CASE REPORTS Behavioral Disconnection Syndrome Manifesting as Combined Mania and Visual-Auditory Hallucinations Secondary to Isolated Right Thalamic Hemorrhage Parunyou Julayanont, M.D., Doungporn Ruthirago, M.D., Khondoker Alam, M.D., Yazan J. Alderazi, M.D. Damage to the thalamus can contribute to the phenomenon of diaschisis manifesting as various behavioral symptoms. We present the case of a 55-year-old man who presented with acute mania and late-onset combined visual and auditory hallucinations after right thalamic hemorrhage. This is the first report, to our knowledge, of a combination of mania and visual-auditory hallucination in a patient with isolated thalamic damage. Details of all previous case reports on isolated thalamic damage presenting with mania or hallucination are provided. We propose the networks of diencephalic damage causing mania and hallucinations, which represent the behavioral disconnection syndromes. It is challenging to localize a single lesion when neuropsychiatric symptoms are the only manifestations. The thalamus is a complex structure connecting between the brainstem and various cortical areas. Damage to the thalamus can contribute to various behavioral conditions. We report the first case, to our knowledge, of a patient who suffered from right thalamic hemorrhage presenting with combined acute mania and visual-auditory hallucinations. The case broadens the clinical approach on the behavioral disturbance secondary to focal brain lesion on the thalamus. We also systematically review the previous reports on the cases of isolated thalamic damage with mania or hallucination. Finally, we provide the proposed networks of diencephalic damage causing mania and hallucinations. CASE REPORT A 55-year-old man without a previous history of psychiatric conditions or substance abuse presented with a 1-week history of acute mania. He had irritability, grandiosity, combative speech, paranoid delusion, high energy levels, decreased need for sleep, pressurized speech, euphoria, and inappropriate cheerfulness. The patient had been a mild-mannered and composed person prior to this event. Neurological examination showed no focal neurologic deficits; urine drug screen was negative; MRI showed cavernous malformation with hemorrhage involving the dorsomedial and pulvinar nucleus of the right thalamus (Figure 1); and electroencephalography J Neuropsychiatry Clin Neurosci 29:4, Fall 2017 was normal. Risperidone was started. At 4 months followup, the manic symptoms resolved, and risperidone was discontinued. One year later, he presented with acute psychosis. He had vividly visual hallucination (transient texts on his phone, unknown people and colorful airplanes). He also reported the musical hallucination that he heard pleasant classical music in particular at night. He denied any commanding or voice hallucination. He had hypnagogic visual and musical hallucinations. He has insight to the hallucinations. MRI head demonstrated stable cavernous malformation (Figure 1). Risperidone was resumed and effectively improved hallucination within a week. DISCUSSION Mania Mania after thalamic lesions has been described in a small number of patients. Symptoms of mania secondary to focal brain lesions are clinically similar to the features of primary psychiatric mania. Some features may help localizing lesions to the thalamus or differentiating from primary mania, such as hemianesthesia, hemiparesis, hypersomnolence, abnormal movement, abnormal gaze, and amnesia. From literature review, we found 18 cases of mania (including our case) caused by isolated thalamic lesions on various thalamic nuclei, including the dorsomedial, intralaminar, pulvinar, anterior, ventrolateral, and ventromedial nuclei (Table 1). It is interesting that, in all of these cases, the lesions involved the right thalamus, with the isolated right thalamus in 72% (N513/18) of cases and both thalami in 28% (N55/18) of cases. The majority of patients (80%) developed mania immediately or within a few days after the damage; however, late-onset mania may occur up to many months after the events. In cases with mild symptoms, patients usually spontaneously recover without medication. In more severe cases, mood stabilizers or atypical antipsychotics are effective treatment. Even though most of the reported patients did not have recurrent mania, a minority of the cases developed hypomania or cyclic depression-mania during the follow-up period. neuro.psychiatryonline.org 401 BEHAVIORAL DISCONNECTION SYNDROME FIGURE 1. MRI Head Showing the Cavernous Malformation Hemorrhage on the Right Thalamus Involving the Dorsomedial and Pulvinar Nucleia a The image shows A) axial view on the fluid-attenuated inversion recovery sequence; B) axial view on the gradient-echo sequence; and C) sagittal view on the T1 sequence. Peduncular Hallucinosis Peduncular hallucinosis classically presents with vivid visual hallucination usually with preserved insight. Midbrain damage with or without thalamic involvement is the typical origin of hallucination. Isolated thalamic lesions were rarely reported to cause this condition (Table 2). From the literature review, we found 15 cases (including our case) of hallucinations secondary to isolated thalamic damage. Even though there is no specific thalamic nucleus consistently reported to cause peduncular hallucinosis, the dorsomedial (46%, N5 6/13 cases), pulvinar (31%, N54/13 cases), and anterior (15%, N52/15 cases) nuclei are the common locations contributing to this condition (Table 2). Unlike mania, there is no relationship between the side of diencephalic lesions and hallucinations. From 15 case reports, the lesions were on the right side in 47% (N57/15 cases), on the left side in 47% (N57/15 cases), and on both sides in 6% (N51/15 case). Similar to mania, the majority of peduncular hallucinosis (66%, N5 10/15 cases) occurred within the first week after damages, but late-onset can present up to a year as reported in our case. Atypical antipsychotics are the drug of choice in severe cases. Even though visual hallucination is the classic type of peduncular hallucinosis, auditory hallucinations also occur after diencephalic damage. To our knowledge, there have been only two case reports of combined visual and auditory hallucinations secondary to isolated thalamic lesions, which involved the anterior and lateral nuclei in each case. Our case is the first report of damage to the dorsomedial and pulvinar nuclei contributing to combined hallucinations. Network Model of Mania and Hallucinations Secondary to Thalamic Insults Mania secondary to diencephalic lesions derives from the phenomenon of diaschisis that is caused by disconnection of the thalamus from the thalamo-prefrontal-limbic networks. 402 neuro.psychiatryonline.org The magnocellular (medial) part of the dorsomedial nucleus connects the thalamus with the limbic system via the orbitofrontal cortex.1 Damage to this network causes disinhibition of inappropriate behaviors and enhanced reward-seeking behaviors.2 The medial part of the dorsomedial nucleus also projects the neuronal network to the amygdala via the amygdalofugal tract, and thus a lesion on this nucleus can lead to emotional dysregulation, aggression, increased oral intake, and hypersexuality. In addition, damage to the intermediate part of dorsomedial nucleus, which links to the dorsolateral prefrontal cortex, can contribute to executive dysfunction. Damage to the anterior nucleus, which is connected to the mammillary bodies and amygdala via the mamillothalamic and ventral amygdalothalamic tract, respectively, causes problem with emotional expression and dysregulation of motivation.1 The pulvinar nucleus is an associative nucleus connecting to multiple cortical areas.1 The medial part of the pulvinar nucleus sends some connections to the anterior insular cortex and functions in controlling emotional awareness that is required for emotional regulation.3 Some fibers from the intermediate part of the pulvinar nucleus also project to the dorsolateral prefrontal cortex and take part in executive performance. The role of the right thalamus in the pathogenesis of mania is supported by previous studies demonstrating decreased right thalamic volume in patients with bipolar disorder compared with normal controls4,5 and reduced right thalamic and ipsilateral prefrontal/orbitofrontal perfusion in cases with diencephalic mania.6–8 It is hypothesized that emotional regulation is lateralized, with the right hemisphere controlling negative moods and the left hemisphere controlling positive emotions. The interhemispheric imbalance, with left-sided hyperfunction and right-sided hypofunction, on the prefrontal, orbitofrontal, and insular cortices, may contribute to the emotional releasing effect from the contralesional side and result in secondary mania.9,10 J Neuropsychiatry Clin Neurosci 29:4, Fall 2017 J Neuropsychiatry Clin Neurosci 29:4, Fall 2017 Female Male NA Kulisevsky et al.16 McGilchrist et al.17 Daum et al.18 64 43 81 NA Three cases 35 Male Starkstein et al.15 47 Female 72 66 Male Gentilini et al.14 Female NA Two cases Cummings et al.13 Bogousslavsky et al.6 Age (Years) Sex Study Anterior Paramedian Ventral lateral and ventromedial Unspecified Paramedian, dorsomedial and ventral lateral Paramedian Paramedian Paramedian Unspecified Locations TABLE 1. Cases With Isolated Thalamic Damage Causing Mania Right Right and Left Right Right Right Right and Left Right and Left Right and Left Right Hemisphere Acute Acute Acute NA Acute Acute Acute Acute Acute Onset Ischemic Stroke Ischemic stroke Hemorrhage and ischemic stroke Ischemic stroke Ischemic stroke Ischemic stroke Ischemic stroke Ischemic Stroke Ischemic stroke Etiologies Hyperphagia and irritability Smiling and inappropriate laughing and jokes, logorrhea, rapid switching of ideas, lack of spontaneity, and disinhibition Mania (unspecified symptoms in each case) Euphoria, talkativeness, grandiosity, flight of ideas, inappropriate jokes, and decreased need for sleep Cyclic elation, hypersexuality, hyperphagia, flight of ideas, and decreased need for sleep Hypersexuality, talkativeness, irritability, mood fluctuation, and verbal aggression Case 1: euphoria, talkativeness, hypersexuality, euphoric, irritable, and poor judgement Case 2: euphoric, decreased need for sleep, and preoccupied with religion Hypersexuality, grandiosity, and cheerfulness Hyperphagia, euphoria, and childish behaviors Manic Symptoms Amnesia Hypersomnolence, cyclical apathy and depression Left hemichorea NA Hypersomnolence, disorientation, Hypersomnolence, abnormal eye movement, and depression Amnesia Amnesia, somnolence, and delusion Hemisensory loss, amnesia, denial of illness, and depression (case 2) Associated Symptoms Treatment neuro.psychiatryonline.org continued Not reported Not reported Haloperidol with improvement after 4 weeks NA Not reported Not reported Not reported Not reported Lithium in one case with improvement; no medication in one case JULAYANONT ET AL. 403 Male Male Male Male Male Inzelberg et al.21 Benke et al.7 Lopez et al8 Routh and Hill22 Julayanont et al. (current case) 55 83 63 38 61 53 Age (Years) Male Sex 63 neuro.psychiatryonline.org Male Study 404 Vuilleumier et al.19 Leibson20 TABLE 1, continued Dorsomedial and pulvinar Posterior Unspecified Dorsomedial, intralaminar and anterior Pulvinar Unspecified Unspecified Locations Right Right Right Right and Left Right Right Right Hemisphere Acute 2 weeks 5 months 4 weeks Acute Acute Acute Onset Hemorrhage Hemorrhage Ischemic stroke Ischemic stroke Ischemic stroke Hemorrhage Ischemic stroke Etiologies Aggressiveness, speech disinhibition, talkativeness, flight of ideas, and inflated self-esteem Irritability, grandiosity, combative speech, high-energy levels, decreased need for sleep, pressurized speech, euphoria, and inappropriate cheerfulness Euphoria, talkativeness, disinhibition, flight of ideas, hypersexuality, decreased need for sleep, and increased goal-directed activity Logorrhea, restlessness, mood elevation, inflated self-esteem, reduced need for food and sleep, and hypersexuality Cyclic mania Mania episode followed by hypomania Talkativeness, cheerfulness, hypersexuality, and increased energy Manic Symptoms Risperidone, valproic acid, and quetiapine for mania Olanzapine Risperidone with improvement after 4 weeks Paranoid delusions and amnesia Low-dose neuroleptic with improvement after 8 weeks Haloperidol with improvement after 8 weeks Resolved 10 weeks after the stroke Not reported Treatment Bipolar symptoms with cyclic depression, and melancholic stupor Paranoid delusions Amnesia, vertical gaze paralysis, and dysarthria Prosopoaffective agnosia Anosognosia, headache and leftsided numbness and weakness, gaze problem, and hemineglect, Left hemichorea Associated Symptoms BEHAVIORAL DISCONNECTION SYNDROME J Neuropsychiatry Clin Neurosci 29:4, Fall 2017 J Neuropsychiatry Clin Neurosci 29:4, Fall 2017 Female Yoshida et al.28 Female Male 46 Male Noda et al.26 Manford and Anderson27 72 Female Inzelberg et al.25 73 58 75 68 Male Serra et al.24 83 Age (Years) Male Sex Feinberg and Rapcsak23 Study Dorsomedial Pulvinar Anterior Dorsomedial Unspecified Posterior Dorsomedial Locations Left Right Left Right Left Right Right Hemisphere TABLE 2. Cases With Isolated Thalamic Damage Causing Hallucinations Ischemic stroke Ischemic stroke Ischemic stroke Ischemic stroke Ischemic stroke Ischemic stroke Ischemic stroke Etiologies 2 months 10 days 4 days 3 days 2–3 days Acute Acute Onset Auditory No Animals in his house (flying birds and dogs), military marching, girls in an examination room Animals and No men’s head No Musical hallucination of popular songs from her youth Vivid recollection No of his old job, dish of sweet potatoes and cigarette between his fingers Parents who Commanding passed away voice: “Don’t eat” 10 years ago, teapot and teacups on a table Ball of light, a No man in a suit, a black butterfly, dwarves, striped fish swimming No Voices telling her about misfortunes, voices of threats and commands, Visual Hallucination Features Resolved over 2 weeks with no reported treatment Improved with no reported treatment Not reported Resolved in 1 week Treatment Anterograde and retrograde amnesia No neuro.psychiatryonline.org continued Risperidone and olanzapine Not reported Resolved over Memory 2 weeks with impairment, right upper limb no reported treatment weakness Hypersomnolence and nocturnal insomnia Left hemiparesis, paraesthesias Right hemiparesis and dysphasia Vertigo, ataxic gait Associated Symptoms JULAYANONT ET AL. 405 406 neuro.psychiatryonline.org Male Male Female Fornazzari et al.12 Delgado and Bogousslavsky33 Male 48 Male Lee et al.32 Julayanont et al. (current case) 61 Female Mittal and Khan31 55 45 20 19 46 Male Güzelcan et al.30 61 Age (Years) Female Sex Mollet et al.29 Study TABLE 2, continued Dorsomedial and pulvinar Paramedian Dorsomedial Lateral and posterior Anterior Ventroanterior Unspecified Lateral Locations Right Right and Left (right .left) Left Left left Left right Right Hemisphere Hemorrhage Ischemic stroke Ischemic stroke Hemorrhage Ischemic stroke Ischemic stroke Tumor Ischemic stroke Etiologies Visual Auditory 12 months Acute Acute 9 months Acute Dangerous No hands and snakes Sound-tactile, sound-color, and grapheme-gustatory synesthesias Body distortion No above the waist, lights and mice running down the wall No Voice and noise distortion made by “dinosaurs” Musical Transient texts hallucination on his phone, unknown people and colorful airplanes College-age Conversation boys in between colorful college boys Hawaiian shirts, men in black religious clothes Not reported Parades of No people, seeing spiders, mice running Acute No Commanding Voices Acute Onset Hallucination Features Treatment Risperidone Disappeared without treatment Disappeared without treatment Risperidone Disorientation Paranoid delusions and amnesia Not reported Transient perioral and left paresthesias No Confusion, flat Risperidone affect, imaginary boyfriend, and paranoid delusion Amnesia, anomia, and Not reported depersonalization No Pain and numbness Not reported at the left hemibody Associated Symptoms BEHAVIORAL DISCONNECTION SYNDROME J Neuropsychiatry Clin Neurosci 29:4, Fall 2017 JULAYANONT ET AL. FIGURE 2. Proposed Network of Mania and Peduncular Hallucinosis Secondary to Thalamic Lesions Amygdala Anterior cingulate cortex Anterior limb of internal capsule Posterior parietal cortex Extrastriate cortex Disinhibition and enhanced motivation for seeking rewards Amygdalofugal tract Amygdalothalamic tract Emotional, drive and motivation dysregulation Aggression Executive dysfunction and perseveration Orbitofrontal cortex Anterior Dorsolateral prefrontal cortex Medial part Dor som edi al Lateral posterior Intermediate part Superior temporal cortex Medial part Pulvinar Lateral part Multimodal somatosensory-visual synesthesia Anterior insular cortex Problem with integration of somatosensory-auditory-visual stimulations resulting in combined hallucinations Posterior parietal cortex Superior temporal cortex Extrastriate cortex Similar to mania, the diaschisis of neural networks also explains the pathogenesis of peduncular hallucinosis. In the classic peduncular hallucinosis from mesencephalic lesions, the disruption along the pathway from the ascending reticular activating system in the brainstem to the thalamus may contribute to the hallucinations. While in the cases with thalamic lesions, dysregulation between the thalamus and the extrastriate cortex and superior temporal gyrus leads to visual and auditory hallucination, respectively. This hypothesis is supported by a study on the lesion-based restingstate networks, which showed the maximal network overlap for visual hallucinations on the extrastriate visual cortex and for auditory hallucinations on the superior temporal gyrus.11 The pulvinar nucleus is the multimodal integrative nucleus connecting to the posterior parietal, superior temporal, and extrastriate cortices. Damage to this structure may also cause problems with somatosensory-auditory-visual integration, resulting in multimodal hallucinations. The lateral posterior nucleus was reported to cause multimodal somatosensoryvisual-auditory-gustatory synesthesia.12 We propose the network explaining the pathogenesis of mania and peduncular hallucinosis secondary to thalamic lesions (see Figure 2). AUTHOR AND ARTICLE INFORMATION From the Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, Tex. (PJ, DR, KA, YJA). J Neuropsychiatry Clin Neurosci 29:4, Fall 2017 Psychosis and auditory hallucination Problem with emotional awareness Send correspondence to Dr. Julayanont; e-mail: prun_u@hotmail.com; p.julayanont@ttuhsc.edu The authors report no financial relationships with commercial interests. Received Nov. 14, 2016; accepted Dec. 12, 2016; published online March 15, 2017. J Neuropsychiatry Clin Neurosci 2017; 29:401–408; doi: 10.1176/ appi.neuropsych.16110308 REFERENCES 1. Schmahmann JD: Vascular syndromes of the thalamus. Stroke 2003; 34:2264–2278 2. 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