Yuji Iwasaki

Characteristic clinical features in a case of fulminant subacute sclerosing panencephalitis

A 12-year-old girl with fulminant subacute sclerosing panencephalitis (SSPE) without myoclonic jerk and periodic EEG complexes is reported. She presented with blurred vision, fell into a coma after 2 weeks and died within 4 months. Magnetic resonance image (MRI) disclosed high intensity lesions in the lateral geniculate bodies, when the patient initially complained of blurred vision. Reviewing the cases of fulminant SSPE in the literature, more than half of the patients showed blurred vision or visual agnosia as an initial symptom. Most of those patients were female and rapidly deteriorated to a comatose state within 2 weeks. Based on the MRI study of the present patient, we speculate that the initial visual impairment in such patients can be attributed to the involvement of the lateral geniculate body.

Pentobarbital therapy for status epilepticus in children: Timing of tapering

Three children with refractory status epilepticus, unresponsive to intravenous administration of diazepam, phenytoin, and lidocaine, received pentobarbital therapy and were monitored by electroencephalography (EEG). They required mechanical ventilation and vasopressor therapy. Intravenous pentobarbital therapy was successful and without distinct sequelae in all 3 patients, and could be incrementally discontinued without breakthrough seizures after 12-65 hours of a burst-suppression or complete suppression pattern on EEG. Obtaining a suppression pattern was important for controlling status epilepticus in children as well as adults. We suggest that 12 hours after a burst-suppression pattern is obtained, tapering of pentobarbital should be attempted to avoid serious complications of extended pentobarbital anesthesia (e.g., respiratory depression, hypotension, pneumonia).

Clinical and immunohistochemical studies of subependymal giant cell astrocytomas associated with tuberous sclerosis

Two cases of TS associated with brain tumors had severe psychomotor retardation and early onset of long-term intractable convulsions, compared with cases without tumors. In one case, the tumor was partially cystic and progressed rapidly. Immunohistochemical studies of neuron specific enolase, glial fibrillary acidic protein and myelin basic protein revealed differences in positivity between cell types and between cases. These results suggested that the origin of the tumor cells could be variably differentiated cells.

Duane retraction syndrome associated with Chiari I malformation

A 13-year-old girl who had Duane retraction syndrome associated with Chiari I malformation is reported. Neuro-ophthalmologic examination revealed severe limitation of abduction of the left eye, as well as narrowing of the palpebral fissure and retraction of the globe on adduction. Electro-oculography of the affected eye revealed decreased saccadic velocity on attempted abduction and adduction. Midsagittal magnetic resonance imaging demonstrated cerebellar tonsillar herniation to 6 mm below a line from the basion to opisthion. Taking into consideration the relative rarity of the two disorders, the association may not be coincidental. Magnetic resonance imaging of the posterior fossa is recommended in Duane retraction syndrome.

Auditory Evoked Responses in Krabbe Disease

Serial auditory evoked responses were investigated in 3 children with Krabbe disease. Auditory brainstem responses revealed prolongation of each wave component and interpeak latency with decreased amplitudes in later components which finally disappeared except for wave I. Long-latency auditory responses (LLRs) persisted in the advanced stage when all wave components of middle-latency auditory responses (MLRs) had disappeared. The results of auditory brainstem responses and MLRs are compatible with magnetic resonance imaging findings and a review of pathologic findings in Krabbe disease, including extensive involvement of brainstem and subcortical structures. It is suggested that the source of LLR waves is different from that of MLR because of the persistent existence of LLR waves. It is speculated that the cerebral cortex and/or subcortical U fibers, which are spared in Krabbe disease, have an important role in generating LLR wave components.

Nationwide survey of Arima syndrome: Revised diagnostic criteria from epidemiological analysis

AIM We have never known any epidemiological study of Arima syndrome since it was first described in 1971. To investigate the number of Arima syndrome patients and clarify the clinical differences between Arima syndrome and Joubert syndrome, we performed the first nationwide survey of Arima syndrome, and herein report its results. Furthermore, we revised the diagnostic criteria for Arima syndrome. METHODS As a primary survey, we sent out self-administered questionnaires to most of the Japanese hospitals with a pediatric clinic, and facilities for persons with severe motor and intellectual disabilities, inquiring as to the number of patients having symptoms of Arima syndrome, including severe psychomotor delay, agenesis or hypoplasia of cerebellar vermis, renal dysfunction, visual dysfunction and with or without ptosis-like appearance. Next, as the second survey, we sent out detailed clinical questionnaires to the institutes having patients with two or more typical symptoms. RESULTS The response rate of the primary survey was 72.7% of hospitals with pediatric clinic, 63.5% of national hospitals and 66.7% of municipal and private facilities. The number of patients with 5 typical symptoms was 13 and that with 2-4 symptoms was 32. The response rate of the secondary survey was 52% (23 patients). After reviewing clinical features of 23 patients, we identified 7 Arima syndrome patients and 16 Joubert syndrome patients. Progressive renal dysfunction was noticed in all Arima syndrome patients, but in 33% of those with Joubert syndrome. CONCLUSION It is sometimes difficult to distinguish Arima syndrome from Joubert syndrome. Some clinicians described a patient with Joubert syndrome and its complications of visual dysfunction and renal dysfunction, whose current diagnosis was Arima syndrome. Thus, the diagnosis of the two syndromes may be confused. Here, we revised the diagnostic criteria for Arima syndrome.

The Usefulness of Low-Dose Oral Contraceptive in the Treatment of Women of Reproductive Age with Severe Motor and Intellectual Disabilities: Five Case Reports

Menstrual cycle has an influence on mind and body of any woman. A collection of symptoms that emerges one or two weeks before menstruation begins is called premenstrual syndrome (PMS), and that involves variety of complex emotional and physical changes. However, aggravation of epileptic attacks during premenstrual period alone has been focused in women with severe motor and intellectual disabilities (SMID). Exacerbation of various symptoms, other than epilepsy, was recognized as PMS in five cases, and these include muscular hypertonia, fever, tachycardia, flushing on face, nausea and vomiting. In these cases, the PMS symptoms were successfully managed with the low-dose oral contraceptive preparations. PMS among patients with SMID are often found to be difficult to diagnose. The use of the low-dose oral contraceptive was effective in women with SMID and improve the quality of their lives (QOL).

Elimination of amyloid precursor protein in senile plaques in the brain of a patient with Alzheimer-type dementia and Down syndrome

The average lifespan of individuals with Down syndrome has approximately doubled over the past three decades to 55-60 years. To reveal the pathogenic process of Alzheimer-type dementia in individuals with Down syndrome, we immunohistochemically examined senile plaque formation in the cerebral cortex in the autopsy brain and compared findings with our previous studies. We described a 52-year-old female with Down syndrome who developed progressively more frequent myoclonus following cognitive decline and died at the age of 59 years. Her karyotype [46XX, inv(9)(p12q13), i(21)(q10)] included triplication of the gene for amyloid precursor protein and the Down syndrome critical region. On microscopy, very few gamma-aminobutyric acid-ergic (GABAergic) neurons, in the form of small granular cells, in the cortex and Purkinje cells in the cerebellum were visible. In our previous study, amyloid precursor protein immunoreactivity was first noted in senile plaques at the age of 32 years. In this patient, even though amyloid β immunoreactivity was detected in the cores of senile plaques and diffuse plaques, amyloid precursor protein immunoreactivity was not noted in senile plaques in the frontal cortex. Amyloid precursor protein and its derivative amyloid-β play an important role in the formation of senile plaques and the time course of immunoreactive expression may be related to the pathogenic process of Alzheimer-type dementia.

Arima syndrome caused by CEP290 specific variant and accompanied with pathological cilium; clinical comparison with Joubert syndrome and its related diseases

OBJECTIVE Arima syndrome (AS) is a rare disease and its clinical features mimic those of Joubert syndrome or Joubert syndrome-related diseases (JSRD). Recently, we clarified the AS diagnostic criteria and its severe phenotype. However, genetic evidence of AS remains unknown. We explored causative genes of AS and compared the clinical and genetic features of AS with the other JSRD. PATIENTS AND METHODS We performed genetic analyses of 4 AS patients of 3 families with combination of whole-exome sequencing and Sanger sequencing. Furthermore, we studied cell biology with the cultured fibroblasts of 3 AS patients. RESULTS All patients had a specific homozygous variant (c.6012-12T>A, p.Arg2004Serfs*7) or compound heterozygous variants (c.1711+1G>A; c.6012-12T>A, p.Gly570Aspfs*19;Arg2004Serfs*7) in centrosomal protein 290 kDa (CEP290) gene. These unique variants lead to abnormal splicing and premature termination. Morphological analysis of cultured fibroblasts from AS patients revealed a marked decrease of the CEP290-positive cell number with significantly longer cilium and naked and protruded ciliary axoneme without ciliary membrane into the cytoplasm. CONCLUSION AS resulted in cilia dysfunction from centrosome disruption. The unique variant of CEP290 could be strongly linked to AS pathology. Here, we provided AS specific genetic evidence, which steers the structure and functions of centrosome that is responsible for normal ciliogenesis. This is the first report that has demonstrated the molecular basis of Arima syndrome.

Reply to the Letter: “Nationwide survey of Arima syndrome: Revised diagnostic criteria from epidemiological analysis”

We appreciate interest and opinion regarding our study [1]. Your opinions may be summarized in two points: (1) Arima syndrome (AS) has a molar tooth sign (MTS), and (2) AS should be included in Joubert syndrome-related diseases (JSRD) [2]. Although several children with AS reportedly showed MTS [3], some were atypical MTS [4]. MTS is the major imaging sign of small midbrain accompanied with the large interpeduncular fossa, elongated superior cerebellar peduncles and absence of their decussation [5]. MTS is closely related to midline defect of cerebellum, but is only one of the findings. In the study, we used the terms “cerebellar vermis agenesis or hypoplasia” and “brainstem malformation” in exchange for “MTS”, which is not adequate for expression of these posterior fossa malformations as observed in autopsy. The important clinical symptom of AS is severe progressive renal dysfunction due to nephronophthisis, resulting in renal failure and necessitating dialysis or transplantation in early childhood [1,3,6]. On the other hand, JSRD obviously shows milder or no renal symptoms, compared to AS. It is therefore important to correctly diagnose AS or JSRD for a renal substitution decision. Thus, AS can indeed be clearly clinically distinguished from JS or most JSRD. In addition, we are basing our argument on genetic analysis of definite AS cases. However, the present study involved epidemiological consideration and we must emphasize the differentiation of AS and JSRD.