Total callosotomy ameliorates epileptic activity and improves cognitive function in a patient with Miller-Dieker syndrome.

Miller-Dieker syndrome (MDS) is characterized by facial abnormalities and lissencephaly and is caused by a microdeletion in the region containing the LIS1 gene at chromosome 17p13.3. We report a case in which postnatal neuroimaging revealed severe lissencephaly. A 9-month-old boy presented with infantile spasms syndrome. Because of the refractory course of seizures and continued poor vitality, total corpus callosotomy was performed at 28 months of age. Intraoperative electroencephalogram (EEG) showed that the bilateral synchronous epileptiform discharges disappeared immediately after the disconnection. Postoperatively, the epileptic spasms (ES) in clusters disappeared, and single ES followed by focal seizures became the main symptom. The patient smiled more and became more responsive to stimuli. Postoperative scalp interictal EEG showed desynchronized multifocal spike and wave discharges with a marked decrease in the bilateral synchronous spike and wave discharges. Our findings suggest that the corpus callosum is involved in the mechanism ES in clusters in MDS-associated lissencephaly, and total callosotomy could be a therapeutic option.

A case of focal cortical dysplasia type IIa with pathologically suspected bilateral Rasmussen syndrome.

BACKGROUND: Rasmussen syndrome (RS) is a rare neurological disorder characterized by unilateral chronic inflammation, drug-resistant epilepsy, and progressive neurological and cognitive deterioration. There has been no detailed pathological evaluation or finding, including focal cortical dysplasia, for bilateral RS. CASE REPORT: A 13-year-old boy presented with status epilepticus with focal to bilateral tonic clonic seizure starting from the left upper limb. At the age of 15, epilepsia partialis continua of the right face and upper extremities appeared, and MRI showed hemispheric abnormal signal intensities with left frontal lobe predominance. Three months later, MRI showed extensive abnormal signal intensities in the right occipitoparietal and left temporal lobes. Tacrolimus was useful in preventing recurrence. Because the seizures were intractable, a corpus callosotomy was performed at 16 years along with a concurrent brain biopsy from the bilateral lateral frontal cortices. We detected dysmorphic neurons in addition to inflammatory changes suspicious for RS, leading to a diagnosis of focal cortical dysplasia (FCD) type Ⅱa and suspected bilateral RS. Total callosotomy and vagus nerve stimulation were not sufficiently effective. CONCLUSIONS: In bilateral RS, FCD may be present in both cerebral hemispheres. In the current case, an autoimmune response to dysmorphic neurons may have contributed to the pathogenesis of intense inflammation.

Generation of D1-1 TALEN isogenic control cell line from Dravet syndrome patient iPSCs using TALEN-mediated editing of the SCN1A gene.

Dravet syndrome (DS) is an infantile epileptic encephalopathy mainly caused by de novo mutations in the SCN1A gene encoding the α1 subunit of the voltage-gated sodium channel Nav1.1. As an in vitro model of this disease, we previously generated an induced pluripotent stem cell (iPSC) line from a patient with DS carrying a c.4933C>T (p.R1645*) substitution in SCN1A. Here, we describe developing a genome-edited control cell line from this DS iPSC line by substituting the point mutation with the wild-type residue. This artificial control iPSC line will be a powerful tool for research into the pathology of DS.

A child with acute transverse myelitis requiring permanent pacemaker implantation.

We diagnosed a 3-year-old girl with acute transverse myelitis (ATM). She presented with weakness of the limbs and developed urination difficulty and respiratory disturbance. Magnetic resonance imaging revealed a symmetric area of high signal intensity on T2-weighted images involving the lower end of the medulla oblongata to the level of the fourth thoracic vertebra. Anti-aquaporin-4 antibody was negative. She was treated with intravenous methylprednisolone pulse therapy, immunoglobulin therapy, and plasmapheresis; however, her clinical symptoms did not change. At 10 and 20days after symptom onset, cardiac arrest occurred on postural change, requiring cardiopulmonary resuscitation. A permanent pacemaker was implanted 23days after onset. In the presence of sympathetic nerve hypofunction, relative hyperactivity of the parasympathetic nerves may have led to severe bradycardia and cardiac arrest in the presence of an inducer, such as a postural change. This is the first reported case of pacemaker implantation for management of ATM.

A pediatric patient of hemorrhagic acute transverse myelitis.

An 11-year-old boy presented with progressive leg hypesthesia but no history of trauma. Dysuria and constipation appeared subsequent to gait difficulty. He was admitted 8days after onset. Spinal magnetic resonance imaging (MRI) revealed longitudinal hyperintensity with cord swelling and hypointensity on T2-weighted images, suggesting severe inflammation and microbleeding change, respectively. Gadolinium contrast-enhanced MRI demonstrated mild enhancement in the lesions. Platelet count and coagulation findings were normal, and cerebrospinal fluid analysis showed no pleocytosis. He was diagnosed with idiopathic acute transverse myelitis (ATM), and intravenous methylprednisolone pulse therapy and plasmapheresis were initiated. On day 14, motor dysfunction aggravated suddenly, accompanied by expanding hemorrhagic lesions. Thereafter, administration of intravenous immunoglobulin, repeated intravenous methylprednisolone pulse therapy and prednisolone for one month resulted in complete recovery four months later. Both anti-aquaporin-4 and anti-myelin oligodendrocyte glycoprotein antibodies were negative. We presented the first pediatric case showing hemorrhagic spinal lesions in the clinical course of ATM. This severe complication should be recognized in the management of ATM.

Quinidine therapy for West syndrome with KCNTI mutation: A case report.

The KCNT1 gene encodes the sodium-dependent potassium channel, with quinidine being a partial antagonist of the KCNT1 channel. Gain-of-function KCNT1 mutations cause early onset epileptic encephalopathies including migrating partial seizures of infancy (MPSI). At 5months of age, our patient presented with epileptic spasms and hypsarrhythmia by electroencephalogram. Psychomotor retardation was observed from early infancy. The patient was diagnosed with West syndrome. Consequently, various anti-epileptic drugs, adrenocorticotropic hormone therapy (twice), and ketogenic diet therapy were tried. However, the epileptic spasms were intractable. Whole exome sequencing identified a KCNT1 mutation (c.1955G>T; p.G652V). At 2years and 6months, the patient had daily epileptic spasms despite valproate and lamotrigine treatment, and was therefore admitted for quinidine therapy. With quinidine therapy, decreased epileptic spasms and decreased epileptiform paroxysmal activity were observed by interictal EEG. Regarding development, babbling, responsiveness, oral feeding and muscle tone were ameliorated. Only transient diarrhea was observed as an adverse effect. Thus, quinidine therapy should be attempted in patients with West syndrome caused by KCNT1 mutations, as reported for MPSI.

A case of succinic semialdehyde dehydrogenase deficiency with status epilepticus and rapid regression.

BACKGROUND: Clinical phenotypic expression of SSADH deficiency is highly heterogeneous, and some infants may develop refractory secondary generalized seizures. PATIENT: A 9-month-old boy manifested partial seizures, developing severe status epilepticus, and conventional antiepileptic drugs were ineffective. Use of ketamine contributed to the control of status epilepticus, achieving a reduction in frequency of partial seizures, and improving EEG findings without apparent complications. Diffusion-weighted images showed hyperintensities in the bilateral basal ganglia and fornix, and multiple T2 hyperintensity lesions were detected. (123)I-iomazenil (IMZ) SPECT revealed a decrease in binding of (123)I-iomazenil predominantly in the left temporal region by the 18th day of hospitalization. However, repeated IMZ-SPECT on the 46th day of hospitalization demonstrated almost no accumulation across a broad region, sparing the left temporal region. The patient showed rapid regression, refractory myoclonus, and severe progressive brain atrophy. CONCLUSION: IMZ-SPECT findings demonstrated reduced benzodiazepine receptor binding and its dynamic changes in an SSADH-deficient patient. Considering the down regulation of the GABAA receptor, ketamine should be included in pharmacotherapeutic strategies for treatment of refractory status epilepticus in SSADH-deficient patients.

Cutaneous necrotizing vasculitis as a manifestation of familial Mediterranean fever.

Familial Mediterranean Fever (FMF) is a hereditary autoinflammatory disease, which is characterized by recurrent and paroxysmal fever, peritonitis, arthritis, myalgia, and skin rashes. Although various skin lesions such as "erysipelas-like erythema", urticaria, nonspecific purpura, and subcutaneous nodules have been described, cutaneous vasculitis is rare. We report a Japanese case of sporadic FMF accompanied by cutaneous arteritis at the time of febrile attacks of FMF. Gene analysis revealed M694I mutation in a single allele of the MEFV gene, and oral colchicine successfully controlled both periodic fever and subcutaneous nodules of arteritis. Cutaneous necrotizing vasculitis repeatedly emerging with febrile attacks should be included among the skin manifestations of FMF.

Biologics are more potent than other treatment modalities for improvement of quality of life in psoriasis patients.

Although mental health is hampered in various skin disorders, few studies regarding anxiety in psoriasis patients are available, and specifically, no evaluation exists between mental health and psoriasis severity or the patients' quality of life. To examine the relation between mental health, psoriasis severity and patient's quality of life, 119 psoriasis vulgaris patients were assessed for anxiety using the General Health Questionnaire (GHQ)-30. Psoriasis area and severity index (PASI) and Dermatological Life Quality Index (DLQI) scores were also measured. The average total GHQ-30 score was significantly decreased from 4.41 to 2.11 (52.2% decrease) in biologics-treated patients. That of patients treated with other systemic agents decreased from 4.36 to 3.32 (23.9% decrease) and that of those treated with topical agents from 4.21 to 3.48 (17.3% decrease). In the biologics-treated group five of the six categories of GHQ-30, i.e., general illness, somatic symptoms, sleep disturbance, social dysfunction, and anxiety and dysphoria, were significantly decreased after the treatment. In contrast, in the other systemic treatment and topical treatment groups, three of the six categories, general illness, somatic symptoms, and sleep disturbance were significantly decreased. There was a significant correlation between GHQ-30 and DLQI, but not with PASI. The psoriasis patients show impaired mental health and among various treatment modalities biologics are superior to other systemic or topical treatments for improving the defective mental state.

Defective barrier function accompanied by structural changes of psoriatic stratum corneum.

Although barrier function of psoriatic skin is shown to be decreased by measuring transepidermal water loss (TEWL), few reports exist examining other physical skin properties and components including stratum corneum hydration, natural moisturizing factor (NMF), free fatty acids (FFA), ß-sheet and α-helix ratio of structural protein(s), and sebum content. We compared the skin properties and components of normal, involved and uninvolved skin of psoriasis. Using a corneometer and attenuated total reflection-infrared spectrometer, we measured TEWL, stratum corneum hydration, NMF, FFA, ß/α ratio and sebum in psoriasis vulgaris patients and healthy controls. TEWL and ß/α ratio of involved psoriatic skin were significantly increased compared with uninvolved skin and normal control skin. In contrast, stratum corneum hydration, NMF and FFA, but not sebum, are significantly decreased in the involved skin compared with uninvolved skin and normal skin. TEWL and stratum corneum hydration returned to the normal levels following clinical improvement of the lesion. Barrier function and hydration of psoriatic skin are defective and secondary structure in stratum corneum protein is altered in the involved psoriatic skin.

Japanese patients with psoriasis and atopic dermatitis show distinct personality profiles.

Personality and emotional factors are supposed to influence the course of skin diseases, such as psoriasis and atopic dermatitis. Few reports exist, however, showing distinct personality traits among patients with psoriasis, atopic dermatitis patients and healthy controls. The aim of the present study was to examine personality differences among psoriasis patients, atopic dermatitis patients and healthy controls in Japan. A total number of 51 psoriasis patients, 97 atopic dermatitis patients and 48 healthy individuals were enrolled in the study. Questionnaires of Yatabe-Guilford Personality Inventory were administered individually. These groups were evaluated by 12 dimensions of temperaments. According to the dimension scores, personality was defined as five groups. Atopic dermatitis patients showed significantly higher scores regarding temperaments of depression, feelings of inferiority, nervousness and lack of objectivity than psoriasis patients. Regarding a temperament of cyclic tendency and lack of cooperativeness, female atopic dermatitis patients showed significantly higher scores than female psoriasis patients. Regarding general activity, female atopic dermatitis patients showed significantly lower scores than those of female psoriasis patients. No significant difference in scores of temperaments of lack of agreeableness, rhathymia, thinking extraversion, ascendance and social extraversion were detected among psoriasis patients, atopic dermatitis patients and healthy controls. The personalities of male psoriasis patients were significantly different from those of atopic dermatitis patients and healthy controls. Female psoriasis patients showed a significantly different personality profile from that of atopic dermatitis patients, but not from healthy controls. Japanese psoriasis and atopic dermatitis patients show distinct personality profiles suggesting that specific a psychosomatic approach may be required during the treatment.

Comparison of clinical effects of psoriasis treatment regimens among calcipotriol alone, narrowband ultraviolet B phototherapy alone, combination of calcipotriol and narrowband ultraviolet B phototherapy once a week, and combination of calcipotriol and narrowband ultraviolet B phototherapy more than twice a week.

We compared the clinical efficacy of various psoriasis treatments among: (i) topical application of calcipotriol ointment twice daily (group I); (ii) topical application of calcipotriol ointment twice daily and narrowband ultraviolet B NB-UVB phototherapy once a week (group II); (iii) topical application of heparinoid ointment twice daily and NB-UVB phototherapy more than twice a week (group III); and (iv) topical application of calcipotriol ointment twice daily and NB-UVB phototherapy more than twice a week (group IV). Ten patients were randomly selected for each group and treated by the indicated regimens for 12 weeks. All treatments were effective and significantly improved Psoriasis Area and Severity Index (PASI) scores, self-administered PASI scores and visual analog scale scores of pruritus. Group IV showed most marked and rapid reduction in PASI and self-PASI scores among the four regimens. Although the serum levels of interleukin (IL)-17, IL-20 and IL-22 and psoriasis disability index were significantly decreased after the treatments, no significant difference was detected among the four groups. Our study indicates that combination of calcipotriol ointment plus NB-UVB more than twice a week is superior to other treatment regimens, rapidly improving psoriasis lesions.

Increased plasma resistin and decreased omentin levels in Japanese patients with psoriasis.

Psoriasis is associated with obesity accompanied by insulin resistance. A recent study disclosed increased plasma resistin and decreased plasma omentin levels in obesity. Few studies of plasma levels of resistin and omentin are available in psoriasis. We analyzed plasma levels of resistin and omentin in psoriasis and compared them with those of healthy controls. Evaluation of plasma levels of resistin and omentin was performed by enzyme-linked immunosorbent assay (ELISA) for 62 psoriasis patients and 58 healthy controls. The severity of psoriasis was evaluated by psoriasis area and severity index (PASI) score. Plasma levels of resistin were significantly increased in psoriasis as compared with those of healthy controls. In contrast, plasma levels of omentin were significantly decreased in psoriasis patients. Plasma levels of resistin and omentin were positively and negatively correlated with PASI scores, respectively. After the treatment of psoriasis, resistin levels were decreased and omentin levels were increased, respectively, compared with those of pretreated. Plasma levels of resistin and omentin might be useful for evaluating the disease activity of psoriasis.

Plasma trough levels of adalimumab and infliximab in terms of clinical efficacy during the treatment of psoriasis.

We examined the relation between adalimumab and infliximab plasma trough levels, anti-adalimumab and anti-infliximab antibody formation. We analyzed plasma from 32 adalimumab-treated and 20 infliximab-treated psoriasis patients for evaluating trough levels of each drug. The presence of anti-adalimumab and anti-infliximab antibodies was analyzed and the severity of psoriasis was evaluated. At week 28, 25 out of 32 and at week 48, 21 out of 30 adalimumab-treated patients maintained as more than PASI 75. At week 28, 12 out of 20 and at week 48, nine out of 18 infliximab-treated patients were evaluated as more than PASI 75. In patients treated with 40 mg adalimumab every other week, the mean trough level was 7.62 µg/mL (range, 0.05-10.6) at week 48. In patients treated with 80 mg adalimumab every other week, the mean trough level was 8.61 µg/mL (range, 0.08-13.5) at week 48. Mean trough level of infliximab-treated cases (4.1-5.2 mg/kg; mean, 4.6) was 4.64 µg/mL (range, 0.03-16.9) at week 48. Anti-adalimumab antibody was detected in five out of 32 cases and anti-infliximab antibody was detected in six out of 20 cases, respectively, at weeks 24 and 48. The optimal cut-off values of adalimumab and infliximab concentration for more than PASI 75 were more than 7.84 µg/mL and more than 0.92 µg/mL, respectively. The trough levels of adalimumab and infliximab in psoriasis patients were positively associated with clinical response and were significantly lower in cases having anti-adalimumab or anti-infliximab antibodies.