Y. Itoyama

Diffusion-weighted MRI abnormalities as an early diagnostic marker for Creutzfeldt-Jakob disease.

Objective: To evaluate the usefulness of diffusion-weighted MRI (DWI) for the early diagnosis of Creutzfeldt–Jakob disease (CJD). Methods: Thirty-six consecutive patients (age 56 to 82 years) were enrolled, and 26 were examined by DWI. Nine were definite based on the World Health Organization criteria, and 27 were probable. The percentages of DWI abnormalities, periodic sharp wave complexes (PSWCs) on the EEG, detection of CSF 14-3-3 protein, and increase of CSF neuron-specific enolase (>25 ng/mL) on the first examination were compared. For DWI, 32 patients (age 31 to 84 years) who showed progressive dementia or impaired consciousness served as disease controls. Results: The percentage of DWI abnormalities was 92.3%, of PSWCs 50.0%, of 14-3-3 protein detection 84.0%, and of NSE increase 73.3%. Two of the 32 control subjects were falsely positive on DWI. The sensitivity of DWI was 92.3% (95% CI 74.8 to 99.5%) and specificity 93.8% (95% CI 79.2 to 99.2%). In 17 patients who did not show PSWCs on the first EEG, abnormal DWI findings were still clearly detected. Four patients who were negative for 14-3-3 protein also showed DWI abnormalities. DWI abnormalities were detected as early as at 3 weeks of symptom duration in four patients in whom PSWCs were not yet evident. Conclusions: DWI can detect characteristic lesions in the majority of patients with CJD regardless of the presence of PSWCs. DWI was the most sensitive test for the early clinical diagnosis of CJD; consideration should be given to its inclusion in the clinical diagnostic criteria of CJD.

Astrocytic damage is far more severe than demyelination in NMO A clinical CSF biomarker study

Introduction: Loss of aquaporin 4 and glial fibrillary acidic protein (GFAP) with necrosis and demyelination is a prominent pathologic feature of neuromyelitis optica (NMO). However, the clinicopathologic significance of astrocytic damage and its relation with demyelination are unknown. Objective: To analyze clinical and pathologic values of a CSF biomarker of astrocytic damage in NMO. Methods: We measured the levels of GFAP, S100B, myelin basic protein (MBP), and neurofilament H (NF-H) in CSF obtained from patients with NMO (n = 33), multiple sclerosis (MS) (n = 27), acute disseminated encephalomyelitis (ADEM), ischemia, meningitis, and other neurologic disease controls (OND). Results: The CSF-GFAP levels during relapse in NMO (2,476.6 ± 8,815.0 ng/mL) were significantly higher than those in MS (0.8 ± 0.4 ng/mL) and OND (0.7 ± 0.5 ng/mL), and much beyond those in ADEM (14.1 ± 27.4 ng/mL). The sensitivity and specificity of CSF-GFAP for NMO was 90.9% and 76.9% in all, but the specificity improved above 90% in cases limited to demyelinating diseases. CSF-S100B showed a similar trend but was less remarkable. In contrast, MBP and NF-H are not different between NMO and MS. Following treatments, the CSF-GFAP rapidly decreased to a normal level, but CSF-MBP remained high. There were strong correlations between the CSF-GFAP, CSF-S100B, or CSF-MBP levels and Expanded Disability Status Scale (EDSS) or spinal lesion length in the acute phase (r > 0.6). Only CSF-GFAP correlated with EDSS at 6-month follow-up (r = 0.51) in NMO. Conclusions: Astrocytic damage reflected by elevated CSF glial fibrillary acidic protein is a clinically relevant, primary pathologic process in neuromyelitis optica, and is far more severe than demyelination.

Temporal changes and geographical differences in multiple sclerosis phenotypes in Japanese: nationwide survey results over 30 years.

Background There are two distinct phenotypes of multiple sclerosis (MS) in Asians, manifesting as optic-spinal (OSMS) and conventional (CMS) forms. In Japan, four nationwide surveys of MS have been conducted. The first three were in 1972, 1982, and 1989, and we performed the fourth in 2004. Results The recent survey showed six main findings as follows: (1) a four-fold increase in the estimated number of clinically definite patients with MS in 2003 (9900; crude MS prevalence, 7.7/100,000) compared with 1972; (2) a shift in the peak age at onset from early 30s in 1989 to early 20s in 2003; (3) a successive proportional decrease in optic-spinal involvement in clinically definite patients with MS; (4) a significant north–south gradient for the CMS/OSMS ratio; (5) after subdivision of the mainland (30–45° North) into northern and southern parts at 37°N, northern-born northern residents (northern patients) showed a significantly higher CMS/OSMS ratio and higher frequency of brain lesions fulfilling the Barkhof criteria (Barkhof brain lesions) than southern-born southern residents (southern patients); (6) among northern patients, the absolute numbers of patients with CMS and those with Barkhof brain lesions rapidly increased with advancing birth year. Conclusions These findings suggest that MS phenotypes are drastically altered by environmental factors, such as latitude and “Westernization.”

CSF hypovolemia vs intracranial hypotension in "spontaneous intracranial hypotension syndrome".

Objectives: To investigate the role of CSF hypovolemia in spontaneous intracranial hypotension (SIH) syndrome because so-called SIH syndrome sometimes lacks intracranial hypotension. Methods: Ten women (aged from 28 to 49 years) with characteristic orthostatic headache without a previous history of dural tear were investigated. In addition to gadolinium (Gd)–enhanced brain MRI, spinal MRI with and without Gd enhancement was performed. Results: Gd-enhanced brain MRI demonstrated diffuse pachymeningeal enhancement in all patients. Sagittal T2-weighted spinal MRI revealed a variable amount of CSF in the extradural space in all patients. Sagittal T2-weighted MRI or axial Gd-enhanced T1-weighted MRI showed dilated epidural veins located in the high cervical portion in each patient. The intensity of dilatation of the epidural veins correlated significantly with the amount of CSF in the epidural space. This suggested that the Monro–Kellie doctrine was applicable in this circumstance. Conclusions: Since some patients with SIH syndrome have normal CSF pressure and since a downward displacement of the brain due to a reduction of the buoyant action of CSF may induce symptoms, CSF hypovolemia, not intracranial hypotension, may be the cause. Based on the Monro–Kellie doctrine, detecting leaked CSF and venous engorgement (epidural vein dilatation and pachymeningeal enhancement) is an important clue to diagnose so-called SIH syndrome. Dilatation of epidural veins suggests CSF hypovolemia in appropriate conditions.

A case of NMO seropositive for aquaporin-4 antibody more than 10 years before onset

Neuromyelitis optica (NMO) is characterized by severe optic neuritis and longitudinally extended transverse myelitis (LETM). The clinical and laboratory features of NMO are different from multiple sclerosis (MS).1 An autoantibody to aquaporin-4 (AQP4) has been detected exclusively in the NMO sera.1 Moreover, we demonstrated an extensive loss of AQP4 and glial fibrillary acidic protein immunoreactivities in the perivascular regions with complement and immunoglobulin deposition in NMO that suggests astrocytic impairment. However, when AQP4 antibody is produced in patients with NMO is unknown, and thus it remains unresolved whether there are long-term asymptomatic AQP4 antibody–positive carriers, whether AQP4 antibody alone can be pathogenic, and whether AQP4 antibody is produced secondarily as a result of tissue destruction in attacks of NMO. We herein report a case of NMO in which AQP4 antibody was detected years before the NMO onset. ### Case report. A 34-year-old healthy woman without previous history of inflammatory or neurologic diseases noticed temporary skin eruptions on her chest and shoulders in June 2007. A dermatologist made the diagnosis of eczema. Three weeks later, when the skin eruptions subsided, she noted progressive paresthesia in the chest and toes. Within a few days, she could not walk well due to right leg weakness, and then she was hospitalized. Neurologic examination on …

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.

Clinical features of Creutzfeldt-Jakob disease with V180I mutation

The authors describe the clinical features of Creutzfeldt-Jakob disease (CJD) with the causative point mutation at codon 180. The symptoms never started with visual or cerebellar involvement. The patients showed slower progression of the disease compared with sporadic CJD. They never showed periodic sharp and wave complexes in EEG. MRI demonstrated remarkable high-intensity areas with swelling in the cerebral cortex except for the medial occipital and cerebellar cortices. These characteristic MRI findings are an important clue for an accurate premortem diagnosis.

Familial neuromyelitis optica (Devic’s syndrome) with late onset in Japan

Neuromyelitis optica (NMO), or Devic’s syndrome, is characterized by the selective involvement of the optic nerves and spinal cord with normal brain MRI, in distinction to typical MS. The majority of NMO cases are sporadic, and the disease usually affects young adults: familial NMO has never previously been reported in Japan, where the nonfamilial form of NMO is relatively common, and none of the 71 cases of NMO seen at the Mayo Clinic was familial, although four patients reported a family history of MS.1 Only two familial NMO cases have been reported in the literature, and the ages at onset in those cases were 2 and 3 years in one family and 24 and 26 years in the other.2,3 We herein report NMO in two elderly Japanese sisters in whom the onset of disease occurred at age 59 and age 62 years. Patient 1. Patient 1 was a 67-year-old woman. When she was 62, right-sided blindness developed over 4 days, but the vision was restored in a year. At age 65, she became quadriplegic and felt numb below the neck. After 3 months of rehabilitation, she could walk using a cane. At age 67, she developed bilateral blurred vision, paraplegia, and dysuria subacutely, …

Familial leptomeningeal amyloidosis with a transthyretin variant Asp18Gly representing repeated subarachnoid haemorrhages with superficial siderosis

Objectives: To report the clinical features of two Japanese brothers with familial leptomeningeal amyloidosis, showing a causative gene abnormality of a transthyretin (TTR) variant Asp18Gly, previously reported only in a Hungarian family. Methods: The authors reported on a 42 year old man (patient 1) and his 45 year old brother (patient 2), both suffering from subarachnoid haemorrhage (SAH) without and with hydrocephalus, respectively. DNA sequences of the TTR gene were determined in both patients and the patients’ clinical features described. A surgical biopsy of the leptomeninges was performed on patient 1. Results: DNA sequence analyses demonstrated the glycine-for-aspartate substitution at position 18 of the TTR variant. Both patients revealed pyramidal tract signs and cerebellar ataxia. Audiometric studies showed bilateral, mild sensorineural hearing loss in the patients whose cerebrospinal fluid (CSF) protein levels increased. T1 weighted MRI after contrast administration showed diffuse leptomeningeal enhancement along the Sylvian fissures and over the surface of the brainstem, cerebellum, and spinal cord. Gradient echo T2* weighted MRI showed superficial siderosis mainly in the cerebellum. A biopsy of the leptomeninges was obtained from the spinal cord of patient 1. While performing the biopsy, the authors observed the varicose, elongating, and fragile veins on the dorsal surface of the spinal cord. Immunohistochemical study revealed marked deposits of TTR derived amyloid on his leptomeninges. Conclusions: This is the second report of familial leptomeningeal amyloidosis with an Asp18Gly TTR gene mutation, clinically causing only CNS symptoms. Repeated SAH from fragile veins on the dorsal surface of the spinal cord seemed to induce superficial siderosis of the CNS. So far, there have been two reliable hallmarks leading to the diagnosis of leptomeningeal amyloidosis: diffuse leptomeningeal enhancement on contrast MRI and greatly increased CSF protein content. This study has contributed a third hallmark: the presence of superficial siderosis is useful in diagnosing leptomeningeal amyloidosis.

Therapeutic effect of neuronal nitric oxide synthase inhibitor (7-nitroindazole) against MPTP neurotoxicity in mice

Effects of neuronal nitric oxide synthase (nNOS) inhibitor (7-nitroindazole), nonselective NOS inhibitor (NG-nitro-L-arginine methyl ester; L-NAME), and monoamine oxidase inhibitor (pargyline) were studied on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. The mice received four intraperitoneal injections of MPTP at 1-h intervals. A significant depletion in dopamine and DOPAC concentration was observed in the striatum from 1 day after MPTP treatment. The pretreatment of 7-nitroindazole and pargyline, but not L-NAME, dose-dependently protected against MPTP-induced depletion in dopamine content 3 days after MPTP treatment. Our histochemical study also showed that 7-nitroindazole and pargyline can prevent a marked decrease in the nigral cells and a marked increase in astrocytes in striatum 7 days after MPTP treatment. The protective effect of 7-nitroindazole against MPTP-induced dopamine and DOPAC depletion in the striatum was not attenuated by intraperitoneal pretreatment with L-arginine. Furthermore, the posttreatment of 7-nitroindazole or pargyline protected against MPTP-induced depletion of dopamine content. These results demonstrate that the protective mechanism by which 7-nitroindazole counteracts MPTP neurotoxicity in mice may be due not only to inhibition of nNOS, but also to MAO-B inhibition. Furthermore, our study suggests that the posttreatment of 7-nitroindazole and pargyline can prevent a significant decrease in dopamine levels in the striatum of MPTP-treated mice. These findings have important implications for the therapeutic time window and choice of nNOS or MAO inhibitors in patients with Parkinsons disease.