Anhedonia in Japanese patients with Parkinson's disease: analysis using the Snaith-Hamilton Pleasure Scale.

BACKGROUND: Anhedonia, a lowered ability to experience physical or social pleasure, has recently been recognized as a non-motor symptom of Parkinson's disease. OBJECTIVE: To identify the frequency of anhedonia and the factors influencing hedonic tone in Japanese patients with Parkinson's disease. PATIENTS AND METHODS: We recruited 86 consecutive outpatients with a clinical diagnosis of PD attending two Japanese hospitals (one university hospital and one community hospital) in February 2010. We used the self-rating Snaith-Hamilton Pleasure Scale (SHAPS) translated into Japanese language from the original English version to assess and quantify hedonic tone as a subjectively experienced phenomenon. We studied the association of anhedonia with the variables age, age at onset, gender, disease duration, disease severity and antiparkinsonian drugs. RESULTS: Thirty-nine patients (45%) were male and 47 (55%) were female. Mean age was 72.01±9.07 (49-89) years, with mean age at onset of 64.93±11.42 (31-88) years. Mean disease duration was 7.20±5.54 (1-23) years. The mean Hoehn and Yahr scale was 2.76±0.78. The mean SHAPS score of the total sample was 1.19±1.86. The SHAPS score of 14 patients (16.3%) was 3 or more, indicating anhedonia. The mean SHAPS score was lower in patients taking pramipexole (0.58±0.97) than in patients not taking pramipexole (1.57±2.16). Multiple linear regression analysis identified pramipexole as a significant negative influencing factor on the SHAPS score, while disease severity and entacapone treatment were identified as positive influencing factors. The age, onset age, gender, disease duration, and use of pergolide, amantadine, zonisamide, selegiline, anticholinergic agents and droxidopa did not significantly affect the SHAPS score. CONCLUSION: Anhedonia is not rare non-motor symptom in Japanese patients with Parkinson's disease. This study suggests an anti-anhedonic property of pramipexole.

Partial SPAST and DPY30 deletions in a Japanese spastic paraplegia type 4 family.

Spastic paraplegia type 4 (SPG4) is the most common autosomal dominant hereditary SPG caused by mutations in the SPAST gene. We studied the four-generation pedigree of a Japanese family with autosomal dominant hereditary SPG both clinically and genetically. Twelve available family members (ten affected; two unaffected) and two spouses were enrolled in the study. The clinical features were hyperreflexia in all four limbs, spasticity of the lower extremities, impaired vibration sense, mild cognitive impairment confirmed by the Wechsler Adult Intelligence Scale-Third Edition, and peripheral neuropathy confirmed by neurophysiological examinations. All four female patients experienced miscarriages. The cerebrospinal fluid tau levels were mildly increased in two of three patients examined. Linkage analyses revealed the highest logarithm of odds score of 2.64 at 2p23-p21 where the SPAST gene is located. Mutation scanning of the entire exonic regions of the SPAST gene by direct sequencing revealed no mutations. Exonic copy number analysis by real-time quantitative polymerase chain reaction revealed heterozygous deletion of exons 1 to 4 of the SPAST gene. Breakpoint analysis showed that the centromeric breakpoint was located within intron 4 of SPAST while the telomeric breakpoint was located within intron 3 of the neighboring DPY30 gene, causing a deletion of approximately 70 kb ranging from exons 1 to 3 of DPY30 to exons 1 to 4 of SPAST. To our knowledge, this is the first report of SPG4 associated with partial deletions of both the SPAST and DPY30 genes. The partial heterozygous deletion of DPY30 could modify the phenotypic expression of SPG4 patients with this pedigree.

Combined treatment with prednisolone and tacrolimus for myasthenia gravis with invasive thymoma.

We describe a case of recurrent invasive thymoma associated with myasthenia gravis that responded to combined treatment with prednisolone and tacrolimus. The patient suffered from a myasthenic crisis and received methylprednisolone pulse therapy and partial thymomectomy. Low maintenance doses of prednisolone and tacrolimus shrank the size of the invasive thymoma and maintained the patient without any myasthenic symptoms. We stress the usefulness of combined treatment with tacrolimus and prednisolone for invasive thymoma, especially for unresectable tumors.

Machado-Joseph disease/SCA3 and myotonic dystrophy type 1 in a single patient.

We report here, for the first time, the case of a 41-year-old man with both Machado-Joseph disease (MJD)/spinocerebellar ataxia type 3 (SCA3) and myotonic dystrophy type 1. The patient noted dysarthria at 14 years of age and unsteady gait at 30 years of age. Similar sized expansions of the CAG trinucleotide repeats in one allele of the ataxin-3 (ATXN3) gene were found in both the patient and his father, although in the other allele the length of the CAG repeats was shorter in the father compared with the patient. In the dystrophia myotonica protein kinase (DMPK) gene the CTG repeats were much more expanded in the patient compared with his father. Thus it is possible that, in the farther, the short CAG repeat in the non-expanded ATXN3 allele delayed the onset of cerebellar symptoms, and/or that the expanded CTG repeat in the DMPK gene in the patient accelerated the pathogenesis of MJD/SCA3.

Symmetrical brainstem encephalitis caused by herpes simplex virus.

We describe a 53-year-old man with herpes simplex virus (HSV) brainstem encephalitis diagnosed based by positive HSV immunoglobulin M antibodies from cerebrospinal fluid. The MRI findings of this case had three unique features. First, the lesions were symmetrical. Second, the lesions may have been associated with reactivation of HSV infection in the region of the trigeminal nerve. Third, diffusion-weighted and apparent diffusion coefficient (ADC) imaging, conducted for the first time on an HSV brainstem encephalitis case, suggested that the lesions were associated with vasogenic edema.

Expansion of the phenotypic spectrum of SCA14 caused by the Gly128Asp mutation in PRKCG.

Two cases of spinocerebellar ataxia type 14 (SCA14) with a G128D mutation in the protein kinase C gamma gene (PRKCG) without a definite family history have been reported previously. Here, we describe the first familial cases of SCA14 with a G128D mutation in PRKCG. Among three family members, the chief complaints varied and included ataxic gait, cervical dystonia, and positional vertigo. Moreover, retinal degeneration and facial muscle weakness were observed, although these are not expected to be present in SCA14. Cerebral blood flow evaluation using single photon emission computed tomography (SPECT) also differed among family members. It is possible that patients with the G128D mutation suffering from SCA14 may sometimes be classified as unaffected due to the varying clinical signs among family members.

Hereditary motor and sensory neuropathy with proximal dominancy in the lower extremities, urinary disturbance, and paroxysmal dry cough.

We studied a four-generation pedigree of a Japanese family with hereditary neuropathy to elucidate the genetic basis of this disease. Twelve members of the family were enrolled in this study. The clinical features were neurogenic muscle weakness with proximal dominancy in the lower extremities, sensory involvement, areflexia, fine postural tremors, painful muscle cramps, elevated creatine kinase levels, recurrent paroxysmal dry cough, and neurogenic bladder. We performed a genome-wide search using genetic loci spaced at about 13 Mb intervals. Although nine chromosomes (1, 3, 4, 5, 6, 10, 17, 19, and 22) had at least one region in which the logarithm of odds (LOD) score was over 1.0, no loci fulfilled the criteria for significant evidence of linkage. Moreover, we analyzed an extra 14 markers on 3p12-q13 (the locus of hereditary motor and sensory neuropathy, proximal dominant form) and an extra five markers on 3p22-p24 (the locus of hereditary sensory neuropathy with chronic cough) and observed LOD scores of <-3 on both 3p12-q13 and 3p22-p24. Mutation scanning of the entire coding regions of the MPZ and PMP22 genes revealed no mutations. We conclude that the disorder described here is a newly classified hereditary motor and sensory neuropathy with autosomal dominant inheritance.

Bell-shaped sensory impairments of all modalities in a neurosarcoidosis patient.

We describe a 45-year-old man with neurosarcoidosis complaining of bell-shaped tightening and pain with sensory disturbance of superficial and deep sensations. The patient showed subacute progressive sensory impairment in bilateral C7-Th12 dermatomes. Triceps and patellar tendon reflexes were decreased. Chest X-ray revealed bilateral hilar lymphadenopathy without pleural effusion. There was abnormal accumulation of gallium in the bilateral hilar lymph nodes, parotid glands, and lacrimal glands on scintigraphy. Examination of bronchoalveolar lavage fluid showed an elevated CD4/CD8 ratio. Transbronchial lung biopsy showed non-caseating granulomas with many epitheloid cells and occasional Langhans giant cells without any necrotic lesion. The tuberculin reaction was negative, and elevation of serum lysozyme and IgG level were seen. These findings fulfilled the clinical criteria for sarcoidosis. Spine MRI demonstrated no abnormality. Studies of short-latency somatosensory evoked potentials showed delayed N13 latency and absent N19 and N28 potentials bilaterally. A nerve conduction study revealed no abnormality. The patient's muscle strength was normal through the entire clinical course. Therefore, we consider that his sensory impairment was caused by peripheral neuropathy, especially in the dorsal root region. Neurosarcoidosis is important for differentiating bell-shaped sensory impairments of all modalities.

Adult meningism and viral meningitis, 1997-2004: clinical data and cerebrospinal fluid cytokines.

OBJECTIVE: Although meningism manifesting acute headache has been observed to be associated with common viral and bacterial infections, its definition and pathogenesis have not been clarified. Clinical findings and cerebrospinal fluid (CSF) cytokines in adult patients with meningism were investigated and compared with those in viral meningitis. PATIENTS AND METHODS: Among the adult inpatients in our hospital from 1997 to 2004, 5 with meningism and 17 with viral meningitis were identified according to the criteria described in this study, and their clinical data were analyzed. In the CSF samples of the 5 patients with meningism and the 17 with viral meningitis, the concentrations of interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), interleukin-2 (IL-2), IL-4, IL-6, and IL-10 were determined using a cytometric bead array. RESULTS: The five patients with meningism all showed fever and meningeal signs such as severe headache and nuchal stiffness without CSF pleocytosis (<5 cells/mm3). Four patients were associated with herpetic Kaposi's eczema, herpes simplex, or herpes zoster, and all five patients had favorable outcomes. The levels of all CSF cytokines in patients with meningism were below normal values, whereas IFN-gamma and IL-6 in patients with viral meningitis were moderately elevated. CONCLUSION: The normal cytokine levels in meningism may possibly reflect the lack of direct viral infection and may be helpful in differentiating both meningism and viral meningitis at an early stage.

Herpes simplex encephalitis presenting with bilateral hippocampal lesions on magnetic resonance imaging, simultaneously complicated by small cell lung carcinoma.

We report a 75-year-old man who developed herpes simplex encephalitis (HSE), presenting with bilateral hippocampal lesions on magnetic resonance imaging, and this case was simultaneously complicated by small cell lung carcinoma. We identified a new anti-neuronal antibody in the cerebrospinal fluid of this patient. Our findings suggest that HSE and paraneoplastic limbic encephalitis (PLE) can overlap, and we discuss the relationships of HSE, PLE, and related disorders.

Herpes simplex virus type 2 recurrent meningitis (Mollaret's meningitis): a consideration for the recurrent pathogenesis.

We report a 44-year-old Japanese woman with herpes simplex virus (HSV) type 2 recurrent meningitis (Mollaret's meningitis). The diagnosis was confirmed by nested polymerase chain reaction in her cerebrospinal fluid, but the patient's conventional HSV antibodies by complement fixation, neutralizing test or enzyme immunoassay showed low titres with low lymphoproliferative response. Several similar cases are discussed. Although the reason for the recurrent pathogenesis is uncertain, our report suggests that the low immune response including immune evasion may be involved in the pathogenesis of HSV type 2 recurrent meningitis. For this patient, long-term suppressive and patient-initiated therapies were conducted to prevent the recurrence of meningitis.

Probable chronic viral encephalitis with microglial nodules in the entire brain: a case report with necropsy.

BACKGROUND: Chronic encephalitis has rarely been seen, probably due to its viral origins, which may produce the disease in healthy or immunocompromised hosts. The etiology and pathophysiology of these types of encephalitis have not yet been clarified. CASE REPORT: A 63-year-old Japanese woman with underlying multiple myeloma developed chronic encephalitis with fever and progressive dementia, bilateral mild thalamic lesions on magnetic resonance imaging, and a prolonged pleocytosis, normal glucose value, and elevated interleukin-6 and interferon-gamma in the cerebrospinal fluid (CSF). The patient died of pneumonia 6 months after the onset of illness, and diffuse microglial nodules were found in the entire brain. No causative viral agents were identified by polymerase chain reaction and serological tests. CONCLUSIONS: The patient was presumed to have suffered from chronic viral encephalitis, based on clinical findings, including CSF and cytokine changes. Microglial nodules are observed in flavivirus group encephalitides, Rickettsia infections, and cytomegalovirus encephalitis in immunocompromised hosts. The possible pathogenesis of this rare encephalitis is discussed.

An unexpected outbreak of Japanese encephalitis in the Chugoku district of Japan, 2002.

Six patients unexpectedly presented with Japanese encephalitis (JE) from early August to mid-September 2002 in the Chugoku district of Japan. The mean age was 67.5 years (range 42 - 89 years); the onset period in two patients shifted to the middle of September. The JE virus was isolated from the cerebrospinal fluid samples from two patients, and the strain isolated in the one was identified as genotype III. Neurologically, consciousness impairment, meningeal signs, rigidity, hemiparesis, tetraparesis, and convulsive seizures were commonly observed. Magnetic resonance imaging uniformly revealed high signal intensities in the bilateral thalami, brainstem (substantia nigra), hippocampi, and brain cortices. In all patients, acyclovir was used, due to the unexpected outbreak of JE. Five patients, except for one without sequelae, had a severe outcome, including one death. This report indicates that JE in Japan is still a threat to adults and the elderly with decreased or absent immunity to the JE virus.

Non-herpetic acute limbic encephalitis: cerebrospinal fluid cytokines and magnetic resonance imaging findings.

OBJECTIVE: Non-herpetic acute limbic encephalitis (non-herpetic ALE) is regarded as a new subgroup of limbic encephalitis. In the present study, clinical findings and cerebrospinal fluid (CSF) cytokines in patients with non-herpetic ALE were investigated. PATIENTS AND METHODS: For adult inpatients in our hospital and related hospitals from 1996 to 2001, non-herpetic ALE was examined according to the criteria described in this study. Six patients were diagnosed as having non-herpetic ALE, and their clinical data and magnetic resonance imaging (MRI) were analyzed. In the CSF samples of the 6 patients with non-herpetic ALE and 6 patients with herpes simplex encephalitis (HSE), the concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and interferon (IFN)-gamma were determined using sandwich-type enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: The six patients with non-herpetic ALE showed all the acute encephalitis features, such as fever, altered consciousness, seizures, memory impairment, and mild CSF pleocytosis. MRI demonstrated selective abnormal signals in the limbic system, including the bilateral hippocampi and amygdalae. The levels of CSF IL-6 and IFN-gamma in patients with non-herpetic ALE were significantly lower than those in patients with HSE (p<0.05 and p<0.01, respectively). The levels of both TNF-alpha and IL-1beta were below the detection limits in both groups. CONCLUSION: Six patients were newly diagnosed as having non-herpetic ALE in this study. These patients revealed both acute limbic encephalitis and MRI abnormalities in the bilateral hippocampi and amygdalae. The levels of IL-6 and IFN-gamma in the CSF of patients with non-herpetic ALE were significantly lower than those of patients with HSE, possibly reflecting an immunological process in this type of ALE rather than direct viral infection.

A case of adult-onset Alexander disease with Arg416Trp human glial fibrillary acidic protein gene mutation.

Heterozygous point mutations in the coding region of the human glial fibrillary acidic protein (GFAP) gene have been reported in patients with various forms of Alexander disease (AD). We report a case of genetically confirmed adult-onset AD with palatal myoclonus, pyramidal tract signs, cerebellar signs, and marked atrophy of the medulla oblongata and spinal cord, autonomic dysfunction and heterozygous R416W GFAP mutation. Interestingly, this R416W mutation has also been reported in both infantile and juvenile forms of Alexander disease. The fact that a R416W mutation causes various types of AD suggests that clinical severities of AD are due not only to the different sites and nature of mutations in GFAP, but also to other modifying factor(s).

Epstein-Barr virus infections of the central nervous system.

OBJECTIVE: Epstein-Barr virus (EBV), a lymphotropic herpes virus causing infectious mononucleosis (IM), also causes various central nervous system (CNS) infections. In the present study, EBV CNS infections were investigated. PATIENTS AND METHODS: For adult inpatients in our hospital and related hospitals between 1984-2002, CNS syndromes with IM symptoms were examined, and serologic positives were assessed according to established criteria. Polymerase chain reaction (PCR) was performed for cerebrospinal fluid (CSF) from seven patients. RESULTS: Ten patients with EBV-related CNS infections were found; their mean age was 36 years (20-79 years). The neurologic forms were as follows: acute encephalitis (4 patients), acute cerebellar ataxia (1), acute disseminated encephalomyelitis (ADEM) (2), myelitis (1), and meningitis (2). The PCR from CSF was positive in two patients with meningitis, one patient with ADEM, and one patient with encephalitis-associated chronic EVB infection. One case of encephalitis and another of relapsing ADEM were attributed to chronic EBV infection. CONCLUSION: Our study identified a variety of EBV-related CNS infections. EBV CNS infections are divided into two groups: 1) CNS syndromes associated with primary EBV or reactivated infection, and 2) those associated with chronic EBV infection; it is notable that in the former, diverse CNS syndromes including ADEM can occur, whereas in the latter, chronic or recurrent CNS syndromes are produced.