Yukio Sawaishi

Review of Alexander disease: Beyond the classical concept of leukodystrophy

Alexander disease is classified as one of the leukodystrophies, which are degenerative diseases primarily affecting the cerebral white matter. Formal diagnosis is achieved by showing diffuse accumulation of Rosenthal fibers in the brain by biopsy or autopsy. Showing a heterozygous mutation in the glial fibrillary acidic protein (GFAP) gene is currently sufficient for diagnosis. The mechanisms of Rosenthal fiber formation remain unclear. However, both the quality and quantity of GFAP are important. GFAP-epsilon (rodent homologous GFAP-delta), one of the alternatively spliced GFAP isoforms, may also play a modulating role in aggregate formation. The current ease of diagnosis has accelerated the accumulation of a wide variety of patients with Alexander disease along with the widespread use of MRI. In contrast to the classical infantile type, patients with juvenile and adult types mainly complain of bulbar symptoms and usually show progressive atrophy of the lower brainstem and cervical spinal cord with mild or minimal leukodystrophic changes. Among the many MRI findings of Alexander disease, periventricular linear lesions with various names depending on the thickness and shape seem to represent the unique pathophysiology, because the subventricular zone of the adult human brain includes special astrocytes that behave as multipotent progenitor cells and specifically produce GFAP-epsilon. Except for a few mutations, no clear phenotype-genotype correlation has been established for Alexander disease, although male preponderance in the infantile type suggests that phenotypes may be partly affected by gender.

Cerebrospinal fluid levels of cytokines and soluble tumour necrosis factor receptor in acute disseminated encephalomyelitis

Abstract. We determined the concentrations of interleukin-1β (IL-1β), IL-6, IL-10, interferon-γ (IFN-γ), tumour necrosis factor-α (TNF-α), and soluble TNF receptor 1 (sTNFR1) in CSF from 18 patients with acute disseminated encephalomyelitis (ADEM) to investigate the role of cytokines in the pathogenesis of the disease in the acute stage. Cytokines and sTNFR1 were measured by ELISA. The CSF IL-6, IL-10, TNF-α, and sTNFR1 concentrations were elevated in 16, 13, 3, and 11 of the 18 patients with ADEM, respectively. CSF concentrations of IL-10 and sTNFR1 correlated positively with each other in the patients (P<0.01). Myelin basic protein levels in CSF of the patients with elevated CSF sTNFR1 levels were significantly higher than those in CSF of the patients with normal CSF sTNFR1 levels (P<0.05). IL-1β and IFN-γ were not elevated in CSF. Our results suggest that IL-6 and TNF-α mediate inflammation in the central nervous systems in ADEM. We speculated that TNF-α is related to demyelination and that IL-10 is induced to modulate TNF-α-induced inflammation in ADEM. Conclusion: these findings suggest that cytokines such as tumour necrosis factor-α, soluble tumour necrosis factor receptor 1, interleukin-6, and interleukin-10 are related to the pathogenesis of acute disseminated encephalomyelitis in the acute stage.

Acute cerebellitis caused by Coxiella burnetii

We report a childhood case of severe acute cerebellitis caused by Coxiella burnetii. After 10 days of fever and headache, the patient fell into a drowsy state. Examination of the cerebrospinal fluid (CSF) revealed pleocytosis, an increased level of protein, and negative results in bacterial and viral studies. Magnetic resonance imaging demonstrated a herniated tonsil compressed by the swollen vermis. Administration of minocycline relieved the patients clinical symptoms. C. burnetii was isolated from the CSF obtained during convalescence. Ann Neurol 1999;45:124–127

Periaxin mutation causes early-onset but slow-progressive Charcot-Marie-Tooth disease

AbstractPeriaxin (PRX) plays a significant role in the myelination of the peripheral nerve. To date, seven nonsense or frameshift PRX mutations have been reported in six pedigrees with Dejerine-Sottas neuropathy or severe Charcot-Marie-Tooth neuropathy (CMT). We detected a PRX mutation in three patients in the screening of 66 Japanese demyelinating CMT patients who were negative for the gene mutation causing dominant or X-linked demyelinating CMT. Three unrelated patients were homozygous for a novel R1070X mutation and presented early-onset but slowly progressive distal motor and sensory neuropathies. Mutations lacking the carboxyl-terminal acidic domain may show loss-of-function effects and cause severe demyelinating CMT.

Progressive facial hemiatrophy after epileptic seizures.

Intractable complex partial seizures developed in a 3-year-old female with normal intracranial findings on computed tomography. Frontal paramedian band-like depression of the skin gradually developed thereafter, and progressive facial hemiatrophy (Parry-Romberg syndrome) was diagnosed. Computed tomography scanning at 5 years of age revealed multiple parenchymal calcifications and low-density areas in the white matter of the frontoparietal lobes. Epileptic seizures, one of the major neurologic complications of progressive facial hemiatrophy, could precede the succeeding neurocutaneous changes.

Abnormal white matter lesions with sensorineural hearing loss caused by congenital cytomegalovirus infection: retrospective diagnosis by PCR using Guthrie cards

We report on two patients with congenital cytomegalovirus (CMV) infection asymptomatic at birth that was diagnosed retrospectively by polymerase chain reaction (PCR) of CMV DNA using blood stored on Guthrie cards. Neuroimaging studies showed abnormal myelination without any gray matter abnormalities. In the differential diagnosis of patients with abnormal white matter lesions and sensorineural hearing loss, one should consider congenital CMV infection. When investigating the etiology of patients with behavioral problems, migrational disorder, or white matter disease, PCR analysis of CMV DNA using blood stored on Guthrie cards might be helpful.

Childhood multiple sclerosis treated with plasmapheresis

We report a case of multiple sclerosis in a 7-year-old boy. He experienced three episodes in 8 months and was repeatedly treated with a high dose of methylprednisolone. During the third episode, to avoid the side effects associated with frequent high doses of steroid, we substituted plasmapheresis for methylprednisolone, initially performing it for 3 days and continuing it every 2 to 3 weeks according to the fluctuating values of antinuclear antibody. The patient improved markedly after initiation of plasmapheresis and has been relapse-free for more than 18 months. The effectiveness of plasmapheresis for treatment of multiple sclerosis in adults is variable and has seldom been reported in children. Our case suggests that plasmapheresis as an alternative therapy is useful for steroid-dependent or severe types of multiple sclerosis even in childhood, especially when its chronic course is assessed by antinuclear antibody titers.

SSPE following neonatal measles infection.

The authors report a case of subacute sclerosing panencephalitis in a child who had measles during the neonatal period. At 3 years, 6 months of age, over a period of a few weeks, the patient lost the ability to sit unaided as a result of progressive truncal ataxia, without apparent cognitive changes, simulating acute cerebellar ataxia. His symptoms improved in 1 month, and he was able to walk again with support, but mental alteration and periodic mild head nodding on awakening followed. His illness was diagnosed as subacute sclerosing panencephalitis on the basis of the elevated titers of measles antibodies in the cerebrospinal fluid. Measles infection before 1 year of age is a risk factor of subacute sclerosing panencephalitis, but reports about patients with neonatal measles infection are rare. Immaturity of the brain at the time of measles infection may not only be a risk factor but may also influence the clinical course of the disease.

Juvenile Alexander disease with a novel mutation in glial fibrillary acidic protein gene

Early-onset (infantile) Alexander disease is associated with mutations in the glial fibrillary acidic protein (GFAP) gene and two hot spots correlate to the severe phenotype. No molecular mechanisms have been elucidated in late-onset (juvenile) Alexander disease. The authors report a novel GFAP mutation in a patient with juvenile Alexander disease. The authors discuss similar molecular mechanisms in another intermediate filament disease and propose a possible molecular pathogenesis in juvenile Alexander disease.

Trial of intraventricular ribavirin therapy for subacute sclerosing panencephalitis in Japan

Ten patients with SSPE were surveyed during the last 4 years from the viewpoint of clinical safety for use of ribavirin therapy. Although effectiveness varied among cases, they were all treated safely with intraventricular ribavirin. This study suggests that treatment is safe and well-tolerated.