Pathological Laughter and Crying in Patients with Multiple System Atrophy-Cerebellar Type

Movement Disorders Vol. 22, No. 6, 2007, pp. 798–803 © 2007 Movement Disorder Society Pathological Laughter and Crying in Patients with Multiple System Atrophy-Cerebellar Type Josef Parvizi, MD, PhD,1* Jeffrey Joseph, MD, PhD,1 Daniel Z. Press, MD,1 and Jeremy D. Schmahmann, MD2 1Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA 2Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA Abstract: In the cerebellar type of multiple system atrophy or crying, or both in 9 more patients. Our finding of about (MSA-C), the burden of pathological changes involves the 36% occurrence suggests that the problem of dysregulation cerebellum and its associated brainstem structures in the of emotional expression is more prevalent in MSA-C basis pontis and the inferior olivary nucleus, and as a result, than the paucity of reports in the literature suggests. Our the clinical phenotype is dominated early on by the cerebel- findings are consistent with the view that the cerebellum and lar dysfunction. We report our clinical and post mor- its interconnected structures may be involved in the regula- tem findings in a patient with MSA-C who exhibited patho- tion of emotional expression. © 2007 Movement Disorder logical laughter in the absence of any congruent changes of Society mood. A review of the clinical notes of 27 other patients Key words: olivopontocerebellar atrophy; disinhibition; with MSA-C revealed a problem with pathological laughter, emotion; behavior; pseudobulbar affect Pathological laughter and crying (PLC) is a condition Numerous terms have been introduced to describe the in which a patient with an underlying neurological dis- problem of inappropriate or exaggerated laughing and order exhibits episodes of laughter or crying or both, crying. The most widely used are “pseudobulbar affect,” without an apparent motivating stimulus or to a stimulus “emotional lability,” “emotionalism,” and “emotional that would not have elicited such emotional response dysregulation.” “Forced laughing and crying,” “involun- prior to the onset of the disease. This problem is char- tary laughing and crying,” “pathological emotionality,” acterized by a deficit in the regulation and coordination and “emotional incontinence” have also been used, al- of emotional expression unlike mood disorders that are though less frequently. In some instances, the same des- characterized by a pervasive and sustained problem of ignations have been applied to clinically different con- emotional experience. In some patients, spells of laugh- ditions, whereas different descriptors have also been ter or crying are out of context and incongruent with, or used to indicate the same clinical presentation. The problem of inappropriate or exaggerated laughing even contradictory to, the valence of the triggering stim- and crying has been reported in patients with stroke, trau- ulus and the mood of the patient. In other patients, spells matic brain injury, multiple sclerosis, amyotrophic lateral of laughing or crying are congruent with the valence of sclerosis, Alzheimer’s disease, frontotemporal dementia, the triggering stimulus and the mood of the patient but brain tumor, central pontine myelinolysis, and corticobasal- pathologically exaggerated in intensity or duration. ganglionic degeneration.1 Here we report the occurrence of the same problem in multiple system atrophy–cerebellar type (MSA-C), a sporadic progressive synucleinopathy characterized by cerebellar dysfunction and autonomic fail- *Correspondence to: Dr. Josef Parvizi, Department of Neurology, ure with lesser degrees of parkinsonism and corticospinal University of California Los Angeles School of Medicine, 710 West- wood Plaza, Los Angeles, CA 90095. E-mail: [email protected] or findings. [email protected] Received 10 June 2006; Revised 17 September 2006; Accepted 17 CASE STUDY October 2006 Published online 8 February 2007 in Wiley InterScience (www. Patient 1 died in 2005 at the age of 80 with the clinical interscience.wiley.com). DOI: 10.1002/mds.21348 diagnosis of MSA-C. He saw a neurologist in 1999 for 798 LAUGHING AND CRYING IN MSA-C 799 the evaluation of falling and was noted to have ataxic phic. In contrast, the cerebral cortex showed age-appro- gait and intermittent tremor in the right hand. A treat- priate atrophy without any structural lesions. The lepto- ment trial with carbidopa/levodopa (Sinemet CR 50/200 meninges were clear, and the ventricles were of normal three times daily) and pergolide (Permax 0.25 mg three size. The basal ganglia structures and the red nuclei times daily) produced no detectable clinical improve- displayed no atrophy or discoloration. The substantia ment. During his first visit with us in 2000, he com- nigra was pigmented. plained of sexual dysfunction that had been present for Selected areas of the brain were examined microscop- ϳ2 years, as well as worsening falls, unsteady gait, ically using conventional silver, H&E, and Bielschowsky slurred speech, and intermittent tremor in the right hand stains. Additional sections were also processed with im- for less than a year. Past medical history was otherwise munohistochemical labeling of ␣-synuclein for glial cy- unremarkable. He did not smoke or drink alcohol. He toplasmic inclusions (GCIs). In the cerebellum there was worked as a farmer most of his life and was still engaged a partial loss of neuropil with preservation of radial glial in landscaping work. He had no history of traumatic fibers in the molecular layer, subtotal loss of Purkinje brain injury, seizures, headaches, or stroke, and did not neurons, and an intact granular layer (Fig. 1). The neu- report any daytime sleepiness or memory problems. His rons of the dentate nucleus were preserved. The white family history was negative for neurological problems. matter of the medullary core and the cerebellar folia was On our initial neurological exam, he had a slightly markedly gliotic and devoid of myelinated axons. Re- reduced verbal fluency and mild dysarthria, with a mod- maining cells contained numerous ␣-synuclein reactive erate degree of bilateral ataxia and a wide-based gait. GCIs. The brainstem revealed gliosis, marked loss of Blood pressure was unchanged from the recumbent to neurons and their myelinated axons, and a dense concen- standing positions. Brain MRI at the outside facility tration of ␣-synuclein reactive GCIs in the basis pontis, revealed brainstem and cerebellar atrophy. Unsteady gait the pontocerebellar fibers, the inferior olivary nuclei, and worsened, resulting in falls. He developed symptomatic the olivocerebellar fibers (Fig. 1). The ventrolateral re- postural hypotension, and unsteadiness and tremor con- gion of the medulla, the gigantocellular nucleus, the tinued to deteriorate to the extent that he had to use two medial and spinal vestibular nuclei, the dorsal motor hands to hold a glass. Later examination revealed hyper- nucleus of vagus, the solitary nucleus of vagus, and the metric saccades, dysmetria of the upper extremities, and area postrema showed less prominent degeneration on worsening of gait ataxia. When he became wheelchair conventional staining in addition to GCIs. There were no bound, the patient reported mood changes and neuroveg- pathological findings on samples obtained from the mid- etative signs consistent with depression (i.e., anhedonia, dle frontal gyrus or hippocampus, nor was there any sign anergia, sleep disturbance, and psychomotor slowing). of degeneration in the red nucleus, raphe nuclei, periaq- At the same time his wife reported that the patient was ueductal gray, ventral tegmental area, locus coeruleus, “more giggly” than before. He had frequent outbursts of nucleus ambiguous, superior cerebellar peduncles, me- emotional expression consistent with happiness despite dial lemniscus, central tegmental tracts, or the cortico- an emotional experience consistent with depression. His spinal tracts. wife reported that he had a tendency to laugh inappro- priately. These laughter spells were “forced,” uncontrol- ADDITIONAL CASES lable, and inappropriate, and “not from his heart.” On our Alerted by the observations in patient 1, we reviewed examination in spring 2002, he was surprisingly jovial the medical records of all patients diagnosed with despite his increasing disability. Six months later, the MSA-C by one of us (J.D.S.) in the Ataxia Unit of the patient complained of worsening depression and his wife Massachusetts General Hospital (MGH). Twenty-seven reported that he had become more irritable and occasion- patients met consensus criteria2 for the clinical diagnosis ally “nasty.” Therapy with citalopram (Table 1) did not of probable MSA-C. These patients had been referred to improve the spells of inappropriate laughter that contin- the Ataxia Unit because of predominant cerebellar defi- ued despite his increasing disability. His condition con- cits rather than neuropsychiatric problems. All patients tinued to decline, and he died in April 2005 from aspi- were currently under the care of JDS and were being ration pneumonia. followed regularly. PLC was recorded in 9 patients, bringing the total Neuropathological Findings number of our MSA-C patients with this problem to 10 On macroscopic inspection, the cerebellum was atro- (Table 1). Five patients had only pathological laughing phic and its white matter sunken and brownish. The base and 5 had pathological laughing and crying. Of note, of the pons was flattened and the olives

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