Pseudobulbar laughter as a levodopa off phenomenon exacerbated by subthalamic deep brain stimulation
© Chattha et al. 2015
Received: 3 June 2015
Accepted: 27 July 2015
Published: 14 August 2015
Pseudobulbar affect is a common symptom in neurodegenerative diseases and can also result from lesions in cortical, subcortical and brainstem regions. In Parkinson’s disease (PD), pseudobulbar affect (PBA) can occur as a wearing off phenomenon, manifested usually as crying without emotionality. In addition, subthalamic (STN) deep brain stimulation (DBS) has been reported to induce PBA in PD patients with no prior history of such episodes.
We present a case of inappropriate laughter lacking mirth as a levodopa OFF phenomenon in a patient with PD, whose laughter also worsened with STN-DBS in his non-medicated state. Levodopa ameliorated his PBA both with and without stimulation.
The case demonstrates pseudobulbar laughter as a levodopa OFF phenomenon that is also exacerbated by STN-DBS.
Pseudobulbar affect (PBA) is described as uncontrollable and inappropriate laughter or crying. It occurs without environmental or internal cues and can be conflicting with an individual’s emotional intentions. It is commonly associated with neurodegenerative disease (i.e., ALS, PSP) as well as with lesions [1–4] in the cortex, subcortical white matter, and brainstem, oftentimes resulting in dysfunction of the corticobulbar tract. The prevalence of PBA in patients with Parkinson’s disease is 5–17 % , and has been reported as a stimulation induced symptom in patients with subthalamic (STN) deep brain stimulation (DBS) [6–8]
We report a case of pseudobulbar laughter in a patient with PD as a levodopa off phenomenon that is further exacerbated by STN-DBS.
A 52-year-old man with Parkinson’s Disease with STN-DBS presented with pseudobulbar laughter in the OFF medication/ON Stimulation state. At the age of 40, the patient developed tremors in his fingers accompanied by stiffness in his limbs and asymmetric left side bradykinesia. In the ensuing years, he was plagued by motor fluctuations and dyskinesia with unpredictable offs and freezing of gait. His presurgical neuropsychiatric assessment did not reveal underlying depression or anxiety. He was never treated with antidepressants or antipsychotic medications. On the morning of his implantation of bilateral subthalamic nucleus (STN) DBS at an outside institution, he reports that he had bouts of uncontrollable laughter without mirth for the first time in the surgical waiting area prior to be taken into the operating room. He was supposedly off of his PD medications for at least 12 h at that time. Following the surgery, which occurred without complications, attempts by other clinicians to program his DBS while he was off his PD medications apparently produced inappropriate episodes of laughter. Over the next 9–12 months, though his dyskinesia improved, he continued to have motor fluctuations with no evidence of PBA.
This case describes pseudobulbar laughter as a levodopa off phenomenon. Non-motor symptoms (NMS) of Parkinson’s disease include anxiety, mood changes, and panic attacks, as well as autonomic changes  (e.g., sweating, abdominal discomfort, numbness, and pain) Such symptoms can occur as an OFF phenomenon that improves with dopaminergic therapy . Pseudobulbar affect is not uncommon in PD especially in the advanced stages. Inappropriate crying is the most common manifestation of PBA in this disease  though it is often associated with a state of depression. It has also been described as occurring in the Off medication state . Our patient’s bouts of laughter, which lacked mirth, is not only indicative of PBA, but its onset and resolution as a function of levodopa dosing supports it as an non-motor OFF phenomenon. Lack of levodopa tends to produce a dysphoric state, which makes the presence of non-mirthful laugher in such a condition very interesting and difficult to differentiate as a product of an emotional stimulus despite this patient not having a history of depression or being on antidepressants.
Stimulation and Stereotactic Surgical Causes of PBA
Okun et al. 
Left subthalamic nucleus
1.5 V, 90 μs, 130Hz
Krack et al. 
Bilateral Subthalamic nucleus
3.6 V/90 μs/160Hz
Right Subthalamic nucleus
5.0–5.5 V/60 μs/130Hz
Low et al. 
Bilateral subthalamic nucleus
0.5 V/60 μs/130Hz
>1.0 V/60 μs/130Hz
Okun et al. 
Right ventral intermedius nucleus (VIM)
The acute worsening of non-mirthful laughter was evident with increased stimulation in our patient through all contacts, though there was a clear propensity for greater effect among the ventral contacts. The STN has several functional regions including: 1) the dorsolateral area, which governs motor control; 2) the ventromedial region that interfaces with limbic circuits. The medial STN is also adjacent to the lateral hypothalamus and embryologically develops along with it. It is plausible that medial STN stimulation impacts cognitive and emotional networks thus triggering PBA. Furthermore, the facial flushing and diaphoresis observed at higher voltages through the ventral contacts, not only supports medial spread of stimulation but also effects on the lateral hypothalamus which could also potentiate it as a limbic release phenomenon.
The fasciorespiratory center lies in the brainstem and was postulated by Wilson  that unknown descending cortical pathways, which when disconnected by a lesion, releases voluntary control of the involuntary laughter and crying centers. Cortical, subcortical and brainstem lesions  have been associated with PBA, with a quantitative MRI study among MS patients with PBA  revealing distribution of putative lesions in the prefrontal, parietal and brainstem. Cognitive studies [16, 17] suggest that the prefrontal cortex is a mediator of emotional expression that receives input from the parietal cortex and also sends projections to the hypothalamus and brainstem. In addition, the cerebellar outflow pathways may also serve as a modulator of involuntary expression of emotion . Therefore, stimulation in fiber tracts surrounding the STN (caudal zona incerta, medial forebrain bundle, prelemniscal, and caudal internal capsule ) could possibly inhibit the voluntary brainstem emotional expression circuit, thus resulting in pseudobulbar laughter. The fact that stimulation worsened PBA in our patient further suggests that the emotional expressivity network may have been primed in the OFF state.
This case highlights pseudobulbar laughter as a novel Parkinson’s off phenomenon that is negatively affected by STN-DBS, yet ameliorated, like all other non-motor offs, with levodopa.
The patient has provided consent for this report and the video that accompanies it.
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- Kim JS. Pathological laughter and crying in unilateral stroke. Stroke. 1997;28:2321.PubMedGoogle Scholar
- Martin JP. Fits of laughter (sham mirth) in organic cerebral disease. Brain. 1950;73:453–64.View ArticlePubMedGoogle Scholar
- Allman P. Poststroke pathological laughing and crying. Am J Psychiatry. 1994;151:291. author reply −2.View ArticlePubMedGoogle Scholar
- Virani MJ, Jain S. Trigeminal schwannoma associated with pathological laughter and crying. Neurol India. 2001;49:162–5.PubMedGoogle Scholar
- Miller A, Pratt H, Schiffer RB. Pseudobulbar affect: the spectrum of clinical presentations, etiologies and treatments. Expert Rev Neurother. 2011;11:1077–88.View ArticlePubMedGoogle Scholar
- Okun MS, Raju DV, Walter BL, Juncos JL, DeLong MR, Heilman K, et al. Pseudobulbar crying induced by stimulation in the region of the subthalamic nucleus. J Neurol Neurosurg Psychiatry. 2004;75:921–3.PubMed CentralView ArticlePubMedGoogle Scholar
- Krack P, Kumar R, Ardouin C, Dowsey PL, McVicker JM, Benabid AL, et al. Mirthful laughter induced by subthalamic nucleus stimulation. Mov Disord. 2001;16:867–75.View ArticlePubMedGoogle Scholar
- Low HL, Sayer FT, Honey CR. Pathological crying caused by high-frequency stimulation in the region of the caudal internal capsule. Arch Neurol. 2008;65:264–6.View ArticlePubMedGoogle Scholar
- Seki M, Takahashi K, Uematsu D, Mihara B, Morita Y, Isozumi K, et al. Clinical features and varieties of non-motor fluctuations in Parkinson’s disease: a Japanese multicenter study. Parkinsonism Relat Disord. 2013;19:104–8.View ArticlePubMedGoogle Scholar
- Strowd RE, Cartwright MS, Okun MS, Haq I, Siddiqui MS. Pseudobulbar affect: prevalence and quality of life impact in movement disorders. J Neurol. 2010;257:1382–7.View ArticlePubMedGoogle Scholar
- Cooper SE, McIntyre CC, Fernandez HH, Vitek JL. Association of deep brain stimulation washout effects with Parkinson disease duration. JAMA Neurol. 2013;70:95–9.View ArticlePubMedGoogle Scholar
- Okun MS, Heilman KM, Vitek JL. Treatment of pseudobulbar laughter after gamma knife thalamotomy. Mov Disord. 2002;17:622–4.View ArticlePubMedGoogle Scholar
- Wilson SA. Original papers: some problems in neurology. J Neurol Psychopathol. 1924;4:299–333.PubMed CentralView ArticlePubMedGoogle Scholar
- Siddiqui MS, Fernandez HH, Garvan CW, Kirsch-Darrow L, Bowers D, Rodriguez RL, et al. Inappropriate crying and laughing in Parkinson disease and movement disorders. World J Biol Psychiatry. 2009;10:234–40.View ArticlePubMedGoogle Scholar
- Ghaffar O, Chamelian L, Feinstein A. Neuroanatomy of pseudobulbar affect : a quantitative MRI study in multiple sclerosis. J Neurol. 2008;255:406–12.View ArticlePubMedGoogle Scholar
- Feinstein A, O’Connor P, Gray T, Feinstein K. Pathological laughing and crying in multiple sclerosis: a preliminary report suggesting a role for the prefrontal cortex. Mult Scler. 1999;5:69–73.View ArticlePubMedGoogle Scholar
- McCullagh S, Moore M, Gawel M, Feinstein A. Pathological laughing and crying in amyotrophic lateral sclerosis: an association with prefrontal cognitive dysfunction. J Neurol Sci. 1999;169:43–8.View ArticlePubMedGoogle Scholar
- Parvizi J, Anderson SW, Martin CO, Damasio H, Damasio AR. Pathological laughter and crying: a link to the cerebellum. Brain. 2001;124:1708–19.View ArticlePubMedGoogle Scholar