotypes DENV-2 and DENV-3.18 We investigated the existing literature on specifically neuropsychiatric sequelae of dengue infection by performing a PubMed search using the keyword “dengue fever” and keywords for neuropsychiatric mood disruption (mania, bipolar, bipolar disorder, manic, manic depressive, mood, mood AND sequelae, neurologic, case study AND neurologic, psychiatric) in humans published in English, French, German, or Spanish. The reference lists of all relevant articles were also searched for relevant publications. Studies were considered relevant if they pertained to known or suspected cases of dengue fever with subsequently noted neuropsychiatric disturbance involving symptoms of a manic state, including but not limited to elevated or expansive mood, irritable or expansive affect, new psychosis, increased goaldirected activity, and decreased need for sleep. The Psychosomatics ]:], ] 2013
Harder et al. literature review revealed 5 previous cases of mania documented after dengue fever. Of the previously documented cases, 3 occurred in young men for whom the manic episode, although occurring in close temporal association with the dengue infection, could theoretically have represented a first episode of mania as a manifestation of primary bipolar disorder. In a case report, Rapp et al.4 described a 21-year-old man returning to Paris after a year in Djibouti with a history of a self-resolving flulike illness with associated thrombocytopenia who was found to have dengue-specific IgM reactivity. He presented with agitation, pressured speech, and flight of ideas, consistent with a manic state. Evaluation revealed no other likely etiologies, and the syndrome, which was felt to be a consequence of dengue fever, resolved without sequelae after 2 months. In this case, the rapid resolution and self-limited nature of the illness would argue against a diagnosis of bipolar disorder. A similar case was that of a 21-year-old man resident of India who contracted IgM antibody– confirmed dengue fever in whom pressured speech, irritability, increased psychomotor activity, grandiose delusions, and decreased need for sleep developed on the sixth day of his illness.5 He was noted to have no personal or family history of bipolar illness, and his symptoms responded to treatment with haloperidol and carbamazepine, with resolution by day 14. A lack of family history of affective illness decreases the likelihood that this was a first presentation of bipolar disorder. Additional information on his course over time would clarify whether this was a first manifestation of bipolar illness. A more complicated case was described by Rittmannsberger et al.6 They report the case of a 21-yearold man who had traveled to India to study abroad, and developed a high fever, followed 1 week after its resolution by impairments in concentration and memory, sleep disturbances, social withdrawal, and signs of confusion followed by seizure. He developed grandiose delusions and became acutely suicidal. Tests for IgG and IgM antibodies were positive for dengue virus and the hemagglutination inhibition assay showed titers positive for the presence of dengue virus type 2. In his case, although there was a family history of affective disorders, he was thought to be having a response to his dengue infection. His psychotic symptoms responded to olanzapine and resolved by Psychosomatics ]:], ] 2013
hospital discharge, but anxiety persisted even with sertraline treatment for a year. Fluorodeoxyglucosepositron emission tomography, interestingly, showed diminished tracer uptake in the mesial temporal and parietal cortical areas; the ubiquitous nonuniform speckled enhancement pattern was thought to corroborate the clinical diagnosis of encephalopathy. In this case, despite a probable genetic predisposition to affective illness, the presentation is more suggestive of psychotic break in the context of encephalopathy given the abnormal glucose metabolism seen on positron emission tomography scan, the impairments in attention, and the accompanying neurologic signs (seizure). Jhanjee et al.7 reported the case of a 28-year-old Indian man with IgM enzyme-linked immunosorbent assay-confirmed dengue infection and associated thrombocytopenia, who presented with elevated mood and self-confidence, decreased need for sleep, increased goal-directed activity and speech production, irritability, grandiosity, delusions, and aggressive outbursts that developed 3 days after onset of his febrile illness. There were no signs of encephalitis or encephalopathy, and workup revealed no other probable cause for his symptoms. There was no family history of mood disorder. He responded to divalproex and risperidone, and he had no recurrence of mania after 3 months of outpatient follow-up. Although this man was older at the time of his illness, he might still be considered to be within the range for a first episode of bipolar mania. A case of later-onset first episode mania in a patient with no predisposing family history provides additional support for the possibility that dengue fever may result in mania. Blum et al.8 described a 52-yearold female patient with no previous psychiatric history and no family history of psychosis in whom headache, fever, diarrhea, and dizziness developed during a 2-month stay in Haiti. On day 2 of a hospital admission for evaluation of syncope, auditory and visual hallucinations, delusional thinking with fears that hospital staff were trying to harm her, agitation, ideas of reference, and labile mood developed. There was no somnolence, seizure, or neurologic deficit. Workup demonstrated highly elevated levels of IgG and IgM antibodies against dengue virus with other causes ruled out with appropriate tests. Her psychosis resolved rapidly with antipsychotic medications, which were continued for 6 weeks. The authors note www.psychosomaticsjournal.org
3
Case Report the uniqueness in the medical literature of psychosis as the primary symptom associated with dengue fever and advocate for consideration of a diagnosis of dengue in any new neuropsychiatric syndrome occurring after exposure in an endemic area. Conclusion Our case highlights a possible relationship between dengue virus infection and neuropsychiatric sequelae. Mr. M, who had never before had hypomanic symptoms despite multiple trials of unopposed antidepressant medications, experienced new-onset symptoms of a manic episode following dengue infection, followed by a severe depressive episode with suicidality. On presentation to our clinic he remained in a somewhat depressed state with possible mixed symptoms (irritability and decreased need for sleep). His condition ultimately stabilized with treatment for his depressive symptoms without the need for mood stabilizers, thus supporting a diagnosis of a unipolar depressive disorder and suggesting that his brief manic symptoms could be attributed to a reaction to dengue virus infection. Our review of the literature provided further support for a neuropsychiatric response to dengue fever that closely resembles the manic state of idiopathic bipolar disorder. This case adds to the body of literature establishing a link between dengue and mania, illustrates the importance of distinguishing between idiopathic and dengue-related mania, and provides data on successful long-term psychiatric management of such patients. It is unclear precisely how dengue directly or indirectly produces its neurologic or neuropsychiatric effects; any discussion of putative mechanisms must
account for the paucity of existing evidence. Rapp et al. suggested 3 possible mechanisms, including encephalopathy precipitated by metabolic or hemodynamic derangements, viral encephalitis, and postviral autoimmune-mediated encephalitis. Puccioni-Sohler et al.9 similarly suggested several possible mechanisms, including metabolic disturbance, direct viral invasion of the central nervous system, intracerebral hemorrhage, and autoimmune reaction secondary to infection. A prospective study of dengue infection in 8 Thai children found encephalitis in the absence of metabolic disturbance in all cases, arguing against that etiology.10 Ramos et al.11 reported isolating dengue virus from cerebral tissue (medulla and cerebellum) in a case of fatal dengue, but also described more generalized immunoreactivity, which might explain a manic reaction and would support an autoimmune etiology. Perhaps, as in some postinfectious autoimmune encephalitides, an antibody to a neural surface antigen is the source of the psychiatric changes.12 More needs to be understood about this emerging disease, particularly as it becomes increasingly common in the United States. Given the pleomorphic neurologic manifestations of dengue virus infection, it is not surprising that neuropsychiatric manifestations should occur as well. Increasing awareness of the possible neuropsychiatric profile of dengue would enable medical and psychiatric providers to identify and manage this condition and would pave the way for better understanding of the mechanisms underlying mania after neuroinflammatory disease. Recognizing manic symptoms secondary to dengue infection as a clinical entity would allow further study of this phenomenon and clarification of best practices for psychiatric management.
References 1. Yacoub S, Kotit S, Yacoub MH: Disease appearance and evolution against a backdrop of climate change and reduced resources. Phil Trans R Soc A 2011; 369(1942):1719–1729 2. Pinheiro FP, Corber SJ: Global situation of dengue and dengue haemorrhagic fever, and its emergence in the Americas. World Health Stat 1997; 50(3–4):161–169 3. Hotez P: Neglected infections of poverty in the United States of America. PLoS One 2008; 2(6):e256 4. Rapp C, Debord T, Imbert P, Roué R: A psychiatric form of dengue after a visit to Djibouti. Presse Med 2002; 31(36):1704 [French] 5. Mendhekar DN, Aggarwal P, Aggarwal A: Classical mania associated with dengue infection. Indian J Med Sci 2006; 60(3):115–116
4
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6. Rittmannsberger H, Foff C, Doppler S, Pichler R: Psychiatric manifestation of a dengue-encephalopathy. Wien KlinWochenschr 2010; 122(3 Suppl):87–90 [German] 7. Jhanjee A, Srivastava S: Mania in dengue fever. Indian J Psychiatry 2011; 20:56–57 8. Blum JA, Pfeifer S, Hatz CF: Psychiatric manifestations as the leading symptom in an expatriate with dengue fever. Infection 2010; 38(4):341–343 9. Puccioni-Sohler M, Soares CN, Papaiz-Alvarenga R, Castro MJ, Faria LC, Peralta JM: Neurologic dengue manifestations associated with intrathecal specific immune response. Neurology 2009; 73(17):1413–1417 10. Kankirawatana P, Chokephaibulkit K, Puthavathana P, Yoksan S, Apintanapong S, Pongthapisit V: Dengue
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