Kinya Hisanaga

Neuro-Sweet disease Clinical manifestations and criteria for diagnosis

Background: Sweet disease, also known as acute febrile neutrophilic dermatosis, is a multisystem inflammatory disorder characterized by painful erythematous plaques and aseptic neutrophilic infiltration of various organs. Skin biopsies typically demonstrate dermal infiltration with neutrophils in the absence of vasculitis. Sweet disease responds to systemic corticosteroids. The CNS can also be involved. Methods: The authors performed a survey on neuro-Sweet disease (NSD) in Japan and obtained detailed information about 16 cases. They analyzed 42 cases, including 26 cases documented in the literature, and assessed clinical and laboratory criteria for the diagnosis. Results: Thirteen cases also fulfilled the criteria for the diagnosis of Behçet disease. The clinical features of 27 cases, which the authors classified as probable NSD, are as follows: 1) both sexes are almost evenly affected; 2) people of ages 30 to 70 years are affected; 3) encephalitis and meningitis are common neurologic manifestations; 4) any region of the CNS can be involved, resulting in a variety of neurologic symptoms; 5) there is a strong human leukocyte antigen-Cw1 association; 6) systemic corticosteroids are highly effective for most of the neurologic manifestations, although recurrences are not infrequent. Conclusions: Neuro-Sweet disease is a distinct entity that may account for some cases of idiopathic encephalomeningitis.

Changes in Levels of Purine and Pyrimidine Nucleotides During Acute Hypoxia and Recovery in Neonatal Rat Brain

Abstract Neonatal rat brains were examined for changes in levels of ATP, ADP, AMP, cyclic AMP, GTP, GDP, UTP, UDP, UMP, and CTP during exposure to 100% nitrogen for 20 min and subsequent recovery in air. During hypoxia, ATP, GTP, UTP, and CTP levels and the GTP/GDP ratio decreased to 38, 50, 26,21, and 21%, respectively, of control levels. No significant change in cyclic AMP level was observed. The decrease in the total uridine nucleotide pool during hypoxia was markedly greater (to 53% of control levels) than that in the total adenine nucleotide pool (to 92% of control levels). During recovery, ATP and GTP levels were rapidly and almost completely restored. On the other hand, CTP levels returned slowly to control values after a 2‐h recovery period. Restoration of the UTP level was slow and incomplete (87% of the control value even after a 3‐h recovery period). The GTP/GDP ratio also did not return to normal. These data suggest that hypoxic insult to the neonate may have an effect on the synthesis of nucleotidyl sugars, phospholipids, and proteins in the brain, resulting in significant problems with developmental processes of the brain. The present study also showed that the delayed restorations of the UTP level and the GTP/GDP ratio were not seen in the brains of adult rats subjected to acute severe hypoxic insult.

Fluoro-DOPA and FDG positron emission tomography in a case of pathologically verified pure diffuse Lewy body disease

Sirs: A 49-year-old Japanese woman had suffered from gait disturbance since 1990 and memory disturbance since 1994. She visited Miyagi National Hospital in 1995, where she was found to have bradykinesia, muscle rigidity of the neck and extremities without laterality, retro-pulsion, dementia, delusion, and visual hallucinations. Tremor and fluctuation in cognitive and motor dysfunction were not noted. Minimental state examination (MMSE) [2] scored 6 points. Computed tomography and magnetic resonance images revealed moderate, diffuse atrophy of the cerebral cortices (not shown). Electroencephalography showed abundance of theta and delta activities without laterality. She was then tentatively diagnosed as “diffuse Lewy body disease (DLBD)” [4, 5]. Levodopa appeared to have no effect upon her symptoms. The clinical course was rapidly progressive, so she was confined to her bed in 1997. To examine regional cerebral metabolic rate of glucose (CMRglc) we performed [18F]fluoro-2deoxy-D-glucose (FDG)-PET in March, 1997. [18F]6-fluorodopa (FDOPA)-PET was performed to measure fluorodopa uptake in May, 1997. PET images were obtained using the PT-931 scanner (CTI Inc., USA) at the Cyclotron and Radioisotope Center, Tohoku University, Sendai, Japan, as described previously [7]. In FDG-PET a series of three emission scans, each of 10 min duration, was performed at standard points 16, 63 and 110 mm above and parallel to the orbitomeatal line 30 min after an intravenous bolus injection of 3.8 mCi of FDG. These studies showed diffuse decreases of CMRglc in the cortices, prominent in the medial temporal cortex (Fig.1). In FDOPA-PET a series of 5 min emission scans were performed over 60 min after an intravenous bolus injection of FDOPA (3.8 mCi). It demonstrated a significant decrease in the accumulation in the caudate nucleus and putamen bilaterally (Fig.2). In August she died of pneumonia, and an autopsy was performed with informed consent of her relatives. Macroscopically almost the entire part of the cerebral cortices showed slight diffuse atrophy without laterality. Moderate discolLETTER TO THE EDITORS

Cholinergic Deficit and Response to Donepezil Therapy in Parkinson’s Disease with Dementia

Background: Although donepezil, an acetylcholinesterase inhibitor, has been proved to be effective in ameliorating cognitive impairment in Parkinson’s disease with dementia (PDD), the responsiveness of patients to donepezil therapy varies. [5-11C-methoxy]donepezil, the radiolabeled form of donepezil, is a ligand for positron emission tomography (PET), which can be exploited for the quantitative analysis of donepezil binding to acetylcholinesterase and for cholinergic imaging. Objectives: To investigate the deficits of the cholinergic system in the brain in PDD and its association with response to donepezil therapy. Methods: Twelve patients with PDD and 13 normal control subjects underwent [5-11C-methoxy]donepezil-PET imaging. For patients with PDD, daily administration of donepezil was started after [5-11C-methoxy]donepezil-PET imaging and continued for 3 months. Results: In the PDD group, the mean total distribution volume of the cerebral cortices was 22.7% lower than that of the normal control group. The mean total distribution volume of the patients with PDD was significantly correlated with improvement of visuoperceptual function after 3 months of donepezil therapy. Conclusion: The results suggest that donepezil therapy is more effective in patients with less decrease in acetylcholinesterase, a binding site of donepezil, at least in the specific cognitive domain.

Counting-backward test for executive function in idiopathic normal pressure hydrocephalus.

The aim of this study was to develop and validate a bedside test for executive function in patients with idiopathic normal pressure hydrocephalus (INPH).

An autopsy case of frontotemporal lobar degeneration with the appearance of fused in sarcoma inclusions (basophilic inclusion body disease) clinically presenting corticobasal syndrome

We describe an autopsy case of basophilic inclusion body disease (BIBD), a subtype of frontotemporal lobar degeneration (FTLD) with the appearance of fused in sarcoma (FUS) inclusions (FTLD‐FUS), clinically presenting corticobasal syndrome (CBS). A 54‐year‐old man initially developed worsening of stuttering and right hand clumsiness. Neurological examinations revealed rigidity in the right upper and lower extremities, buccofacial apraxia, and right‐side dominant limb‐kinetic and ideomotor apraxia. Neuroimaging showed asymmetric left‐dominant brain atrophy and a cerebral blood flow reduction in the ipsilateral frontal region. At 56 years, his apraxia had advanced, and ideational apraxia was observed. Furthermore, the asymmetry in the limb‐kinetic and ideomotor apraxia had disappeared, and both conditions had become bilateral. He had a new onset of aphasia. His symptoms progressed and he died 9 years after the initial symptoms. The brain weighed 955 g. Diffuse brain atrophy was most obvious in the bilateral frontotemporal regions. The atrophy of the left superior frontal and precentral gyri and bilateral basal ganglia was remarkable. Histologically, there was a marked loss of neurons with gliosis in the affected areas, where basophilic neuronal cytoplasmic inclusions were observed. The inclusions were immunoreactive for FUS, p62, and TATA‐binding protein‐associated factor 15 (TAF15), but not for phosphorylated tau, transactive response DNA‐binding protein of 43 kDa (TDP‐43), neurofilament protein, or Ewing sarcoma (EWS). From these pathological findings, this case was diagnosed as having BIBD as an FTLD‐FUS variant. Spinal cord lower motor neurons were spared in number, similar to primary lateral sclerosis. Mutations in FUS were undetectable. Common background pathologies for CBS include corticobasal degeneration, Alzheimers disease, PSP, FTLD with phosphorylated TDP‐43 inclusions (FTLD‐TDP), Picks disease, Lewy body disease and CJD. However, FTLD‐FUS (BIBD) has been rarely reported. Our case suggested further pathological heterogeneity in CBS than had previously been reported. It is necessary to consider FTLD‐FUS (BIBD) as a background pathology for CBS in the future.

An autopsy case of superficial siderosis of the central nervous system accompanied by anterior sacral polycystic meningocele in neurofibromatosis type 1.

A 74-year-old female patient, who was diagnosed with neurofibromatosis type 1 (NF1) at the age of 40, was admitted with complaints of flickering vision and gait disturbance for the last 2 years. On admission, neurological examination revealed mild bilateral hearing loss and ataxia in the limb and trunk. Laboratory tests revealed anti-hepatitis C virus (HCV) antibody positivity and elevated HCV RNA by real-time polymerase chain reaction. The cerebrospinal fluid examination revealed a slightly yellowish appearance with elevated total protein levels. Gradient echo T2*-weighted brain magnetic resonance imaging (MRI) demonstrated a rim of hypointense lesions surrounding the surface of the cerebellum, brainstem, frontal and temporal lobes, and thalamus, which was considered as hemosiderin depositions. From these MRI findings, she was diagnosed as having superficial siderosis of the central nervous system. Cerebral angiography revealed an aneurysm-like dilatation at the bifurcation of the right internal carotid-posterior communicating artery. (99m)Tc-ethyl cysteinate dimer single-photon emission computed tomography revealed hypoperfusion in the bilateral frontal and temporal lobes. Pelvic plain X-ray, pelvic computed tomography, and lumbosacral MRI revealed a sacral defect and an anterior sacral polycystic meningocele communicating with the spinal subarachnoid space. The patients symptoms gradually worsened, and she died of septic shock because of pyelonephritis at the age of 77. An autopsy was performed; on pathological examination, we did not observe any findings associated with rupture of the aneurysm-like dilatation in the bifurcation of the right internal carotid-posterior communicating artery and cerebral amyloid angiopathy. Because duropathies-a new neurological disease concept-have been implicated as a cause of bleeding in the superficial siderosis, the anterior sacral polycystic meningocele, a type of duropathies, was presumed to be the most probable bleeding source of the superficial siderosis in this patient. Bleeding from the meningocele might result from the vulnerability of vessel walls in NF1.

上位頸髄背側の小病変のみが出現した抗myelin oligodendrocyte glycoprotein抗体陽性の再発性脊髄炎の1例

A 65-year-old man initially developed numbness and hypesthesia in the right shoulder and brachial regions that disappeared within several months. MRI revealed a small lesion extending to a vertebral segment in the right dorsal region of the cervical spinal cord at the vertebral height of C2/3. About 15 months later, the intermittent lancinating pain identical to the right trigeminal and occipital neuralgia with pain and hypesthesia distributed in the right C2-C4 dermatome regions appeared. MRI revealed a new oval lesion with gadolinium enhancement in the right dorsal region of the cervical spinal cord at the vertebral height of C1, which was thought to involve the posterior column and lower part of the spinal tract nucleus of the trigeminal nerve. There was no optic nerve, brain, or other spinal cord lesions that suggested demyelination on MRI. A titer of serum anti-aquaporin-4 antibody was negative, but anti-myelin oligodendrocyte glycoprotein (MOG) antibody was found to be positive. The symptoms were relieved by corticosteroid treatment. Our report presents a rare case of anti-MOG antibody-positive recurrent myelitis that developed only as localized short upper cervical spinal cord lesions, not meeting the diagnostic criteria for neuromyelitis optica spectrum disorders.

Diffuse neuroaxonal leukodystrophy with spheroids of adult onset: MRI and pathological studies

A case of sudanophilic leukoencephalopathy of adult onset was reported. A 42‐year‐old Japanese woman showed progressive dementia, gait disturbance, apraxia of the left hand, left hemiparesis, and urinary and fecal incontinence. Magnetic resonance imaging (T2‐weighted scans and proton images) revealed a symmetrical widespread increase in the signal intensity of cerebral white matter, more prominent in the frontal lobes. Blood levels of very long chain fatty acids and arylsulfatase A were within normal limits. A needle biopsy specimen from the frontal lobe revealed severe demyelination with sudanophilic granules and neurofilament protein‐immunoreactive neuroaxonal spheroids in the white matter. The patients mother was known to have similar symptoms and died at the age of 45, indicating an autosomal dominant inheritance. Because of the dominant inheritance, the psychiatric and neurological symptoms, and the characteristic neuroaxonal spheroids, the case was tentatively diagnosed as ‘hereditary diffuse leukoencephalopathy with spheroids’, a condition that has not been previously reported in Japan.