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A Case of Abulia From Left Middle Cerebral Artery Stroke in an Adolescent Treated Successfully With Short Duration Olanzapine

Connor, Andrew T. DO; Crawford, Alex MBBS; Levy, Rebecca J. MD, PhD; Schneider, Lauren M. PsyD; Hollander, Seth A. MD; Shaw, Richard J. MD

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doi: 10.1097/WNF.0000000000000389
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Abstract

Abulia is defined as a pathological state of amotivation, apathy, and global absence of willpower seen in a number of diverse conditions including Alzheimer disease, Parkinson's disease, stroke, and depression.1 The neurobiological etiology is still unclear but postulated to be related to deficits in the dopaminergic reward circuitry in the frontal-subcortical-mesolimbic regions. Previous case reports show benefit in modulation of the dopamine circuitry following treatment with psychostimulants, bromocriptine, carbidopa/levodopa, as well as atypical antipsychotics. We describe a case of an adolescent male who developed abulia after placement of a ventricular assist device (VAD) and who had a subacute history of left MCA infarct treated who was successfully with intramuscular (IM) olanzapine.

CASE HISTORY

C. is a 17-year-old left-handed boy of normal health who suffered a generalized seizure and right hemiparesis while at school and was subsequently found to have a left MCA thrombus secondary to previously undiagnosed dilated cardiomyopathy. He was treated with tissue plasminogen activator and mechanical thrombectomy and later was discharged with minimal neurological sequelae except for mild right-sided facial/limb weakness, spasticity, and tremor. However, he was noted to have transient amotivation about engaging in activities, such as getting out of bed, eating, showering, and participating in physical therapy. Additionally, his mother described a blunting of his personality after the stroke, for example, showing no investment in subjects for which he had previously been very opinionated.

C. was admitted to the cardiovascular intensive care unit 2 months after the initial event for concerns of decompensating left ventricular heart failure. He failed medical management with milrinone. Psychiatry was consulted as part of the routine pretransplant evaluation to complete a general mental health screening and risk assessment. We found no prior psychiatric risks aside from chronic cannabis abuse and witnessing domestic abuse as a child. Although listing for cardiac transplant was recommended, C. was unwilling to commit to abstaining from marijuana. He instead consented to undergo indefinite VAD placement rather than VAD placement as a temporary bridge to transplant. There were no intraoperative complications of note. His postprocedure course was complicated by severe mutism, insomnia, anorexia, and nonadherence to medications or rehabilitation. His pre- and post-VAD head imaging showed encephalomalacia within the left MCA territory consistent with his history specifically showing involvement of the left inferior frontal, basal ganglia, insula, and temporal lobe. Neurology consultation suggested no interval large infarctions on imaging and stable physical examination (see Fig. 1).

FIGURE 1
FIGURE 1:
CT head without contrast after admission to our hospital demonstrating hypodensity of left middle cerebral artery territory consistent with a prior infarct and encephalomalacia of the left (A) temporal pole, (B) superior temporal lobe, (C) inferior frontal cortex and insula, and (D) basal ganglia.

Psychiatry consultation was requested to evaluate possible etiologies for C.'s changes in mental status. His differential diagnosis included delirium, catatonia, heart failure-related depression, cannabis-related amotivation, post-VAD mutism, behavioral/volitional problems, and hypoxic neurological sequalae from the procedure. Of particular concern was C.'s passive refusal to take any medications or eat, even with strong prompting. This involved anticoagulation management indicated for recurrent stroke prevention and the eventual need for total parenteral nutrition due to electrolyte disturbances leading to further cardiac decompensation from malnutrition. C. denied any subjective depressed mood or rationale for his behaviors. There was no waxing or waning of his mentation or orientation. His score on the Montreal Cognitive Assessment was 6 with limitations from minimal participation by C. His initial Bush-Francis Catatonia Rating screening score was 5, with positive findings for immobility, mutism, and withdrawal; however, he did not meet clinical criteria for catatonia.

C. was treated initially with oral mirtazapine including oral disintegrating tablets to target symptoms of insomnia and food refusal, yet he was initially not willing to take this. Consideration was given to transcutaneous stimulants; however, his parent declined consent due to fears of addiction and cardiac risks. Bromocriptine, which has an indication for abulia, was considered but C. was again unwilling to take oral medications.

Based on a previous case study wherein a geriatric patient with similar dominant MCA stroke-related abulia was successfully treated with olanzapine, C. was started on a trial of IM olanzapine 2.5 mg at night.1 On day 3, olanzapine was increased to 5 mg/d followed by his first spontaneous social interaction since his symptom onset, where he initiated a phone call with his mother. On day 5, C.'s olanzapine was increased to 7.5 mg/d, and on day 6, he participated in a daily weight check and took oral cardiac medications crushed in orange juice. By day 7, C. was showing more social behaviors with reciprocal smiling, conversing in more structured phrases, taking all oral medications, and willingly taking a shower. On day 8, C. communicated in full sentences, requested to be part of the decision making during rounds, and ambulated around the unit with physical therapy. By day 12, C. continued to be expressive and incrementally more social, eating full meals, and taking all oral medications. He had insight that his behavior had changed but was unable to give an explanation for his previous apathy and amotivation.

By the time of his discharge, C.'s abulia had nearly fully resolved. His olanzapine was tapered and discontinued over the course of 2 weeks, and he was discharged on methylphenidate 5 mg by mouth daily after parent reconsidered consent to treat residual amotivation and mirtazapine 7.5 mg by mouth nightly for sleep/appetite. He expressed a renewed desire to pursue sobriety and investment in being considered for cardiac transplant.

DISCUSSION

Abulia is a condition with growing clinical recognition.2–11 A number of neuroanatomical areas have been postulated to play a role, with some of the most predominant in the literature involving the mesolimbic dopamine systems.12–18 In particular, pathology affecting the medial prefrontal cortex and anterior cingulate cortex have been noted in a number of cases. Areas surrounding these structures have also been implicated, including the basal ganglia, internal capsules, the corona radiata, orbitofrontal cortex, the dorsolateral prefrontal cortex, and the supplementary motor areas.12–15 It has also been suggested that the cerebellum may play a role, with several abulic patients found to have damage to the cerebellum, frontocerebellar pathways, neuronal damage due to alcohol or status-post cerebellar tumor resection.11,19 Furthermore, there have been cases reporting abulia in the presence of more generalized pathology, namely, obstructive hydrocephalus and pathological periventricular white matter, intraventricular hemorrhage, and subarachnoid hemorrhage.11,20 There have also been some inconsistent data that suggest a right versus left hemisphere dominance in producing apathy.21 Finally, in some cases of abulia, there has been an absence of overt anatomical pathology noted on imaging, with only abnormalities on functional MRI imaging.22,23 In summary, abulia may be a symptom of focal or diffuse brain injury, including ischemic or hemorrhagic stroke, and is likely underdiagnosed because it does not localize readily to one brain region but instead to disruptions to a complex circuit.

It is essential to differentiate between abulia and the myriad of other poststroke symptoms which may also be comorbid in a patient. Stroke survivors may experience neglect of visual or other sensory fields, aphasia or other language deficits, and/or impaired cognition that impacts socialization, all of which can mimic and contribute to abulia. Moreover, there is a high incidence of depression after stroke. Meta-analyses estimate the rate of poststroke depression at 31% and onset can be immediate within days or delayed by years, whereas abulia is found in 20% to 25% of patients with similarly variable time of onset from days to months and up to 50% of the patients carried both diagnoses.24–26 This creates a diagnostic dilemma best addressed by validated screening tools and careful clinical assessment of patients.

Although the exact anatomical basis for abulia is yet to be determined, some of the most robust clinical evidence, thus far, implicates dopamine networks.27,28 There are plentiful anecdotal reports of symptomatic improvements in response to various dopaminergic treatment methods, including antipsychotics, dopamine antagonists, carbidopa/levodopa, and methylphenidate/amantadine.11,13,14,29 Commonly, first-line treatment for abulia includes bromocriptine, amantadine, or carbidopa/levodopa. However, in the case of our patient, his refusal to take oral medications led us to the choice of IM olanzapine which resulted in a rapid and significant clinical response.

Understanding the mechanisms of action of the atypical antipsychotic drugs (APDs) may help further elucidate the primary pathophysiology of abulia. A number of APDs have been used in the treatment of abulic patients, in particular, olanzapine and sulpiride. Antipsychotic drugs have long been known to be effective in treating negative symptoms in schizophrenia, including amotivation, mutism, and flattened affect.30 Antipsychotic drugs are typically known as D2 selective antagonists, which is counterintuitive given the proposed importance of dopamine in treating abulia; however, it has been shown that overall APDs increase dopamine in the prefrontal cortex.18,20,29–34 The exact mechanism behind this is unclear; however, it is theorized to result from the antagonism of 5-HT 1A and 2A receptors by APDs, and their consequent disinhibition of D2 receptors.32,35 For example, it was shown that APDs with greater 5-HT 2A receptor affinity resulted in greater prefrontal cortex dopamine release.28 In contradiction to this, in 5-HT 2A KO mice, olanzapine was shown to still increase cortical dopamine, but in 5-HT 1A KO mice, no increased dopamine was observed.31

One theory suggests that the relative blockade of D2 receptors in the mesolimbic pathway and 5-HT 2A receptor blockade in the mesocortical pathway leads to an increase in cortical dopamine.18 Interestingly, in 1 case report, an abulic patient who was initially responding positively to treatment with bromocriptine alone, once started on concurrent sulpiride, experienced symptom regression.14 This further suggests the importance of the selective antagonism of these specific receptors on the pathways involved in abulia.

Questions not answered with respect to the use of APSs include reports that only brief treatment is required for symptom relief, as was the case with our patient.1 To maintain C's clinical response, and to address underlying issues with amotivation, possibly connected to his history of chronic marijuana abuse, he was started on methylphenidate (5 mg PO daily). Like amantadine, methylphenidate inhibits dopamine reuptake, increasing the synaptic concentration of dopamine, and has been shown to be effective for a number of abulic patients.29,36,37 However, there have also been several abulia cases which failed to respond to either methylphenidate or amantadine, despite later responding to treatment with carbidopa/levodopa.11 This indicates that although effective in some abulic patients, the therapeutic benefit may be dependent on the location of the lesion. The natural history of untreated poststroke abulia is not clear in the literature especially in regard to an adolescent population; one study found that patients with subcortical infarcts had increasing rates of apathy and cognitive abulia over 24 months, raising concern that abulia does not self-resolve without intervention.38

Another interesting aspect of this case is that this patient developed marked abulia shortly after implantation of a continuous flow VAD. Surgical implantation of a VAD is similar to other cardiac surgery inasmuch as cardiopulmonary bypass is required, however, is unique in its ability to rapidly restore normal cardiac output. Prior studies have shown that such an abrupt improvement in cardiac output, particularly in the form of continuous flow, may lead to disruption of several physiologic processes, including the functioning of the autonomic nervous system via abnormal neurosignaling of aortic baroreceptors.39–43

We have observed in the early postimplant period a peculiar phenomenon in which children, previously friendly and engaged, will temporarily become aphasic, expressionless, and detached while at the same time awake and hyperalert. Interestingly, this phenomenon is not observed in children after traditional surgery for congenital heart disease even when cardiopulmonary bypass is used, and appears to be specific to children with implanted VADs. This behavior is also not observed in adults after VAD implantation. These symptoms, which we have characterized as catatonic dissociation, are distinct from what we observed in this patient, some of his symptoms do overlap with those we have observed in other patients.

CONCLUSIONS

This case report describes for the first time the effective use of olanzapine in the treatment of an adolescent with abulia. Further research is needed to develop a better understanding of the pathophysiologic mechanisms underlying abulia, possibly targeting dopaminergic circuitry. This will hopefully lead to more effective treatment algorithms, including more specific diagnostic tools to discern a myriad of similarly presenting pathologies and to establish whether the location of the lesion should also be considered when making treatment decisions. Of particular importance to our case is the availability of IM medications as a potentially lifesaving option for those patients who are refusing oral medications.

REFERENCES

1. Spiegel D, Chatterjee A. A case of abulia, status/post right middle cerebral artery territory infarct, treated successfully with olanzapine. Clin Neuropharmacol 2014;37(6):186–189.
2. Marin RS. Differential diagnosis and classification of apathy. Am J Psychiatry 1990;147(1):22–30.
3. Marin RS. Apathy: a neuropsychiatric syndrome. J Neuropsychiatry Clin Neurosci 1991;3(3):243–254.
4. Stuss DT, Van Reekum R, Murphy KJ. Differentiation of states and causes of apathy. In: The neuropsychology of emotion. New York, NY: Oxford University Press; 2000:340–363.
5. Marin RS, Biedrzycki RC, Firinciogullari S. Reliability and validity of the apathy evaluation scale. Psychiatry Res 1991;38(2):143–162.
6. Cummings JL, Mega M, Gray K, et al. The neuropsychiatric inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994;44(12):2308–2314.
7. Steriade M, Botez MI, Petrovici I. On certain dissociations of consciousness levels within the syndrome of akinetic mutism. Psychiatr Neurol Bael 1961;141:38–58.
8. Sadock BJ, Sadock VA. Comprehensive Textbook of Psychiatry. 7th ed. Philadelphia: Williams & Wilkins; 2000.
9. Anderson CA, Arciniegas DB, Huddle DC, et al. Akinetic mutism following unilateral anterior cerebral artery occlusion. J Neuropsychiatry Clin Neurosci 2003;15(3):385–386.
10. Burruss JW, Chacko RC. Episodically remitting akinetic mutism following subarachnoid hemorrhage. J Neuropsychiatry Clin Neurosci 1999;11(1):100–102.
11. Drubach DA, Zeilig G, Perez J, Peralta L, Makley M. Treatment of abulia with carbidopa/levodopa. J Neurol Rehabil 1995;9(3), 151–155.
12. Vijayaraghavan L, Krishnamoorthy ES, Brown RG, et al. Abulia: a delphi survey of British neurologists and psychiatrists. Mov Disord 2002;17(5):1052–1057.
13. Ross ED, Stewart RM. Akinetic mutism from hypothalamic damage: successful treatment with dopamine agonists. Neurology 1981;31(11):1435–1439.
14. Barrett K. Treating organic abulia with bromocriptine and lisuride: four case studies. J Neurol Neurosurg Psychiatry 1991;54(8):718–721. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1014478/.
15. Bakheit A, Fletcher K, Brennan A. Successful treatment of severe abulia with co-beneldopa. NeuroRehabilitation 2011;29:347–351.
16. Trzepacz P, Meagher D. Delirium, in Textbook of Psychosomatic Medicine. In: Levenson JL, ed. 1st ed. Arlington, VA: American Psychiatric Publishing, Inc.; 2005:91–130.
17. Combarros O, Infante J, Berciano J. Akinetic mutism from frontal lobe damage responding to levodopa. J Neurol 2000;247(7):568–569.
18. Spiegel D, Casella DP, Callender DM, et al. Treatment of akinetic mutism with intramuscular olanzapine: a case series. J Neuropsychiatry Clin Neurosci 2008;20(1):93–95.
19. Steinlin M, Imfeld S, Zulauf P, et al. Neuropsychological long-term sequelae after posterior fossa tumour resection during childhood. Brain 2003;126(Pt 9):1998–2008.
20. Ferro JM. Hyperacute cognitive stroke syndromes. J Neurol 2001;248(10):841–849.
21. Härtel C, Schilling S, Sperner J, et al. The clinical outcomes of neonatal and childhood stroke: review of the literature and implications for future research. Eur J Neurol 2004;11(7):431–438.
22. Ichise M, Chung DG, Wang P, et al. Technetium-99m-HMPAO SPECT, CT and MRI in the evaluation of patients with chronic traumatic brain injury: a correlation with neuropsychological performance. J Nucl Med 1994;35(2):217–226.
23. Drubach DA, Carmona S, Meyerrose GE, et al. Brain SPECT in a case of cortical blindness. Stroke 1994;25(5):1061–1064.
24. Starkstein SE, Fedoroff JP, Price TR, et al. Apathy following cerebrovascular lesions. Stroke 1993;24(11):1625–1630.
25. Robinson RG, Jorge RE. Post-stroke depression: a review. Am J Psychiatry 2016;173(3):221–231.
26. Jorge RE, Starkstein SE, Robinson RG. Apathy following stroke. Can J Psychiatry 2010;55(6):350–354.
27. Azulay J-P, Mesure S, Amblard B, et al. Visual control of locomotion in Parkinson's disease. Brain 1999;122(1):111–120.
28. Ichikawa J, Ishii H, Bonaccorso S, et al. 5-HT(2A) and D(2) receptor blockade increases cortical DA release via 5-HT(1A) receptor activation: a possible mechanism of atypical antipsychotic-induced cortical dopamine release. J Neurochem 2001;76(5):1521–1531.
29. Challman TD, Lipsky JJ. Methylphenidate: its pharmacology and uses. Mayo Clin Proc 2000;75(7):711–721.
30. Fleet WS, Watson RT, Valenstein E, et al. Dopamine agonist therapy for neglect. Neurology 1986;36(Suppl 1):347.
31. Bortolozzi A, Masana M, Díaz-Mataix L, et al. Dopamine release induced by atypical antipsychotics in prefrontal cortex requires 5-HT(1A) receptors but not 5-HT(2A) receptors. Int J Neuropsychopharmacol 2010;13(10):1299–1314.
32. Stahl SM. Describing an atypical antipsychotic receptor binding and its role in pathophysiology. Prim Care Companion J Clin Psychiatry 2003;5:9–1.
33. Marangell LB, Johnson CR, Kertz B, et al. Olanzapine in the treatment of apathy in previously depressed participants maintained with selective serotonin reuptake inhibitors: an open-label, flexible-dose study. J Clin Psychiatry 2002;63(5):391–395.
34. Tollefson GD, Sanger TM. Negative symptoms: a path analytic approach to a double-blind, placebo- and haloperidol-controlled clinical trial with olanzapine. Am J Psychiatry 1997;154(4):466–474.
35. Etkin A, Egner T, Kalisch R. Emotional processing in anterior cingulate and medial prefrontal cortex. Trends Cogn Sci 2011;15(2):85–93.
36. Daly DD, Love JG. Akinetic mutism. Neurology 1958;8(3):238–242.
37. Kaplitz SE. Withdrawn, apathetic geriatric patients responsive to methylphenidate. J Am Geriatr Soc 1975;23(6):271–276.
38. Moretti R, Torre P, Antonello RM, et al. Behavioral alterations and vascular dementia. Neurologist 2006;12(1):43–47.
39. Tank J, Heusser K, Malehsa D, et al. Patients with continuous-flow left ventricular assist devices provide insight in human baroreflex physiology. Hypertension 2012;60(3):849–855.
40. Markham DW, Fu Q, Palmer MD, et al. Sympathetic neural and hemodynamic responses to upright tilt in patients with pulsatile and nonpulsatile left ventricular assist devices. Circ Heart Fail 2013;6(2):293–299.
41. Dimopoulos S, Diakos N, Tseliou E, et al. Chronotropic incompetence and abnormal heart rate recovery early after left ventricular assist device implantation. Pacing Clin Electrophysiol 2011;34(12):1607–1614.
42. Shomura Y, Shimpo H, Tanaka K, et al. The cause of the difference between the arterial baroreceptor reflex under natural pulsatile circulation and under nonpulsatile systemic circulation. J Artif Organs 1999;2(1):30–34.
43. Nunan D, Sandercock GR, George RS, et al. Cardiovascular autonomic control in patients undergoing left ventricular assist device (LVAD) support and pharmacologic therapy. Int J Cardiol 2013;168(4):4145–4149.
Keywords:

abulia; MCA infarction; VAD; olanzapine; adolescent

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