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Three cases of Creutzfeldt–Jakob disease with prion protein gene codon180 mutation presenting with pathological laughing and crying
Journal of the Neurological Sciences 319 (2012) 47–50
Contents lists available at SciVerse ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Three cases of Creutzfeldt–Jakob disease with prion protein gene codon180 mutation presenting with pathological laughing and crying Yasushi Iwasaki ⁎ Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University, 1‐1 Yazakokarimata, 480‐1195 Nagakute, Japan
a r t i c l e
i n f o
Article history: Received 24 March 2012 Received in revised form 7 May 2012 Accepted 9 May 2012 Available online 31 May 2012 Keywords: Creutzfeldt–Jakob disease Codon180 Pathological laughing and crying Startle reaction Widespread cerebral cortical imvolvement
a b s t r a c t Although there are no reports of pathological laughing and crying being observed in patients with Creutzfeldt–Jakob disease (CJD), the author experienced three patients with CJD with prion protein gene codon180 mutation (V180I CJD) who showed this characteristic clinical finding. This finding was observed from the early disease stage in all 3 patients and continued for several months. Startle reaction was also remarkable in all patients, although myoclonus was generally mild. The dissociation between the startle reaction and myoclonus was suspected to be another feature of V180I CJD. The pathological laughing and crying co-occured with the startle reaction and stopped right before the onset of akinetic mutism, and the degree of both symptoms was almost parallel during this period. On the basis of MRI and autopsy findings, pathological laughing and crying was suspected of being induced by the widespread cerebral cortical involvement that is characteristic of V180I CJD. From the present observations, the author speculated that pathological laughing and crying may be a comparatively frequent observation in V180I CJD patients. © 2012 Elsevier B.V. All rights reserved.
1. Introduction
2.1. Case 1
Pathological laughing and crying is a clinical condition that occurs in patients with various neurological disorders [1,2]. This characteristic neurological finding is defined by the presence of inappropriate or exaggerated outbursts of laughter and crying without commensurate feelings and is usually observed to be paroxysmal and episodic [1,2]. Although there are no reports, to the author's knowledge, of this finding being observed in patients with Creutzfeldt–Jakob disease (CJD), the author encountered three patients with CJD with prion protein (PrP) gene codon180 mutation (V180I CJD) showing this finding. Clinical observations, including magnetic resonance imaging (MRI) and neuropathological findings, were investigated, and the author speculated upon the relation between these observations and pathological laughing and crying.
The patient began to show slowly progressive disorientation with memory disturbance at the age of 78 years. MRI showed widespread gyriform hyperintensity in the bilateral cerebral cortex on diffusionweighted imaging (DWI) (Fig. 1). Swelling of the bilateral cerebral cortex was also observed on T2-weighted images. Pathological laughing and crying was observed from 2 months after disease onset and disappeared 15 months after onset. A severe startle reaction was also observed for almost the same duration. Myoclonus was generally very mild. The patient reached a state of akinetic mutism 16 months after the onset of symptoms and was still alive at 18 months after onset. Presently, no periodic sharpwave complexes (PSWCs) have been observed on the electroencephalogram (EEG). 2.2. Case 2
2. Patients and results Clinical features of the three cases of V180I CJD are shown in the Table 1. All patients were Japanese and had no family history of prion disease. Methionine homozygosity at codon 129 was observed in cases 1 and 2, whereas case 3 had valine heterozygosity at a different allele of the V180I mutation. No patient had a past history of neuropsychiatric disorder. ⁎ Tel.: + 81 561 62 3311; fax: + 81 561 63 3531. E-mail address: [email protected]. 0022-510X/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2012.05.023
The patient began to show abnormal behavior with memory disturbance at the age of 76 years. MRI showed widespread gyriform hyperintensity on DWI along with swelling of the bilateral cerebral cortex on T2-weighted images. Pathological laughing and crying was observed 2 months after disease onset and continued for 13 months. A startle reaction was also apparent, whereas very mild myoclonus was observed. The patient reached a state of akinetic mutism 17 months after the onset of symptoms and was still alive at 18 months after onset. To date, no PSWCs have been observed on the EEG.
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Y. Iwasaki / Journal of the Neurological Sciences 319 (2012) 47–50
Table 1 Clinical characteristics of the patients with Creutzfeldt–Jakob disease with the V180I mutation.
Clinical features Age at onset Age at death Sex Family history Total disease duration Initial symptom
Major symptoms and signs Cerebral cortical dysfunction Visual symptoms Parkinsonism Cerebellar symptoms Myoclonus (Observed period)
Degree of the symptom Startle reaction (Observed period)
Degree of the symptom Pathologic laughing and crying (Observed period)
Degree of symptomsa Akinetic mutism state (Time to reach) Cause of death MRI study T2 cortical swelling DWI hyperintensity (Observed region)
Case 1
Case 2
Case 3 [3]
78 Alive Female − >18 months Disorientation
76 Alive Female − >18 months Abnormal behavior
Dementia, abnormal behavior +
Dementia, disorientation
80 82 Male − 21 months Right hemiparesis, motor aphasia Dementia, tremor
+
+
− + − + (4 to 14 months after onset)
− + − + (5 to 14 months after onset)
− + − + (7 to 10 months after onset) Very mild Very mild Mild + + + (2 to 15 months (2 to 15 months (1 to 10 after onset) after onset) months after onset) Moderate Moderate to Moderate severe + + + (2 to 15 months (2 to 15 months (1 to 9 after onset) after onset) months after onset) Moderate Moderate to Moderate severe + + + (16 months) (17 months) (9 months) Alive Alive Pneumonia
+ + (cerebral cortex, basal ganglia) Cerebral white matter lesion − CSF study NSE (ng/ml) 25 14-3-3 protein (μg/ml) 1435 Tau protein (pg/ml) 1370 EEG study PSWCs − Slowing + PrP gene analysis Codon 129 polymorphism Met/Met Codon 219 polymorphism Glu/Glu Pathological findings Brain weight (g) Spongiform degenerationin in the cerebral cortex PrP immunostaining Cerebellar lesions Brainstem lesions Neurofibrillary tangles Senile plaques Western blot analysis of PrP
+ + (cerebral cortex, basal ganglia) −
+ N.E.
−
67.7 5618.1 >1300
29.9 N.E. N.E.
− +
− +
Met/Met Glu/Glu
Met/Val Glu/Glu
Fig. 1. Magnetic resonance imaging obtained 10 months after the onset of symptoms in case 1 shows widespread high signal intensity regions on diffusion-weighted images bilaterally in the frontal, temporal, parietal, and occipital cortices except for the medial occipital region. The basal ganglia also show slightly high signal intensity. Cerebral atrophy and ventricular dilatation are not readily apparent. Clinically, pathological laughing and crying was remarkable at this stage. R, right side.
2.3. Case 3 The patient showed relatively acute onset of aphasia-like symptoms and right hemiparesis at the age of 80 years. Pathological laughing and crying were present in the early disease stage at 1 month after the onset of symptoms. A startle reaction was apparent, but myoclonus was mild. MRI showed swelling of the left temporal lobe on T2-weighted imaging (DWI was not performed) and later progression to other cortical regions. No PSWCs on repetitive EEGs were observed throughout the clinical course. Pathological laughing and crying gradually disappeared, and an akinetic mutism state was observed 9 months after disease onset. The patient died from pneumonia 21 months after disease onset at the age of 82 years, and an autopsy was performed. Widespread severe spongiform change was observed in the cerebral cortex and basal ganglia (Fig. 2), and synaptic-type PrP deposition was very weakly observed in these structures. The cerebral white matter, cerebellum, and brainstem were preserved. Although the clinicopathological findings
1060 Widely observed Very weak and synaptic − − Sparse Absent Characteristic pattern
+, Present; −, absent; MRI, magnetic resonance imaging; DWI, diffusion-weighted imaging; N.E., not examined; CSF, cerebrospinal fluid; NSE, neuron-specific enolase; EEG, electroencephalogram; PSWCs, periodic sharp-wave complexes; PrP, prion protein, Met, methionine; Val, valine; Glu, glutamic acid. a Degree of symptoms was judged as follows: mild, occasionally appears with some stimulus; moderate, sometimes appears with a stimulus; severe, often appears with a light stimulus.
Fig. 2. Photomicrograph of the cerebral neocortex from case 3 shows innumerable fine vacuoles with moderate gliosis. In spite of the prolonged disease duration and severe spongiform change, neurons are relatively preserved in shape and number, and hypertrophic astrocytosis is generally mild (temporal lobe). Hematoxylin–eosin staining. Scale bar = 200 μm.
Y. Iwasaki / Journal of the Neurological Sciences 319 (2012) 47–50
Fig. 3. Pathological laughing and crying. This photograph of the patient in case 2 was taken 8 months after the onset of symptoms. The expression is one of a forced smile in which laughing and crying took place simultaneously. (Permission to publish this photograph was obtained from the patient's family.)
of this case were described previously [3], the finding of pathological laughing and crying was not described in the original paper. 2.4. Pathological laughing and crying Although these patients do not laugh or cry at all times while awake, the outbursts occur easily and frequently occur triggered by light external stimuli such as speaking to the patients, lightly touching their bodies, or by a sudden nearby noise (Fig. 3). The outburst continues briefly for several to several tens of seconds. Although daily conversation had already become difficult for the patients at the time this finding was observed, they had not yet reached a state of akinetic mutism. In addition, the patients did not experience impairments of consciousness, such as delirium or stupor. In all three cases, myoclonus was generally mild compared with that in sporadic CJD, whereas the startle reaction was also remarkable for several months. The duration of the observed pathological laughing and crying was almost the same as that of the startle reaction, and the degree of both findings was similar. Both conditions appeared in the early disease stage and disappeared gradually after the patients reached a state of akinetic mutism. No medications were administered to treat the pathological laughing and crying or startle reaction. 3. Discussion CJD can be classified as sporadic, genetic (hereditary), or acquired [4]. The genetic form of CJD is further classified into many haplotypes based on the individual PrP gene mutation [4]. The majority of sporadic CJD cases present with rapidly progressive dementia, myoclonus, and PSWCs on the EEG [4–6], whereas many types of genetic CJD cases are characterized by the absence of one or more of these hallmarks, and the clinicopathological presentation depends on the respective mutation [4,5]. V180I CJD is extremely rare in European and North American CJD patients [7], but it is the most frequent type of genetic CJD in Japan [8]. According to some reports [3,9,10], the clinical features of V180I CJD are relatively uniform but considerably different from those of sporadic CJD as follows: 1) older age of
49
onset; 2) prolonged disease duration with a slower progression course; 3) unique clinical symptoms such as frequent higher cortical dysfunction; 4) lower positive rate of brain-specific proteins such as neuron-specific enolase, total tau protein, and 14-3-3 protein in the cerebrospinal fluid; 5) no PSWCs on the EEG throughout the disease course; 6) a lack of affected family members and appearance as a sporadic neurodegenerative disorder. These clinical features make a premortem diagnosis of CJD difficult without PrP gene analysis, and cases may be misdiagnosed as neurodegenerative disorders with dementia such as corticobasal degeneration or Alzheimer's disease [9,10]. These reported clinical findings of V180I CJD were well matched in the present case series except for the pathological laughing and crying. It has already been noted that compared with sporadic CJD, V180I CJD presents a less prominent myoclonus, and the time of myoclonus appearance is later [10]. In the present series, all three patients showed conspicuous pathological laughing and crying and startle reaction, whereas myoclonus was generally mild. This dissociation of findings between startle reaction and myoclonus may be another feature of V180I CJD. A very important observation in these 3 patients is that the pathological laughing and crying occured in tandem with the startle reaction and stopped right before the onset of akinetic mutism. Although the author has examined more than 20 patients with sporadic CJD who have not yet reached the akinetic mutism state, pathological laughing and crying did not exist in all cases. This finding occurred only in the three patients with V180I CJD reported herein, none of whom who had yet reached a state of akinetic mutism. The clinical condition of pathological laughing and crying has been known by different names such as “pseudobulbar affect”, “emotional lability”, “emotional incontinence”, and “forced crying and laughing” [1,2]. Pathological laughing and crying has been encountered in varying frequency and severity in patients suffering from stroke, traumatic brain injury, multiple sclerosis, amyotrophic lateral sclerosis, brain tumor, central pontine myelinolysis, Parkinson's disease, and multiple system atrophy [1,2]. These patients also suffer from problems with dysregulation of emotional expression and have as a cause widespread damage to the cerebral cortex or the subcortical white matter [1,2]. In the present patients, no apparent involvement of the cerebral white matter, cerebellum, and brainstem was observed on MRI, and these structures were preserved in case 3 at autopsy. According to these findings, the author supected the pathogenesis of the pathological laughing and crying to be a dysfunction of communication between the cerebral cortex and the subcortical structures. Previous investigators have reported that neuroradiological findings in V180I CJD cases show a characteristic swollen cerebral cortex on T2-weighted MRI [3,9,10] and widespread cortical hyperintensity on DWI except in the medial occipital and cerebellar cortices [10]. An MRI finding of a disproportionately prominent cerebral cortical lesion in V180I CJD may also be related to pathological laughing and crying. According to autopsy case reports of V180I CJD, diffuse spongiform change in the cerebral cortex and basal ganglia was observed, but cerebellar and brainstem lesions were absent or mild despite the prolonged disease duration [3,9]. The neurons of the cerebral neocortex showed a tendency towards preservation in spite of the severe spongiform change and long disease duration [3,9]. It has been hypothesized on the basis of these neuropathological findings that an unknown protective factor associated with V180I CJD against rapid progression of the clinical course and development of pathological involvement is suggested [3,9]. This widespread cerebral cortical pathology, which was similar to that of the MRI findings, would appear to be strongly related to the pathogenesis of pathological laughing and crying observed in the present series of V180I CJD cases. On the basis of these findings, the author suspects that pathological laughing and crying may be a comparatively pathognomonic finding in V180I CJD cases. Because of the presence of widespread cerebral cortical involvement on MRI and in the pathological findings
50
Y. Iwasaki / Journal of the Neurological Sciences 319 (2012) 47–50
of V180I CJD, the fact that pathological laughing and crying is observed in this genetic CJD type may not be surprising. The number of reported V180I CJD cases from Japan is small and limited; therefore, evaluation of additional cases will be necessary to clarify the specificity and frequency of the finding of the pathological crying and laughing. Conflict of Interest The author has declared that no conflict of interest exists. Acknowledgements This work was supported by Grants-in-Aid from the Research Committee of Prion Diseases and Slow Virus Infection, the Ministry of Health, Labour Welfare of Japan. References [1] Parvizi J, Coburn KL, Shillcutt SD, Coffey CE, Lauterbach EC, Mendez MF. Neuroanatomy of pathological laughing and crying: a report of the American Neuropsychiatric Association Committee on Research. J Neuropsychiatry Clin Neurosci 2009;21:75–87.
[2] Parvizi J, Arciniegas DB, Bernardini GL, Hoffmann MW, Mohr JP, Rapoport MJ, et al. Diagnosis and management of pathological laughter and crying. Mayo Clin Proc 2006;81:1482–6. [3] Iwasaki Y, Sone M, Kato T, Yoshida E, Indo T, Yoshida M, et al. Clinicopathological characteristics of Creutzfeldt–Jakob disease with a PrP V180I mutation and M129V polymorphism on different alleles. Rinsho Shinkeigaku 1999;39:800–6 (In Japanese with English abstract). [4] Gambetti P, Kong Q, Zou W, Parchi P, Chen SG. Sporadic and familial CJD: classification and characterization. Br Med Bull 2003;66:213–39. [5] Iwasaki Y, Mimuro M, Yoshida M, Sobue G, Hashizume Y. Clinical diagnosis of Creutzfeldt–Jakob disease: accuracy based on analysis of autopsy-confirmed cases. J Neurol Sci 2009;277:119–23. [6] Iwasaki Y, Yoshida M, Hashizume Y, Kitamoto T, Sobue G. Clinicopathologic characteristics of sporadic Japanese Creutzfeldt–Jakob disease classified according to prion protein gene polymorphism and prion protein type. Acta Neuropathol 2006;112:561–71. [7] Kovács GG, Puopolo M, Ladogana A, Pocchiari M, Budka H, van Duijn C, et al. Genetic prion disease: the EUROCJD experience. Hum Genet 2005;118: 166–74. [8] Nozaki I, Hamaguchi T, Sanjo N, Noguchi-Shinohara M, Sakai K, Nakamura Y, et al. Prospective 10-year surveillance of human prion diseases in Japan. Brain 2010;133:3043–57. [9] Iwasaki Y, Mori K, Ito M, Nagaoka M, Ieda T, Kitamoto T, et al. An autopsied case of V180I Creutzfeldt–Jakob disease presenting with panencephalopathic-type pathology and a characteristic prion protein type. Neuropathology 2010;31: 540–8. [10] Jin K, Shiga Y, Shibuya S, Chida K, Sato Y, Konno H, et al. Clinical features of Creutzfeldt–Jakob disease with V180I mutation. Neurology 2004;62:502–5.
Contents lists available at SciVerse ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Three cases of Creutzfeldt–Jakob disease with prion protein gene codon180 mutation presenting with pathological laughing and crying Yasushi Iwasaki ⁎ Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University, 1‐1 Yazakokarimata, 480‐1195 Nagakute, Japan
a r t i c l e
i n f o
Article history: Received 24 March 2012 Received in revised form 7 May 2012 Accepted 9 May 2012 Available online 31 May 2012 Keywords: Creutzfeldt–Jakob disease Codon180 Pathological laughing and crying Startle reaction Widespread cerebral cortical imvolvement
a b s t r a c t Although there are no reports of pathological laughing and crying being observed in patients with Creutzfeldt–Jakob disease (CJD), the author experienced three patients with CJD with prion protein gene codon180 mutation (V180I CJD) who showed this characteristic clinical finding. This finding was observed from the early disease stage in all 3 patients and continued for several months. Startle reaction was also remarkable in all patients, although myoclonus was generally mild. The dissociation between the startle reaction and myoclonus was suspected to be another feature of V180I CJD. The pathological laughing and crying co-occured with the startle reaction and stopped right before the onset of akinetic mutism, and the degree of both symptoms was almost parallel during this period. On the basis of MRI and autopsy findings, pathological laughing and crying was suspected of being induced by the widespread cerebral cortical involvement that is characteristic of V180I CJD. From the present observations, the author speculated that pathological laughing and crying may be a comparatively frequent observation in V180I CJD patients. © 2012 Elsevier B.V. All rights reserved.
1. Introduction
2.1. Case 1
Pathological laughing and crying is a clinical condition that occurs in patients with various neurological disorders [1,2]. This characteristic neurological finding is defined by the presence of inappropriate or exaggerated outbursts of laughter and crying without commensurate feelings and is usually observed to be paroxysmal and episodic [1,2]. Although there are no reports, to the author's knowledge, of this finding being observed in patients with Creutzfeldt–Jakob disease (CJD), the author encountered three patients with CJD with prion protein (PrP) gene codon180 mutation (V180I CJD) showing this finding. Clinical observations, including magnetic resonance imaging (MRI) and neuropathological findings, were investigated, and the author speculated upon the relation between these observations and pathological laughing and crying.
The patient began to show slowly progressive disorientation with memory disturbance at the age of 78 years. MRI showed widespread gyriform hyperintensity in the bilateral cerebral cortex on diffusionweighted imaging (DWI) (Fig. 1). Swelling of the bilateral cerebral cortex was also observed on T2-weighted images. Pathological laughing and crying was observed from 2 months after disease onset and disappeared 15 months after onset. A severe startle reaction was also observed for almost the same duration. Myoclonus was generally very mild. The patient reached a state of akinetic mutism 16 months after the onset of symptoms and was still alive at 18 months after onset. Presently, no periodic sharpwave complexes (PSWCs) have been observed on the electroencephalogram (EEG). 2.2. Case 2
2. Patients and results Clinical features of the three cases of V180I CJD are shown in the Table 1. All patients were Japanese and had no family history of prion disease. Methionine homozygosity at codon 129 was observed in cases 1 and 2, whereas case 3 had valine heterozygosity at a different allele of the V180I mutation. No patient had a past history of neuropsychiatric disorder. ⁎ Tel.: + 81 561 62 3311; fax: + 81 561 63 3531. E-mail address: [email protected]. 0022-510X/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2012.05.023
The patient began to show abnormal behavior with memory disturbance at the age of 76 years. MRI showed widespread gyriform hyperintensity on DWI along with swelling of the bilateral cerebral cortex on T2-weighted images. Pathological laughing and crying was observed 2 months after disease onset and continued for 13 months. A startle reaction was also apparent, whereas very mild myoclonus was observed. The patient reached a state of akinetic mutism 17 months after the onset of symptoms and was still alive at 18 months after onset. To date, no PSWCs have been observed on the EEG.
48
Y. Iwasaki / Journal of the Neurological Sciences 319 (2012) 47–50
Table 1 Clinical characteristics of the patients with Creutzfeldt–Jakob disease with the V180I mutation.
Clinical features Age at onset Age at death Sex Family history Total disease duration Initial symptom
Major symptoms and signs Cerebral cortical dysfunction Visual symptoms Parkinsonism Cerebellar symptoms Myoclonus (Observed period)
Degree of the symptom Startle reaction (Observed period)
Degree of the symptom Pathologic laughing and crying (Observed period)
Degree of symptomsa Akinetic mutism state (Time to reach) Cause of death MRI study T2 cortical swelling DWI hyperintensity (Observed region)
Case 1
Case 2
Case 3 [3]
78 Alive Female − >18 months Disorientation
76 Alive Female − >18 months Abnormal behavior
Dementia, abnormal behavior +
Dementia, disorientation
80 82 Male − 21 months Right hemiparesis, motor aphasia Dementia, tremor
+
+
− + − + (4 to 14 months after onset)
− + − + (5 to 14 months after onset)
− + − + (7 to 10 months after onset) Very mild Very mild Mild + + + (2 to 15 months (2 to 15 months (1 to 10 after onset) after onset) months after onset) Moderate Moderate to Moderate severe + + + (2 to 15 months (2 to 15 months (1 to 9 after onset) after onset) months after onset) Moderate Moderate to Moderate severe + + + (16 months) (17 months) (9 months) Alive Alive Pneumonia
+ + (cerebral cortex, basal ganglia) Cerebral white matter lesion − CSF study NSE (ng/ml) 25 14-3-3 protein (μg/ml) 1435 Tau protein (pg/ml) 1370 EEG study PSWCs − Slowing + PrP gene analysis Codon 129 polymorphism Met/Met Codon 219 polymorphism Glu/Glu Pathological findings Brain weight (g) Spongiform degenerationin in the cerebral cortex PrP immunostaining Cerebellar lesions Brainstem lesions Neurofibrillary tangles Senile plaques Western blot analysis of PrP
+ + (cerebral cortex, basal ganglia) −
+ N.E.
−
67.7 5618.1 >1300
29.9 N.E. N.E.
− +
− +
Met/Met Glu/Glu
Met/Val Glu/Glu
Fig. 1. Magnetic resonance imaging obtained 10 months after the onset of symptoms in case 1 shows widespread high signal intensity regions on diffusion-weighted images bilaterally in the frontal, temporal, parietal, and occipital cortices except for the medial occipital region. The basal ganglia also show slightly high signal intensity. Cerebral atrophy and ventricular dilatation are not readily apparent. Clinically, pathological laughing and crying was remarkable at this stage. R, right side.
2.3. Case 3 The patient showed relatively acute onset of aphasia-like symptoms and right hemiparesis at the age of 80 years. Pathological laughing and crying were present in the early disease stage at 1 month after the onset of symptoms. A startle reaction was apparent, but myoclonus was mild. MRI showed swelling of the left temporal lobe on T2-weighted imaging (DWI was not performed) and later progression to other cortical regions. No PSWCs on repetitive EEGs were observed throughout the clinical course. Pathological laughing and crying gradually disappeared, and an akinetic mutism state was observed 9 months after disease onset. The patient died from pneumonia 21 months after disease onset at the age of 82 years, and an autopsy was performed. Widespread severe spongiform change was observed in the cerebral cortex and basal ganglia (Fig. 2), and synaptic-type PrP deposition was very weakly observed in these structures. The cerebral white matter, cerebellum, and brainstem were preserved. Although the clinicopathological findings
1060 Widely observed Very weak and synaptic − − Sparse Absent Characteristic pattern
+, Present; −, absent; MRI, magnetic resonance imaging; DWI, diffusion-weighted imaging; N.E., not examined; CSF, cerebrospinal fluid; NSE, neuron-specific enolase; EEG, electroencephalogram; PSWCs, periodic sharp-wave complexes; PrP, prion protein, Met, methionine; Val, valine; Glu, glutamic acid. a Degree of symptoms was judged as follows: mild, occasionally appears with some stimulus; moderate, sometimes appears with a stimulus; severe, often appears with a light stimulus.
Fig. 2. Photomicrograph of the cerebral neocortex from case 3 shows innumerable fine vacuoles with moderate gliosis. In spite of the prolonged disease duration and severe spongiform change, neurons are relatively preserved in shape and number, and hypertrophic astrocytosis is generally mild (temporal lobe). Hematoxylin–eosin staining. Scale bar = 200 μm.
Y. Iwasaki / Journal of the Neurological Sciences 319 (2012) 47–50
Fig. 3. Pathological laughing and crying. This photograph of the patient in case 2 was taken 8 months after the onset of symptoms. The expression is one of a forced smile in which laughing and crying took place simultaneously. (Permission to publish this photograph was obtained from the patient's family.)
of this case were described previously [3], the finding of pathological laughing and crying was not described in the original paper. 2.4. Pathological laughing and crying Although these patients do not laugh or cry at all times while awake, the outbursts occur easily and frequently occur triggered by light external stimuli such as speaking to the patients, lightly touching their bodies, or by a sudden nearby noise (Fig. 3). The outburst continues briefly for several to several tens of seconds. Although daily conversation had already become difficult for the patients at the time this finding was observed, they had not yet reached a state of akinetic mutism. In addition, the patients did not experience impairments of consciousness, such as delirium or stupor. In all three cases, myoclonus was generally mild compared with that in sporadic CJD, whereas the startle reaction was also remarkable for several months. The duration of the observed pathological laughing and crying was almost the same as that of the startle reaction, and the degree of both findings was similar. Both conditions appeared in the early disease stage and disappeared gradually after the patients reached a state of akinetic mutism. No medications were administered to treat the pathological laughing and crying or startle reaction. 3. Discussion CJD can be classified as sporadic, genetic (hereditary), or acquired [4]. The genetic form of CJD is further classified into many haplotypes based on the individual PrP gene mutation [4]. The majority of sporadic CJD cases present with rapidly progressive dementia, myoclonus, and PSWCs on the EEG [4–6], whereas many types of genetic CJD cases are characterized by the absence of one or more of these hallmarks, and the clinicopathological presentation depends on the respective mutation [4,5]. V180I CJD is extremely rare in European and North American CJD patients [7], but it is the most frequent type of genetic CJD in Japan [8]. According to some reports [3,9,10], the clinical features of V180I CJD are relatively uniform but considerably different from those of sporadic CJD as follows: 1) older age of
49
onset; 2) prolonged disease duration with a slower progression course; 3) unique clinical symptoms such as frequent higher cortical dysfunction; 4) lower positive rate of brain-specific proteins such as neuron-specific enolase, total tau protein, and 14-3-3 protein in the cerebrospinal fluid; 5) no PSWCs on the EEG throughout the disease course; 6) a lack of affected family members and appearance as a sporadic neurodegenerative disorder. These clinical features make a premortem diagnosis of CJD difficult without PrP gene analysis, and cases may be misdiagnosed as neurodegenerative disorders with dementia such as corticobasal degeneration or Alzheimer's disease [9,10]. These reported clinical findings of V180I CJD were well matched in the present case series except for the pathological laughing and crying. It has already been noted that compared with sporadic CJD, V180I CJD presents a less prominent myoclonus, and the time of myoclonus appearance is later [10]. In the present series, all three patients showed conspicuous pathological laughing and crying and startle reaction, whereas myoclonus was generally mild. This dissociation of findings between startle reaction and myoclonus may be another feature of V180I CJD. A very important observation in these 3 patients is that the pathological laughing and crying occured in tandem with the startle reaction and stopped right before the onset of akinetic mutism. Although the author has examined more than 20 patients with sporadic CJD who have not yet reached the akinetic mutism state, pathological laughing and crying did not exist in all cases. This finding occurred only in the three patients with V180I CJD reported herein, none of whom who had yet reached a state of akinetic mutism. The clinical condition of pathological laughing and crying has been known by different names such as “pseudobulbar affect”, “emotional lability”, “emotional incontinence”, and “forced crying and laughing” [1,2]. Pathological laughing and crying has been encountered in varying frequency and severity in patients suffering from stroke, traumatic brain injury, multiple sclerosis, amyotrophic lateral sclerosis, brain tumor, central pontine myelinolysis, Parkinson's disease, and multiple system atrophy [1,2]. These patients also suffer from problems with dysregulation of emotional expression and have as a cause widespread damage to the cerebral cortex or the subcortical white matter [1,2]. In the present patients, no apparent involvement of the cerebral white matter, cerebellum, and brainstem was observed on MRI, and these structures were preserved in case 3 at autopsy. According to these findings, the author supected the pathogenesis of the pathological laughing and crying to be a dysfunction of communication between the cerebral cortex and the subcortical structures. Previous investigators have reported that neuroradiological findings in V180I CJD cases show a characteristic swollen cerebral cortex on T2-weighted MRI [3,9,10] and widespread cortical hyperintensity on DWI except in the medial occipital and cerebellar cortices [10]. An MRI finding of a disproportionately prominent cerebral cortical lesion in V180I CJD may also be related to pathological laughing and crying. According to autopsy case reports of V180I CJD, diffuse spongiform change in the cerebral cortex and basal ganglia was observed, but cerebellar and brainstem lesions were absent or mild despite the prolonged disease duration [3,9]. The neurons of the cerebral neocortex showed a tendency towards preservation in spite of the severe spongiform change and long disease duration [3,9]. It has been hypothesized on the basis of these neuropathological findings that an unknown protective factor associated with V180I CJD against rapid progression of the clinical course and development of pathological involvement is suggested [3,9]. This widespread cerebral cortical pathology, which was similar to that of the MRI findings, would appear to be strongly related to the pathogenesis of pathological laughing and crying observed in the present series of V180I CJD cases. On the basis of these findings, the author suspects that pathological laughing and crying may be a comparatively pathognomonic finding in V180I CJD cases. Because of the presence of widespread cerebral cortical involvement on MRI and in the pathological findings
50
Y. Iwasaki / Journal of the Neurological Sciences 319 (2012) 47–50
of V180I CJD, the fact that pathological laughing and crying is observed in this genetic CJD type may not be surprising. The number of reported V180I CJD cases from Japan is small and limited; therefore, evaluation of additional cases will be necessary to clarify the specificity and frequency of the finding of the pathological crying and laughing. Conflict of Interest The author has declared that no conflict of interest exists. Acknowledgements This work was supported by Grants-in-Aid from the Research Committee of Prion Diseases and Slow Virus Infection, the Ministry of Health, Labour Welfare of Japan. References [1] Parvizi J, Coburn KL, Shillcutt SD, Coffey CE, Lauterbach EC, Mendez MF. Neuroanatomy of pathological laughing and crying: a report of the American Neuropsychiatric Association Committee on Research. J Neuropsychiatry Clin Neurosci 2009;21:75–87.
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