Apathy Due to Cerebrovascular Accidents Successfully Treated With Methylphenidate: A Case Series

M otivation is essential to adaptive functioning. One major syndrome of diminished motivation is apathy, which is defined as a lack of motivation not attributable to delirium, dementia, or emotional distress 1 (i.e., symptoms not caused by cognitive impairment, emotional distress, or diminished level of consciousness). In other words, apathy is not precipitated by a neurological insult or neurogenic apathy. 2 Levy and Dubois 3 added that apathy should also include a reduction of self-generated voluntary and purposeful behavior.

Apathy is often present after direct lesions of the prefrontal cortex. It is also common in clinical features of basal ganglia disease. Therefore, a disruption in the prefrontal cortex-basal ganglia axis may present clinically as apathy. In particular, the emotional-affective component of apathy has been ascribed to lesions in the medial prefrontal cortex and its connection to the ventral striatum. The cognitive component of apathy has been delineated to lesions in the lateral prefrontal cortex, and its striatal input, the dorsal caudate nucleus. Finally, the behavioral component of apathy has been linked to lesions in the globus pallidus, thalamus, and dorsal-medial aspects of the prefrontal cortex. 3

Criteria proposed by Marin 2 for the syndrome of apathy include lack of motivation as manifested by diminished goal-directed overt behavior (e.g., lack of effort or initiative from previous level of functioning); diminished goal-directed cognition (lack of interest in learning new things, in new experiences, or lack of concern about one’s personal health or functional problems); and diminished emotional concomitants of goal-directed behavior (e.g., unchanging or flat affect or absence of excitement or emotional intensity).

Apathy may occur in a variety of neuropsychiatric illnesses whose etiologies include cerebrovascular accidents. 4 While patients with apathy may appear depressed, they lack dysphoria and other signs of depression. Furthermore, these patients tend to respond more robustly to dopamine agonists than to antidepressants. 3 Preliminary but methodologically limited evidence has demonstrated a role for bromocriptine, amantadine, and psychostimulants in the treatment of neurogenic apathy. 5 Psychostimulants have been shown to repeatedly enhance the rate of recovery in certain populations of neurological-based illness, including recovery of motor and speech deficits in stroke patients. 6 While there have been reports of spontaneous improvement of apathy occurring after 3–6 weeks, untreated apathy (especially when comorbid with major depression after a cerebrovascular accident) has been reported to spontaneously remit as long as 1–2 years after a stroke. 7 We now present three patients from our inpatient psychiatric consultation-liaison service who developed apathy status after cerebrovascular accident, with a rapid response to methylphenidate.

Case Reports

Case 1

Our patient is a 53-year-old black man admitted to our teaching hospital after an intracranial hemorrhage involving posterior basal ganglia. The patient was able to give minimal history, and collateral information was sparse at the time of the consultation.

The morning of admission the patient developed dysarthria. In the emergency department, an initial head CT scan showed an intracranial hemorrhage in the posterior left basal ganglia. After evaluation, neurosurgeons declined surgical intervention due to involvement of his dominant hemisphere.

We were consulted regarding the patient’s capacity to make medical decisions. The patient denied dysphoria, psychoses, and suicidal ideation, intent, or plan. Mental status examination was distinguished by diminished goal directed behavior. Our patient spent little time in activities other than viewing TV. He showed decreased spontaneous initiative as he would not engage in physical therapy. He also had diminished socialization, as evidenced by communication with staff or family.

Our patient also displayed diminished goal-directed cognition, such as a lack of concern about his own health. He also had diminished emotional components of goal-directed behavior, such as a flat and unchanging affect. He scored a 16 on the apathy/indifference portion of the Neuropsychiatric Inventory. 8 The patient scored a 24/30 on the Mini-Mental State Examination (MMSE).

We started methylphenidate, 2.5 mg every morning, 5 days after his intracranial hemorrhage, gradually increasing the dose to 7.5 mg every morning and 5 mg at noon.

Two days after beginning methylphenidate our patient continued to have cognitive deficits, but showed improvement in apathy. He was able to initiate conversation, asking more questions concerning his condition and engaging in physical and speech therapy. He also started to read the newspaper and seemed to enjoy the TV programs he was watching. His apathy/indifference score on the Neuropsychiatric Inventory decreased to 3 by the time of his discharge. While our patient’s blood pressure and pulse increased slightly after initiating methylphenidate therapy, it remained normotensive and without tachycardia.

Our patient was discharged to a skilled nursing facility, continuing on methylphenidate. A 1-month follow up at the facility indicated our patient maintained his motivation for therapy.

Case 2

Our patient is a 51-year-old black man with paraplegia. He was admitted to our teaching hospital for treatment of multiple nonhealing decubiti ulcers. As such, a bilateral below-knee amputation was planned. An MRI scan of the head demonstrated an acute left insular cortex infarct. We were consulted to evaluate this patient’s decision-making capacity to consent for the amputation.

On evaluation, he was noted to have significant speech latency. When asked about the amputation, he seemed unconcerned. He understood why he needed it, but did not seem interested in the urgency for the amputation (which was the development of gangrene). In short, he felt he would “eventually” make a decision, but was indifferent in completing the consent process.

He denied dysphoria, psychoses, or suicidal ideation, intent, or plan. On mental status examination, he showed diminished goal-directed behavior as indicated by a lack of effort in participating in the evaluation process with significant increase in speech latency. He lacked goal-directed cognition manifested by his lack of concern about his health problem. Finally, our patient had a flat affect with lack of emotional responsivity regarding his potentially life-threatening condition. The patient scored an 18 on the apathy/indifference part of the Neuropsychiatric Inventory and a 23/30 on the MMSE.

Seven days after the insular cortex infarct, we placed this patient on methylphenidate and increased the dose to 5 mg every morning and noon. Two days after beginning the methylphenidate, he became more alert with decreased speech latency. Two days after this, he began initiating conversation, asking more questions concerning his medical condition and surgery and, after consenting to the below-knee amputation, engaging in physical therapy.

By discharge, our patient scored a 2 on the apathy/indifference scale of the Neuropsychiatric Inventory. His blood pressure and pulse continued to be within normal limits during the treatment course. He remained on methylphenidate at discharge, and on 1 month follow-up, he was reportedly actively engaged in physical therapy.

Case 3

Our patient is a 66-year-old black man admitted to our teaching hospital’s physiatry unit to improve function of his paretic right leg and arm after an ischemic insult to left anterior cerebral artery. An MRI of his brain showed an acute cortical infarct involving most of the left anterior cerebral artery territory. Our consultation service was contacted because the patient was reportedly “feeling depressed.” At the time the consultation was called he was status postcerebrovascular accident for 11 days.

On initial evaluation, our patient had a paucity of speech and only responded to direct questioning. He denied psychoses or dysphoria, but endorsed criteria for alcohol dependence. On mental status examination, our patient demonstrated diminished goal directed behavior, such as a paucity of speech and lack of initiative in engaging in conversation, physical therapy, or interactions with others (socialization). He had decreased goal-directed cognition, as evidenced by his lack of overall interest in the milieu. As for diminished emotional constituents of apathy, our patient generally had a flat affect. He scored a 20 on the apathy/indifference part of the Neuropsychiatric Inventory and a 20/30 on the MMSE.

We initiated methylphenidate, 2.5 mg p.o. every morning for 2 days (day 11, status postcerebrovascular accident), and then increased to 5 mg p.o. every morning. The day after beginning methylphenidate, our patient stated that he “felt better.” His affect was more full range and speech was of normal content. His improvement in motivation enhanced his participation in physical therapy. He also spontaneously began conversation with the treatment team and other patients. His apathy/indifference score on the Neuropsychiatric Inventory decreased to 6 by discharge. Additionally, his blood pressure and pulse remained within normal limits throughout the treatment with methylphenidate.

The patient was discharged from the hospital on methylphenidate; however, given his history of alcohol dependence, he was closely monitored for symptoms of tolerance. According to reports from the skilled nursing facility, he continued to be engaged in physical therapy and rehabilitation.

DISCUSSION

Apathy appears to be common in many disorders of the brain, is associated with a number of adverse outcomes, and is potentially treatable. As tried by others, 9 we utilized methylphenidate for the treatment of apathy due to cerebrovascular accidents.

Apathy is often present after lesions of the prefrontal cortex. It is also a common clinical feature after focal lesions of the basal ganglia and thalamic nuclei, which combined with prefrontal cortex comprise a series of cortical-striatal-pallidal-thalamic-cortical loops influencing motor and nonmotor frontal functions. 4 Levy and Dubois 3 describe three different manifestations of apathy. The first encompasses an affective component of apathy, the second involves cognitive inertia/apathy, and the third involves difficulties in self-activating thoughts or behaviors. 3

We feel that our three patients share features of each of these components of apathy. For instance, each patient demonstrated lack of initiative and effort (behavioral), lack of concern about their own health with an overall decrease of interests (cognitive), and flat affect (emotional).

Interestingly, all three patients had cerebrovascular accidents in different locations of the cortical-striatal-pallidal-thalamic-cortical loop yet presented with similar symptoms. In patient two, the lesion was located in the left insular cortex, which connects to the anterior cingulate cortex (ACC), 10 a purported area (of the “affective” type) of apathy. Rosen 11 later verified this relationship between the right insular cortex and apathy. In patient three, left anterior cerebral artery ischemia resulted in apathy. The left anterior cerebral artery perfuses the ACC 12 and, as such, (“affective”) apathy can be explained.

Patient one’s clinical presentation of apathy could potentially be explained by the lesion in the basal ganglia. It is possible that a subcortical lesion in the cortical-striatal-pallidal-thalamic-cortical system could potentially result in interference of axonal transmission throughout the entire circuit, thereby leading to a failure of activation in the prefrontal targets. 3

Nonetheless, as our patients demonstrated all three components of apathy, this suggests that the prefrontal cortex is functionally and anatomically heterogeneous. 3 Therefore, a structural scan (MRI) may not fully delineate the prefrontal cortex regions involved in the pathogenesis of apathy.

Methylphenidate has been utilized for postcerebrovascular accident depression and traumatic brain injury. Although the potential for abuse of the drug does exist, it is generally well tolerated with a rapid onset of action. 13 A positron emission tomography study showing decreased basal ganglia activity with methylphenidate infusion in healthy volunteers suggests that its mechanism of action may relate to alteration in the functioning of cortical-striatal-pallidal-thalamic-cortical loops at the level of the basal ganglia. 5 The proposed pathophysiology of apathy involves decreased dopamine agonist transmission from the ventral striatum. 14 Methylphenidate works by stimulating dopamine agonist and norepinephrine release and has shown potential in improving mood and functional symptoms in postcerebrovascular accident patients. 15

Our results need to be interpreted with caution, as studies suggest clinical benefits in ischemic cerebrovascular accident occur when psychostimulants are started within 30 days of the insult, although these authors did not rule out that potential benefit could occur outside of this 1-month window 6 Additionally, motor recovery from cerebrovascular accident can occur without psychostimulants as early as 56 days with physical therapy. Another confounding variable about psychostimulant treatment of apathy is that the behavioral, cognitive, and emotional components of apathy can each be improved by the acute mood elevating effects of methylphenidate. 6

Nonetheless, each of our patients’ responded rapidly with a marked decrease in their apathy/indifference Neuropsychiatric Inventory score after as little as 1 to 2 days of methylphenidate. While each of the three patients had an improvement in their ability to participate in rehabilitation, they were all lost to follow up with regard to longer term functioning. Therefore, we feel that our case series needs to be replicated in placebo control studies, both with regard to improvement in apathy and longer term functioning.