Tomohiko Mizutani

Evaluation of combination therapy using aciclovir and corticosteroid in adult patients with herpes simplex virus encephalitis

Objective: Herpes simplex virus encephalitis (HSVE) is associated with significant morbidity and mortality, even with appropriate antiviral therapy. In the present investigation, the first to assess efficacy of corticosteroid treatment with aciclovir therapy in HSVE, multiple logistic regression analysis was performed of predictors of outcome in adult patients with HSVE. Methods: A non-randomised retrospective study of 45 patients with HSVE treated with aciclovir was conducted. The patients were divided into poor and good groups based on outcome at three months after completion of aciclovir treatment. The variables evaluated were: clinical variables (sex, age, days after onset at initiation of aciclovir, Glasgow Coma Scale (GCS) at initiation of aciclovir, initial and maximum values for the cell numbers and protein concentration in the cerebrospinal fluid, and corticosteroid administration); neuroradiological variables (detection of lesions by initial cranial computed tomography and by initial magnetic resonance imaging); and one neurophysiological variable (detection of periodic lateralised epileptiform discharges on the initial electroencephalogram). Single variable logistic regression analysis was performed followed by multiple logistic regression analysis. The best set of predictors for the outcome of HSVE was estimated by stepwise logistic regression analysis. Results: A poor outcome was evident with older age, lower GCS score at initiation of aciclovir, and no administration of corticosteroid. Patient age, GCS at initiation of aciclovir, and corticosteroid administration were found to be significant independent predictors of outcome on multiple logistic regression analysis, and these three variables also formed the best set of predictors (R2 = 0.594, p<0.0001). Conclusion: Combination therapy using both aciclovir and corticosteroid represents one of the predictors of outcome in HSVE.

Amyotrophic lateral sclerosis with ophthalmoplegia and multisystem degeneration in patients on long-term use of respirators

SummaryWe describe two patients with sporadic amyotrophic lateral sclerosis (ALS), who had developed progressive external ophthalmoplegia of a predominantly supranuclear type while they survived on respirators, and displayed histopathological abnormalities both typical and atypical of ALS. Patient 1 was a 43-year-old man with ALS of 5-year duration, who had initially exhibited fulminant ALS, and remained on a respirator for 4 years. Patient 2 was a 51-year-old man with ALS of 13-year duration, who remained on a respirator for 8 years. Both patients died in a “totally locked-in state”. Autopsy of both patients revealed not only histopathological abnormalities consistent with ALS, but also multisystem degeneration which involved the pontine tegmentum, substantia nigra, Clarkes dorsal nuclei and spinocerebellar tracts. In addition, Patient 2 displayed intracyto-plasmic neuronal basophilic inclusion bodies which exhibited marked immunoreactivity to anti-ubiquitin antibodies. Our case reports indicate that the longer survival which is possible through the use of respirators may make one subgroup of ALS patients prone to develop atypical clinical and neuropathological features which are not observed during the natural cours of ALS.

Clinical analysis of longstanding subacute myelo-optico-neuropathy: sequelae of clioquinol at 32 years after its ban

One thousand and thirty-one longstanding patients with subacute myelo-optico-neuropathy (SMON; 275 males, 756 females; mean age +/- S.D., 72.9 +/- 9.6 years; age at onset 37.6 +/- 9.8 years; duration of illness 35.3 +/- 4.0 years) were examined in 2002, 32 years after banning of clioquinol. At onset, 66.7% of patients were unable to walk, and 4.7% complete blindness. At present time, about 41% of patients were still difficult to walk independently, including 15.8% of completely loss of locomotion. One point six percent of patients were in complete blindness and 5.8% had severe visual impairment. The majority (95.6 - 97.7%) of patients exhibited sensory disturbances including superficial and vibratory sensations and dysesthesia. Dysautonomia was observed as leg hypothermia in 79.8%, urinary incontinence in 60.7%, and bowel disturbance in 95.3%. As complication, high incidence was revealed with cataract (56.2%), hypertension (40.2%), vertebral disease (35.5%), and limb articular disease (31.5%). These results indicate the serious sequelae of clioquinol intoxication, SMON.

Development of ophthalmoplegia in amyotrophic lateral sclerosis during long-term use of respirators

Patients with amyotrophic lateral sclerosis (ALS), who survive longer on a life-support system, exceeding the natural course of this disease, show new features of ALS. We report here a clinico-pathologic study of a 51-year-old patient with sporadic ALS who developed progressive external ophthalmoplegia 3 years after he remained on a respirator and died 5 years later, 13 years after the onset of his illness. The external ophthalmoplegia was initially accompanied by preserved dolls eye phenomenon, which later became absent. Autopsy revealed not only degeneration of the upper and lower motor neuron systems typical of ALS, but also degeneration of the Clarkes dorsal nuclei, spinocerebellar tracts, substantia nigra and inferior olives in addition to intracytoplasmic neuronal inclusion bodies in various areas. The oculomotor and abducens nuclei were variably involved, accompanied by neurogenic atrophy of the extraocular muscles. Our case report is consistent with the idea that ALS comprises a heterogeneous group of disorders, and also indicates that long-term use of respirators may make some patients with this illness prone to developing atypical clinical and neuropathologic features which are not observed during the natural course of ALS.

Comparison of quantitative EEGs between Parkinson disease and age-adjusted normal controls.

Summary: Quantitative EEG (qEEG) findings in Parkinson disease (PD) have been reported in only five previous studies. In these studies, the sample size was small and the distribution of qEEG changes was not estimated. This is the first qEEG evaluation not only employing multiple logistic regression analysis but also estimating the distribution of qEEG changes. The subjects comprised 45 PD patients without remarkable dementia and 40 age-adjusted normal controls. The lack of ischemic lesions in all subjects was confirmed by MRI. Absolute power values were measured for four frequency bands from delta to beta. The electrodes were divided into six, viz. frontal pole, frontal, central, parietal, temporal, and occipital locations. We calculated the spectral ratio, i.e., the sum of the power values in the alpha and beta waves divided by the sum of the values in the slow waves. The dependent variable was either PD or normal control; the independent variables were the spectral ratios, age, sex, and Mini-Mental State Examination score. The significant predictive variables in PD were the spectral ratios at all electrode locations except for the frontal pole (frontal location: P = 0.025, other locations: P < 0.01). PD presented diffuse slowing in the qEEG when compared with age-adjusted normal controls.

NACP/α-synuclein and tau constitute two distinctive subsets of filaments in the same neuronal inclusions in brains from a family of parkinsonism and dementia with Lewy bodies: double-immunolabeling fluorescence and electron microscopic studies

Abstract The co-localization of NACP/α-synuclein and tau epitopes was examined in the brain stem and hippocampal formation in two patients from a family of autosomal dominant parkinsonism and dementia with Lewy bodies (LBs) without two reported missense mutations in the NACP gene. Double-labeling immunofluorescence study revealed that some brain stem LBs, cortical LBs, pale bodies, Lewy-related neurites, and neurofibrillary tangles expressed both NACP epitopes and the PHF tau AT8 epitope. Double-immunolabeling electron microscopy demonstrated that the NACP antibody selectively labeled 9- to 13-nm-thick straight filaments (LB filaments), whereas AT8 recognized twisted tubules with 80- to 100-nm-interval constrictions in the same neuronal inclusions. We show that NACP and tau aggregate into different filamentous components even if both proteins are incorporated into the same inclusions.

A continuing high incidence of subacute sclerosing panencephalitis (SSPE) in the Eastern highlands of Papua New Guinea

The aims of this descriptive study were to confirm the high incidence of subacute sclerosing panencephalitis (SSPE) previously reported from Papua New Guinea (PNG) and to relate SSPE to previous measles vaccination and measles illness. From February 1997 to April 1999 we diagnosed a total of 55 patients with SSPE at Goroka Base General Hospital in Eastern Highlands Province (EHP) of PNG. The diagnosis was based on high cerebrospinal fluid and serum measles virus antibody titres with progressive neurological disorder and myoclonic jerks. Of these 55 patients 42 were from EHP, including 32 whose onset was in the 2-year period 1997-1998. The annual incidence of SSPE in EHP in these 2 years was 98 per million population under 20 years of age, the highest ever reported. This incidence was more than ten times higher than the highest incidence in the prevaccine era reported from elsewhere. The mean age of onset of SSPE was 7.7 years (range 2.8-14.8 years) and the interval between measles and the onset of SSPE, where known, had a mean of 5.9 years and a range of 2.5-11.1 years. Among the SSPE patients 19 had a documented history of measles vaccination. Eight of these 19 also had documentation of previous measles illness; of these, seven were vaccinated after the development of measles and one was vaccinated 20 days before measles illness. Two non-SSPE children received vaccination twice which was documented and subsequently developed measles which was also substantiated by documentation. Two patients with SSPE yielded amplified nucleotide sequences of measles virus that were different from any of the vaccine strains. We found no evidence to implicate measles vaccination in the development of SSPE.

Nested polymerase chain reaction for assessing the clinical course of tuberculous meningitis

The authors examined the usefulness of nested PCR (N-PCR) to detect Mycobacterium tuberculosis (MTB) DNA in CSF for assessing the clinical course of tuberculous meningitis (TBM). N-PCR successfully detected MTB DNA in all nine CSF samples from patients with suspected TBM. During anti-tuberculosis treatments, N-PCR results converted from positive to negative, correlating with the improvement of the patient’s clinical condition.

Prognostic value of cerebrospinal fluid cytokine changes in herpes simplex virus encephalitis

A recent trial suggested that corticosteroid was beneficial in herpes simplex virus encephalitis (HSVE), but that precise role remains unclear. We assessed the differences of cerebrospinal fluid (CSF) cytokine changes between different outcomes and between patients with and without corticosteroid administration at the acute stage of HSVE. Interleukin (IL)-1beta, IL-2, IL-6, IL-10, interferon (IFN)-gamma, and tumor necrosis factor-alpha were measured in 56 serial CSFs taken from 20 adult HSVE patients. Their outcomes were poor in 7 and good in 13 patients, and corticosteroid was administered in 10. The differences in the initial and maximum cytokine values were assessed among the different outcomes. The decline rate of cytokine values between the initial and second CSF samples was also assessed between patients with and without corticosteroid. The initial IFN-gamma and maximum IL-6 with a poor outcome were higher than those with a good outcome (p=0.019 for IFN-gamma and p=0.013 for IL-6). The decline rate of IL-6 in patients with corticosteroid was higher than that without corticosteroid (p=0.034). The initial IFN-gamma and maximum IL-6 CSF values represented prognostic biomarkers in HSVE. One pharmacological mechanism related to corticosteroid in HSVE is apparently inhibition of pro-inflammatory cytokines such as IL-6.

Familial parkinsonism and dementia with ballooned neurons, argyrophilic neuronal inclusions, atypical neurofibrillary tangles, tau-negative astrocytic fibrillary tangles, and Lewy bodies

Abstract We report four patients with a new type of familial parkinsonism and dementia consisting of an autosomal dominant inheritance, dopa-responsive parkinsonism, severe dementia, variable myoclonus and autonomic disturbances. Autopsy of two patients revealed symmetrical cerebral atrophy with fronto-temporal dominant distribution, and marked depigmentation in the substantia nigra and locus ceruleus. Neuronal loss and gliosis were observed in the deep cerebral cortex and amygdala as well as in the areas vulnerable to Parkinson’s disease. In the cerebral cortex, swollen neurons with frequent granulovacuolar changes were observed, consisting of ballooned neurons and those with argyrophilic intracytoplasmic inclusions, in addition to neuropil threads. Atypical neurofibrillary tangles, which barely stained with tau antibodies, were numerous in the upper cortical layers, consisting of 15-nm straight tubules. In addition, tau-negative astrocytic fibrillary tangles were also frequent. Electron microscopically, the ballooned neurons and argyrophilic neuronal inclusions contained filamentous structures coated with fuzzy electron-dense deposits. The inclusions showed immunohistochemical features different from those of cortical Lewy bodies and Pick bodies. Occasional Lewy bodies were present in the brain stem lesions of both patients. In two of our patients, the pathology in the brain stem was similar to that of Parkinson’s disease, whereas their cerebral pathology was unusual and has not been reported previously.