[Refractory multiple myeloma with impaired consciousness accompanied by hyperammonemia and leukoencephalopathy-like findings].

A 81-year-old female was diagnosed with symptomatic multiple myeloma (MM; IgG κ type, D&S: IIB, ISS: 2) in August 2017. Although treatment with lenalidomide and dexamethasone was started, she developed deep venous thrombosis in the lower extremities as a complication; therefore, the treatment was changed to DBd. In February 2018, she required hospitalization due to general weakness and altered consciousness. Her IgG level and κ/λ ratio were elevated at 4,156 mg/dl and 605.56, respectively, revealing that MM was treatment-resistant. A protein-cell dissociation (cell blood count, 0/µl; protein, 100.6 mg/dl) was detected in the cerebrospinal fluid, whereas the ammonia level in serum was high (172 µg/dl). T2-weighted magnetic resonance imaging showed a broad range of high-density area in deep cerebral white matter suggesting leukoencephalopathy, whereas the cerebrospinal fluid was negative for JC virus. No pathological conditions causing secondary hyperammonemia were found. Although the involvement of drug-induced leukoencephalopathy in altered consciousness could not be ruled out since the chromosome with the normal karyotype at the first visit had a complex chromosomal abnormality, an originally minor clone of MM cells with a chromosomal abnormality might have contributed to the ammonia production resulting in altered consciousness.

[Successful Prophylactic Minocycline Treatment for Recurrent Helicobacter Cinaedi Sepsis during Chemotherapy in a Patient with Follicular Lymphoma].

A 63-year-old man with follicular lymphoma was administered standard R-CHOP chemotherapy. Six days after the second course of chemotherapy, the patient developed fever and chills. Blood cultures yielded rod-shaped gram-negative bacteria, but no further identification was obtained. High fever and chills returned on the fifth and sixth days after the third and fourth courses of R-CHOP, respectively. These blood cultures were also positive. Since we detected spiral-shaped gram-negative rods, we performed a prolonged culture during the febrile period after the fourth course of R-CHOP. This revealed the formation of characteristic film-like colonies, and Helicobacter cinaedi(H. cinaedi)bacteria was identified. After final identification, the patient was administered prophylactic minocycline treatment. Subsequent blood cultures were negative, fever did not recur, and we were able to complete 6 courses of R-CHOP. Although H. cinaedi has been reported to be a cause of sepsis in immunocompromised patients, standard correlation has not been established. Our case suggests that H. cinaedi should be considered when recurrent fever is observed after chemotherapy. Prophylactic antibiotic treatment with minocycline may prevent sepsis, as observed in our case.

Clinicopathological features of adult-onset neuronal intranuclear inclusion disease.

Neuronal intranuclear inclusion disease (NIID) is a slowly progressive neurodegenerative disease characterized by eosinophilic hyaline intranuclear inclusions in the central and peripheral nervous system, and also in the visceral organs. NIID has been considered to be a heterogeneous disease because of the highly variable clinical manifestations, and ante-mortem diagnosis has been difficult. However, since we reported the usefulness of skin biopsy for the diagnosis of NIID, the number of NIID diagnoses has increased, in particular adult-onset NIID. In this study, we studied 57 cases of adult-onset NIID and described their clinical and pathological features. We analysed both NIID cases diagnosed by post-mortem dissection and by ante-mortem skin biopsy based on the presence of characteristic eosinophilic, hyaline and ubiquitin-positive intanuclear inclusion: 38 sporadic cases and 19 familial cases, from six families. In the sporadic NIID cases with onset age from 51 to 76, dementia was the most prominent initial symptom (94.7%) as designated 'dementia dominant group', followed by miosis, ataxia and unconsciousness. Muscle weakness and sensory disturbance were also observed. It was observed that, in familial NIID cases with onset age less than 40 years, muscle weakness was seen most frequently (100%), as designated 'limb weakness group', followed by sensory disturbance, miosis, bladder dysfunction, and dementia. In familial cases with more than 40 years of onset age, dementia was most prominent (100%). Elevated cerebrospinal fluid protein and abnormal nerve conduction were frequently observed in both sporadic and familial NIID cases. Head magnetic resonance imaging showed high intensity signal in corticomedullary junction in diffusion-weighted image in both sporadic and familial NIID cases, a strong clue to the diagnosis. All of the dementia dominant cases presented with this type of leukoencephalopathy on head magnetic resonance imaging. Both sporadic and familial NIID cases presented with a decline in Mini-Mental State Examination and Frontal Assessment Battery scores. Based on these clinicopathological features, we proposed a diagnosis flow chart of adult-onset NIID. Our study suggested that the prevalence rate of adult-onset NIID may be higher than previously thought, and that NIID may be underdiagnosed. We should take NIID into account for differential diagnosis of leukoencephalopathy and neuropathy.

[Bortezomib-associated acute congestive heart failure in a patient with multiple myeloma].

We report an 81-year-old woman with multiple myeloma who developed acute cardiac injury after receiving bortezomib. The patient received weekly intravenous bortezomib. She developed shortness of breath and bilateral pedal edema on day 19. Electrocardiography showed no ST-T changes but the cardio-thoracic ratio was increased, the ejection fraction was decreased, the ventricular septum showed hypokinesis and mitral regurgitation was noted. We stopped bortezomib and started acute congestive heart failure treatment. ST-T changes were detected after the patient's condition improved. There was no evidence of coronary stenosis on CT angiography. Acute cardiac injury is rare during bortezomib administration, but patients should be monitored carefully during treatment.

Neuronal intranuclear inclusion disease presenting with resting tremor.

Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease with various neurological symptoms. A 73-year-old woman presented with slowly progressive tremor in both hands. The resting tremor was enhanced by cognitive activity and walking. However, there were no other signs of parkinsonism. Levodopa and trihexyphenidyl were ineffective against the tremor. A diagnosis of NIID was made based on skin biopsy findings. The tremor in this case was very similar to that seen in Parkinson's disease (PD). Previous reports and the present case indicate that NIID patients can develop tremor that is similar in character to that seen in PD. NIID should be considered in the differential diagnosis of resting tremor similar to PD.

Posterior spinal artery syndrome showing marked swelling of the spinal cord: a clinico-pathological study.

OBJECTIVE: To describe a rare autopsy case of posterior spinal artery syndrome with marked swelling of the spinal cord, an unusually subacute onset and short clinical course. METHODS: Case report. FINDINGS: An 84-year-old Japanese woman presented with bilateral muscle weakness of the lower legs and sensory disturbance 1 week after head contusion. Neurological findings worsened gradually. She developed phrenic nerve paralysis and died of respiratory failure 6 weeks after the onset of neurological symptoms. On pathological examination, the spinal cord was markedly swollen in the cervical and upper thoracic segments. Microscopically, there was loss of myelin sheath in the bilateral posterior columns and neuronal loss of the posterior horns in all of the spinal segments. However, findings were unremarkable in the bilateral anterior columns and bilateral anterior horns in most of the spinal segments. Posterior spinal arteries had no stenosis, occlusion, or thrombosis. We considered that pathogenesis was infarction associated with head injury. CONCLUSION: To our knowledge, this is the first report of a case of posterior spinal artery syndrome with a markedly swollen spinal cord and poor prognosis.

Thrombotic thrombocytopenic purpura presenting with reversible posterior leukoencephalopathy syndrome.

A 48-year-old man presented with consciousness disturbance with vasogenic edema in the occipital lobe on brain CT. The diagnosis of reversible posterior leukoencephalopathy syndrome (RPLS) was made. His hypertension was refractory to treatment, and his neurological disabilities and CT abnormalities, along with renal dysfunction, became worse. Hemodialysis and strict management of blood pressure resolved the neurological findings and the lesions on brain CT. However, one week later, consciousness disturbance and brain CT abnormalities recurred. At that time, hemolytic anemia with fragmented erythrocytes, thrombocytopenia, and renal dysfunction became apparent. We therefore diagnosed thrombotic thrombocytopenic purpura (TTP). Plasma exchange and vincristine administration improved not only the clinical findings of TTP, but also consciousness disturbance and brain CT abnormalities. We concluded that latent TTP had caused RPLS in this patient.

[Trial of rituximab in three patients with neuromyelitis optica].

Patients with relapsing neuromyelitis optica (NMO) showing contiguous long spinal cord lesions extending over three vertebral segments on the MRI and with positive anti-aquaporin 4 antibodies in sera are usually treated with glucocorticoids or azathioprine. However, some NMO patients even after adequate treatments show relapses. Rituximab (anti-CD 20) therapy has recently been reported to inhibit relapses. We used rituximab to treat three NMO patients defined by the revised NMO criteria of Wingerchuk et al, with rituximab for 2 years and 3 months (mean) at an intervals of about nine months. The annualized relapse rate for the 3 patients during the year before rituximab therapy was 4, 5, and 6, respectively, and this decreased to 3, 1, and 0 in the year after therapy. Case 1 showed three relapses after therapy: however, the symptoms and signs of each of the relapses were milder and the patient showed good responses to steroid pulse therapy. One year after therapy, relapses had disappeared in all cases (observation periods; 18, 18, and 9 months, respectively). After rituximab therapy, these NMO patients showed a decreased mean annualized relapse rate (from 5.0 to 0.6) and EDSS score (from 8.7 to 8.0) after rituximab therapy. No adverse effects were seen. We recommend rituximab therapy for NMO patients resistant to other immunosuppressive therapies such as oral glucocorticoid administration introduced after a severe relapse. However, during long term rituximab treatment, attention needs to be given to infections such as progressive multifocal leucoencephalopathy.

High risk factors for valvular heart disease from dopamine agonists in patients with Parkinson's disease.

An association between ergot-derived dopamine agonists and asymptomatic valvular heart disease in Parkinson's disease has been established. For safe use of these agonists, it is important to specify those at high risk for valvular heart disease among patients with Parkinson's disease. We performed a nested case-control study of 223 patients with Parkinson's disease. In results of multivariable logistic analyses, use of pergolide, use of cabergoline, age, male sex, and hypertension were independent significant risk factors for left-sided valvular regurgitation. In patients receiving cabergoline or pergolide, elderly (>or=70 years) hypertensive patients had a markedly high risk for valvular regurgitation (odds ratio 94.5) as compared to non-elderly (<70 years) patients without hypertension. The risk of valvular regurgitation caused by pergolide or cabergoline was found to be highly enhanced by comorbid hypertension or aging, suggesting that special attention should be paid when prescribing cabergoline or pergolide for those patients.

[Mitoxantrone for the treatment of Japanese patients with multiple sclerosis].

We retrospectively evaluated the benefits of mitoxantrone (MITX) treatment in Japanese patients with multiple sclerosis (MS) with more than 3 relapses per year or a deterioration of more than one Expanded Disability Status Scale (EDSS) of Kurtzke score per year despite having IFN beta 1b therapy. Monthly intravenous injections of MITX, 10-12 mg/m2, for 3 months were followed by an additional treatment every 3 months. Nine patients (6 women, 3 men) with a mean age of 39 years, a mean disease duration of 3.9 years, and a mean EDSS score of 6.7 were studied. Seven patients had long spinal cord lesions (LCL-MS). Most patients tolerated the treatment, although 2 patients stopped MITX therapy after 3 injections because of severe appetite loss. The 7 patients who continued MITX therapy for more than 3 times significantly decreased their relapse rate and EDSS deterioration. The average relapse count in the year preceding initiation of MITX therapy was 4.3 (range: 3-6)/year, EDSS score increased by 2.7 (range: 1-7)/year. The average relapse count was 2.3 (range: 0-4)/year from 0 to 6 months after MITX therapy (p = 0.114), and 1.1 (range: 0-4)/year from 7 to 12 months (p = 0.285). The average EDSS deterioration was -0.4 (range -2-1) from 0 to 6 months after MITX therapy (p = 0.018), and there was no deterioration from 7 to 12 months. Most patients received granulocyte colony stimulating factor because of leukocytopenia caused by MITX. No patients showed any decrease in cardiac ejection fraction during this observation period. For Japanese MS patients, MITX therapy was very effective to suppress relapses without incurring severe adverse events.

Presenilin 1 is involved in the maturation of beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1).

One of the pathologic hallmarks of Alzheimer's disease is the excessive deposition of beta-amyloid peptides (Abeta) in senile plaques. Abeta is generated when beta-amyloid precursor protein (APP) is cleaved sequentially by beta-secretase, identified as beta-site APP-cleaving enzyme 1 (BACE1), and gamma-secretase, a putative enzymatic complex containing presenilin 1 (PS1). However, functional interaction between PS1 and BACE1 has never been known. In addition to this classical role in the generation of Abeta peptides, it has also been proposed that PS1 affects the intracellular trafficking and maturation of selected membrane proteins. We show that the levels of exogenous and endogenous mature BACE1 expressed in presenilin-deficient mouse embryonic fibroblasts (PS-/-MEFs) were reduced significantly compared to those in wild-type MEFs. Moreover, the levels of mature BACE1 were increased in human neuroblastoma cell line, SH-SY5Y, stably expressing wild-type PS1, compared to native cells. Conversely, the maturation of BACE1 was compromised under the stable expression of dominant-negative mutant PS1 overexpression. Immunoprecipitation assay showed that PS1 preferably interacts with proBACE1 rather than mature BACE1, indicating that PS1 can be directly involved in the maturation process of BACE1. Further, endogenous PS1 was immunoprecipitated with endogenous BACE1 in SH-SY5Y cells and mouse brain tissue. We conclude that PS1 is directly involved in the maturation of BACE1, thus possibly functioning as a regulator of both beta- and gamma-secretase in Abeta generation.

Presenilin 1 is involved in maturation and trafficking of N-cadherin to the plasma membrane.

One pathological characteristic of Alzheimer's disease (AD) is extensive synapse loss. Presenilin 1 (PS1) is linked to the pathogenesis of early onset familial Alzheimer's disease (FAD) and is localized at the synapse, where it binds N-cadherin and modulates its adhesive activity. To elucidate the role of the PS1/N-cadherin interaction in synaptic contact, we established SH-SY5Y cells stably expressing wild-type (wt) PS1 and dominant-negative (D385A) PS1. We show that the formation of cadherin-based cell-cell contact among SH-SY5Y cells stably expressing D385A PS1 was suppressed. Conversely, wt PS1 cells exhibited enhanced cell-cell contact and colony formation. Suppression of cell-cell contact in D385A cells was accompanied by an alteration in N-cadherin subcellular localization; N-cadherin was retained mainly in the endoplasmic reticulum (ER) and cell surface expression was reduced. We conclude that PS1 is essential for efficient trafficking of N-cadherin from the ER to the plasma membrane. PS1-mediated delivery of N-cadherin to the plasma membrane is important for N-cadherin to exert its physiological function, and it may control the state of cell-cell contact.

Presenilin 1 mediates retinoic acid-induced differentiation of SH-SY5Y cells through facilitation of Wnt signaling.

Presenilin 1 interacts with beta-catenin, an essential component of the Wnt signaling pathway. To elucidate the role of presenilin 1-beta-catenin interaction in neuronal differentiation, we established SH-SY5Y cells stably expressing wild-type presenilin 1, P117L mutant presenilin 1, which is linked to the early-onset familial form of Alzheimer's disease, and D385A mutant presenilin 1, which has no aspartyl proteinase activity. We demonstrate that SH-SY5Y cells stably expressing D385A mutant presenilin 1 failed to differentiate in response to retinoic acid treatment. Retinoic acid caused an increase in nuclear beta-catenin levels in SH-SY5Y cells, which was followed by an increase in cyclin D1 protein levels. Abnormal cellular accumulation of beta-catenin was observed in D385A mutant transfected cells, whereas nuclear beta-catenin and cellular cyclin D1 levels failed to increase. Conversely, SH-SY5Y cells expressing the P117L mutant differentiated normally and showed increased nuclear beta-catenin and cellular cyclin D1 levels. These findings suggest that neuronal differentiation of SH-SY5Y cells involves the Wnt signaling pathway and that presenilin 1 plays a crucial role in Wnt signal transduction by regulating the nuclear translocation of beta-catenin.

The role of the presenilin-1 homologue gene sel-12 of Caenorhabditis elegans in apoptotic activities.

Many cases of autosomal dominant early onset familial Alzheimer's disease result from mutations in presenilin-1 (PS1). In this study, we examined the role of the PS1 homologue gene sel-12 of Caenorhabditis elegans under oxidative stress and clarified the sel-12-induced apoptosis. A genetic null allele mutant, sel-12(ar171), showed resistance to oxidative stress and prevented mitochondrial dysfunction-induced apoptosis. On the other hand, another allele mutant, sel-12(ar131), that carries a missense mutation showed a proapoptotic activity, which may be the result of a gain of function property. Also, sel-12(ar131)-induced apoptosis was ced-3- and ced-4-dependent. Dantrolene, which specifically inhibits Ca(2+) release from endoplasmic reticulum stores, prevents sel-12(ar131)-induced apoptosis. SEL-12, which is localized in the endoplasmic reticulum, may induce apoptosis through abnormal calcium release from the endoplasmic reticulum. Together, with the previous finding that human PS1 could substitute for SEL-12, these results suggest the similar involvement of PS1-inducing apoptosis under oxidative stress and mitochondrial dysfunction in the Alzheimer's Disease brain.