Clinical course of pathologically confirmed corticobasal degeneration and corticobasal syndrome.

The clinical presentation of corticobasal degeneration is diverse, while the background pathology of corticobasal syndrome is also heterogeneous. Therefore, predicting the pathological background of corticobasal syndrome is extremely difficult. Herein, we investigated the clinical findings and course in patients with pathologically, genetically and biochemically verified corticobasal degeneration and corticobasal syndrome with background pathology to determine findings suggestive of background disorder. Thirty-two patients were identified as having corticobasal degeneration. The median intervals from the initial symptoms to the onset of key milestones were as follows: gait disturbance, 0.0 year; behavioural changes, 1.0 year; falls, 2.0 years; cognitive impairment, 2.0 years; speech impairment, 2.5 years; supranuclear gaze palsy, 3.0 years; urinary incontinence, 3.0 years; and dysphagia, 5.0 years. The median survival time was 7.0 years; 50% of corticobasal degeneration was diagnosed as corticobasal degeneration/corticobasal syndrome at the final presentation. Background pathologies of corticobasal syndrome (n = 48) included corticobasal degeneration (33.3%), progressive supranuclear palsy (29.2%) and Alzheimer's disease (12.5%). The common course of corticobasal syndrome was initial gait disturbance and early fall. In addition, corticobasal degeneration-corticobasal syndrome manifested behavioural change (2.5 years) and cognitive impairment (3.0 years), as the patient with progressive supranuclear palsy-corticobasal syndrome developed speech impairment (1.0 years) and supranuclear gaze palsy (6.0 years). The Alzheimer's disease-corticobasal syndrome patients showed cognitive impairment (1.0 years). The frequency of frozen gait at onset was higher in the corticobasal degeneration-corticobasal syndrome group than in the progressive supranuclear palsy-corticobasal syndrome group [P = 0.005, odds ratio (95% confidence interval): 31.67 (1.46-685.34)]. Dysarthria at presentation was higher in progressive supranuclear palsy-corticobasal syndrome than in corticobasal degeneration-corticobasal syndrome [P = 0.047, 6.75 (1.16-39.20)]. Pyramidal sign at presentation and personality change during the entire course were higher in Alzheimer's disease-corticobasal syndrome than in progressive supranuclear palsy-corticobasal syndrome [P = 0.011, 27.44 (1.25-601.61), and P = 0.013, 40.00 (1.98-807.14), respectively]. In corticobasal syndrome, decision tree analysis revealed that 'freezing at onset' or 'no dysarthria at presentation and age at onset under 66 years in the case without freezing at onset' predicted corticobasal degeneration pathology with a sensitivity of 81.3% and specificity of 84.4%. 'Dysarthria at presentation and age at onset over 61 years' suggested progressive supranuclear palsy pathology, and 'pyramidal sign at presentation and personality change during the entire course' implied Alzheimer's disease pathology. In conclusion, frozen gait at onset, dysarthria, personality change and pyramidal signs may be useful clinical signs for predicting background pathologies in corticobasal syndrome.

Clinical features and a mutation with late onset of limb girdle muscular dystrophy 2B.

OBJECTIVE AND METHODS: Dysferlin encoded by DYSF deficiency leads to two main phenotypes, limb girdle muscular dystrophy (LGMD) 2B and Miyoshi myopathy. To reveal in detail the mutational and clinical features of LGMD2B in Japan, we observed 40 Japanese patients in 36 families with LGMD2B in whom dysferlin mutations were confirmed. RESULTS AND CONCLUSIONS: Three mutations (c.1566C>G, c.2997G>T and c.4497delT) were relatively more prevalent. The c.2997G>T mutation was associated with late onset, proximal dominant forms of dysferlinopathy, a high probability that muscle weakness started in an upper limb and lower serum creatine kinase (CK) levels. The clinical features of LGMD2B are as follows: (1) onset in the late teens or early adulthood, except patients homozygous for the c.2997G>T mutation; (2) lower limb weakness at onset; (3) distal change of lower limbs on muscle CT at an early stage; (4) impairment of lumbar erector spinal muscles on muscle CT at an early stage; (5) predominant involvement of proximal upper limbs; (6) preservation of function of the hands at late stage; (7) preservation of strength in neck muscles at late stage; (8) lack of facial weakness or dysphagia; (9) avoidance of scoliosis; (10) hyper-Ckaemia; (11) preservation of cardiac function; and (12) a tendency for respiratory function to decline with disease duration. It is important that the late onset phenotype is found with prevalent mutations.

Clinicopathological features of acute autonomic and sensory neuropathy.

Acute autonomic and sensory neuropathy is a rare disorder that has been only anecdotally reported. We characterized the clinical, electrophysiological, pathological and prognostic features of 21 patients with acute autonomic and sensory neuropathy. An antecedent event, mostly an upper respiratory tract or gastrointestinal tract infection, was reported in two-thirds of patients. Profound autonomic failure with various degrees of sensory impairment characterized the neuropathic features in all patients. The initial symptoms were those related to autonomic disturbance or superficial sensory impairment in all patients, while deep sensory impairment accompanied by sensory ataxia subsequently appeared in 12 patients. The severity of sensory ataxia tended to become worse as the duration from the onset to the peak phase of neuropathy became longer (P<0.001). The distribution of sensory manifestations included the proximal regions of the limbs, face, scalp and trunk in most patients. It tended to be asymmetrical and segmental, rather than presenting as a symmetric polyneuropathy. Pain of the involved region was a common and serious symptom. In addition to autonomic and sensory symptoms, coughing episodes, psychiatric symptoms, sleep apnoea and aspiration, pneumonia made it difficult to manage the clinical condition. Nerve conduction studies revealed the reduction of sensory nerve action potentials in patients with sensory ataxia, while it was relatively preserved in patients without sensory ataxia. Magnetic resonance imaging of the spinal cord revealed a high-intensity area in the posterior column on T(2)*-weighted gradient echo image in patients with sensory ataxia but not in those without it. Sural nerve biopsy revealed small-fibre predominant axonal loss without evidence of nerve regeneration. In an autopsy case with impairment of both superficial and deep sensations, we observed severe neuronal cell loss in the thoracic sympathetic and dorsal root ganglia, and Auerbach's plexus with well preserved anterior hone cells. Myelinated fibres in the anterior spinal root were preserved, while those in the posterior spinal root and the posterior column of the spinal cord were depleted. Although recovery of sensory impairment was poor, autonomic dysfunction was ameliorated to some degree within several months in most patients. In conclusion, an immune-mediated mechanism may be associated with acute autonomic and sensory neuropathy. Small neuronal cells in the autonomic and sensory ganglia may be affected in the initial phase, and subsequently, large neuronal cells in the sensory ganglia are damaged.

Distinct characteristics of amyloid deposits in early- and late-onset transthyretin Val30Met familial amyloid polyneuropathy.

Late-onset transthyretin Val30Met-associated familial amyloid polyneuropathy (FAP ATTR Val30Met) cases unrelated to endemic foci in Japan show different clinicopathological features from the conventional early-onset cases in endemic foci. We compared the characteristics of amyloid deposits in early-onset FAP ATTR Val30Met cases in endemic foci and late-onset cases in non-endemic areas. Amyloid deposits in three early-onset cases from endemic foci and five late-onset cases from non-endemic areas were systematically examined post-mortem. Amyloid deposits in early-onset cases were highly congophilic and showed strong apple-green birefringence with Congo red staining and had long, parallel fibrils in most organs. On the other hand, those in late-onset cases were generally weakly congophilic and showed faint apple-green birefringence with Congo red staining and had short, haphazard fibrils. In the renal glomus and adrenal gland of early-onset cases, the characteristics of amyloid deposits were similar to those observed in late-onset cases. Analysis of cardiac amyloid using surface enhanced desorption/ionization time-of-flight mass spectrometry indicated that most transthyretin (TTR) was variant in early-onset cases, while more than half was composed of wild-type TTR in late-onset cases. Although characteristics of amyloid deposits may differ among individual organs of respective cases, especially in early-onset cases, the pattern was distinct between early- and late-onset cases. Amyloid deposition in late-onset cases may be similar to that observed in senile systemic amyloidosis with wild-type TTR deposition, suggesting that aging may play an important role in these cases.

[Clinical features and course of 5 cases with HIV encephalopathy].

Clinical features and courses of 5 cases with HIV encephalopathy were reported. The subjects were among the patients registered as HIV patients at the Nagoya Medical Center, between 1996 and 2005. There were 458 patients with HIV infection including 127 cases of AIDS. All patients suffered from severe immunological deficiency when HIV encephalopathy developed. Other opportunistic infections had also occurred in three patients. HIV encephalopathy was one of the presenting manifestations of HIV infection in four patients, and no patients had received antiretroviral therapy. HAART improved motor disturbance and their ADL became independent except for one case. Improvements in neuropsychological examination scores were noted in all cases. Recovery from psychiatric symptoms, however, was incomplete. Four patients could not work, and 3 needed psychological treatment due to behavioral abnormalities. HIV encephalopathy is not a lethal disease but the functional prognosis was very poor. New therapy is needed for HIV encephalopathy.

Nationwide survey of juvenile muscular atrophy of distal upper extremity (Hirayama disease) in Japan.

Juvenile muscular atrophy of the distal upper extremity (JMADUE, Hirayama disease) was first reported in 1959 as 'juvenile muscular atrophy of unilateral upper extremity'. Since then, similar patients in their teens or 20s have been described, under a variety of names, not only in Japan, but also in other Asian countries, as well as Europe and North America. Biomechanical abnormalities associated with JMADUE have recently been reported through various imaging examinations, proposing its disease mechanism. Since JMADUE differs from motor neuron disease, or spinal muscular atrophy, this disease entity should be more widely recognized, and early detection and effective treatments should be considered. We report an epidemiological study in Japan. Two nationwide questionnaire-based surveys, conducted in Japan from 1996 to 1998, identified 333 cases. The numbers of patients per year, distribution of ages at onset, mode of onset, time lapse between onset and quiescence, neurological signs and symptoms, imaging findings, and the effects of conservative treatments were analyzed. The peak age was 15 to 17 years, with a marked male preponderance, usually a slow onset and progression, and quiescence six or fewer years after onset. There was a predominantly unilateral hand and forearm involvement with 'cold paresis'. The imaging findings are described.

Widespread active inflammatory lesions in a case of HTLV-I-associated myelopathy lasting 29 years.

An autopsy case of human T-lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM) of 29 years' duration is reported. The patient had no history of surgery or blood transfusion and likely contracted HTLV-I sexually while traveling in an endemic area. At age 45, the patient began to experience gait disturbance; he later developed spastic tetraparesis. Autopsy revealed marked gross spinal cord atrophy, particularly in the middle to lower thoracic levels. Myelin and axonal degeneration were identified predominantly in the middle to lower thoracic spinal cord, extending into the medulla oblongata and lumbar cord. Inflammatory infiltrates of mononuclear cells were diffuse in the white and gray matter of the spinal cord and medulla oblongata, particularly in perivascular areas. These infiltrates were also observed in perivascular areas of the pons, midbrain, cerebellum, and cerebrum. More than half of the infiltrating cells were positive for the pan-T cell marker UCHL-1, but some were positive for the B cell marker SL-26. There were far more CD8-positive cells than CD4-positive cells in the spinal parenchyma and perivascular areas. Neurons in the anterior horn, Clarke's column, and intermediolateral column were relatively well preserved. Active chronic inflammation was indicated. Despite the 29-year history of HAM, the presence of an active inflammatory reaction is surprising. We discuss possible modulation of the histopathological manifestations of HAM by corticosteroid therapy.

Clinical study of FK506 in patients with myasthenia gravis.

To investigate the usefulness of low-dose FK506 for the treatment of myasthenia gravis (MG), we treated 19 patients with generalized MG in a 16-week open clinical trial of FK506 (3-5 mg/day). At the end of the trial, total MG scores (range: 0-27 points) improved by 3 points or more in 7 of 19 patients (37%), and activities of daily living (ADL) scores (range: 0-6 points) also improved by 1 point or more in 8 of 19 patients (42%). Nine of 19 patients (47%) showed improvement in either MG or ADL scores. Significant reduction of anti-acetylcholine receptor antibody titers and interleukin 2 production were observed at the end of this study. Minor but commonly observed side effects were an increase in neutrophil count and a decrease in lymphocyte count. No serious adverse events such as renal toxicity or diabetes mellitus were observed during the 16-week treatment period. FK506 could safely serve as an adjunct to steroid therapy for MG at low dosage.

[Excessive daytime sleepiness and low CSF orexin-A/hypocretin-I levels in a patient with probable progressive supranuclear palsy].

We report a 74-year-old woman with excessive daytime sleepiness (EDS) who were diagnosed as probable progressive supranuclear palsy (PSP). Her EDS mimicked narcolepsy without cataplexy, because multiple sleep latency tests showed short latencies, human leukocyte antigen testing was positive for DR2/DQB1, and orexin A (hypocretin-I) concentration in her cerebrospinal fluid was undetectable. In PSP, neurofibrillary tangles appears in the hypothalamus, neuronal loss and gliosis are seen in a number of pontine and mesencephalic tegmental nuclei, substantia nigra, locus caeruleus. These neuropathological changes of PSP may cause decreased pre- or post-synaptic hypothalamic orexin neurotransmission because orexin neurons are located in the hypothalamus and project widely to the forebrain and the brain stem. In our patient, the treatment with methylphenidate HCl was effective on EDS.

Failure to detect Epstein-Barr virus (EBV) DNA in plasma by real-time PCR in a case of EBV-associated posttransplantation lymphoproliferative disorder confined to the central nervous system.

We report here a patient who developed multiple central nervous system (CNS) space-occupying lesions 6 months after bone marrow transplantation from an HLA-matched unrelated donor. He had extensive chronic graft-versus-host disease and severe thrombocytopenia. Posttransplantation lymphoproliferative disorder (PTLD) was diagnosed after biopsy of the lesion was facilitated by the transfusion of 40 units of platelets. Epstein-Barr virus (EBV) DNA was not initially detected in the peripheral blood by real-time polymerase chain reaction, and the blood became positive for EBV at a low level only after more than 6 weeks had passed since the initial identification of detectable intracranial lesions. The patient died of cerebral herniation while donor leukocyte infusion was being prepared, and an autopsy confirmed the diagnosis of EBV-associated PTLD restricted to the CNS.

Progression and prognosis in multiple system atrophy: an analysis of 230 Japanese patients.

We investigated the disease progression and survival in 230 Japanese patients with multiple system atrophy (MSA; 131 men, 99 women; 208 probable MSA, 22 definite; mean age at onset, 55.4 years). Cerebellar dysfunction (multiple system atrophy-cerebellar; MSA-C) predominated in 155 patients, and parkinsonism (multiple system atrophy-parkinsonian; MSA-P) in 75. The median time from initial symptom to combined motor and autonomic dysfunction was 2 years (range 1-10). Median intervals from onset to aid-requiring walking, confinement to a wheelchair, a bedridden state and death were 3, 5, 8 and 9 years, respectively. Patients manifesting combined motor and autonomic involvement within 3 years of onset had a significantly increased risk of not only developing advanced disease stage but also shorter survival (P < 0.01). MSA-P patients had more rapid functional deterioration than MSA-C patients (aid-requiring walking, P = 0.03; confinement to a wheelchair, P < 0.01; bedridden state, P < 0.01), but showed similar survival. Onset in older individuals showed increased risk of confinement to a wheelchair (P < 0.05), bedridden state (P = 0.03) and death (P < 0.01). Patients initially complaining of motor symptoms had accelerated risk of aid-requiring walking (P < 0.01) and confinement to a wheelchair (P < 0.01) compared with those initially complaining of autonomic symptoms, while the time until confinement to a bedridden state and survival were no worse. Gender was not associated with differences in worsening of function or survival. On MRI, a hyperintense rim at the lateral edge of the dorsolateral putamen was seen in 34.5% of cases, and a 'hot cross bun' sign in the pontine basis (PB) in 63.3%. These putaminal and pontine abnormalities became more prominent as MSA-P and MSA-C features advanced. The atrophy of the cerebellar vermis and PB showed a significant correlation particularly with the interval following the appearance of cerebellar symptoms in MSA-C (r = 0.71, P < 0.01, r = 0.76 and P < 0.01, respectively), but the relationship between atrophy and functional status was highly variable among the individuals, suggesting that other factors influenced the functional deterioration. Atrophy of the corpus callosum was seen in a subpopulation of MSA, suggesting hemispheric involvement in a subgroup of MSA patients. The present study suggested that many factors are involved in the progression of MSA but, most importantly, the interval from initial symptom to combined motor and autonomic dysfunction can predict functional deterioration and survival in MSA.