Two Cases of Kikuchi Disease Presenting with Aseptic Meningitis and Encephalitis.

Kikuchi disease, also called histiocytic necrotizing lymphadenitis, is an idiopathic and generally self-limiting disease affecting young adults and children. Kikuchi disease does not commonly manifest neurological complications at its initial presentation. We herein report two cases of Kikuchi disease that initially presented with aseptic meningitis and encephalitis rather than the more common signs of lymphadenopathy, rash, and arthritis. A 15-year-old boy presented with aseptic meningitis with an extremely high intracranial pressure. A 28-year-old man presented with dysesthesia of the right lower extremity, coinciding with abnormal magnetic resonance imaging findings. In both cases, painful cervical lymphadenopathy was observed following the central nervous system symptoms. Both patients improved after treatment with steroids. Kikuchi disease occasionally affects the central nervous system, to which lymphadenitis may be observed subsequently. A repeated, careful physical examination of the cervical lymph nodes may be helpful for the diagnosis.

rt-PA with Antithrombotic Therapies in a Case with Capsular Warning Syndrome.

We herein report a case of capsular warning syndrome (CWS) that was successfully treated with recombinant tissue plasminogen activator (rt-PA). A 70-year-old woman had repeated stereotyped transient ischemic attacks (TIAs) of right hemiparesis and dysarthria. After hospitalization, argatroban, aspirin, and cilostazol were started but were ineffective. Thirteen hours after the first episode of TIAs, severe symptoms occurred. Magnetic resonance imaging showed acute infarctions in the internal capsule to corona radiata, so we used rt-PA. Since then, the TIAs have not occurred, and the symptoms have considerably improved. This case suggests that rt-PA might be effective and safe for use in treating CWS.

[Case of an elderly woman with dementia showing episodic involuntary movement of the tongue].

We report a 93-year-old woman with dementia who developed generalized convulsion and involuntary movement of her tongue. She could independently walk and eat meals until 8 months ago, however she turned into bedridden. When she was admitted to our emergency room due to status epilepticus, her tongue intermittently moved from the midline to the left. She could not eat or speak during this episodic tongue movement. MR imaging study revealed brain atrophy in the bilateral mesial temporal lobe, consistent with senile dementia of Alzheimer type. Despite her tongue movements seemingly developing to the generalized convulsion, EEG study did not indicate epileptiform discharges corresponding to this movement. Although antiepileptic drug therapy was effective, we needed polytherapy to control this movement. Paroxysmal tongue movements were previously reported in cases of epilepsy, brain tumor, and stroke, observed bilaterally in most cases. This episodic tongue movement would be rare in terms of the clear laterality. The etiology of this movement was presumed as focal seizure, palatal tremor, dyskinesia or others, but was undetermined. Episodic movements involving tongue decrease the quality of daily life especially in the elderly. Therefore, we should pay more attention to it and try to treat it earlier.

Interaction of presenilins with FKBP38 promotes apoptosis by reducing mitochondrial Bcl-2.

Presenilins 1 and 2 (PS1/2), causative molecules for familial Alzheimer's disease (FAD), are multipass transmembrane proteins localized predominantly in the endoplasmic reticulum (ER) and Golgi apparatus. Heteromeric protein complexes containing PS1/2 are thought to participate in several functions, including intramembrane proteolysis mediated by their gamma-secretase activities. Previous studies have shown that PS1/2 are also involved in the regulation of apoptotic cell death, although the underlying mechanism remains unknown. Here, we demonstrate that FKBP38, an immunophilin family member residing in the mitochondrial membrane, is an authentic PS1/2-interacting protein. PS1/2 and FKBP38 form macromolecular complexes together with anti-apoptotic Bcl-2. PS1/2 promote the degradation of FKBP38 and Bcl-2 and sequester these proteins in the ER/Golgi compartments, thereby inhibiting FKBP38-mediated mitochondrial targeting of Bcl-2 via a gamma-secretase-independent mechanism. Thus, PS1/2 increase the susceptibility to apoptosis by antagonizing the anti-apoptotic function of FKBP38. In contrast, C-terminal fragments of caspase-processed PS1/2 redistribute Bcl-2 to the mitochondria by abrogating the activity of full-length PS1/2, resulting in a dominant-negative anti-apoptotic effect. In cultured cells and mutant PS1-knockin mice brains, FAD-linked PS1/2 mutants enhance the pro-apoptotic activity by causing a more efficient reduction in mitochondrial Bcl-2 than wild-type PS1/2. These results suggest a novel molecular mechanism for the regulation of mitochondria-mediated apoptosis by competition between PS1/2 and FKBP38 for subcellular targeting of Bcl-2. Excessive pro-apoptotic activity of PS1/2 may play a role in the pathogenesis of FAD.

Random mutagenesis of presenilin-1 identifies novel mutants exclusively generating long amyloid beta-peptides.

Familial Alzheimer disease-causing mutations in the presenilins increase production of longer pathogenic amyloid beta-peptides (A beta(42/43)) by altering gamma-secretase activity. The mechanism underlying this effect remains unknown, although it has been proposed that heteromeric macromolecular complexes containing presenilins mediate gamma-secretase cleavage of the amyloid beta-precursor protein. Using a random mutagenesis screen of presenilin-1 (PS1) for PS1 endoproteolysis-impairing mutations, we identified five unique mutants, including R278I-PS1 and L435H-PS1, that exclusively generated a high level of A beta43, but did not support physiological PS1 endoproteolysis or A beta40 generation. These mutants did not measurably alter the molecular size or subcellular localization of PS1 complexes. Pharmacological studies indicated that the up-regulation of activity for A beta43 generation by these mutations was not further enhanced by the difluoroketone inhibitor DFK167 and was refractory to inhibition by sulindac sulfide. These results suggest that PS1 mutations can lead to a wide spectrum of changes in the activity and specificity of gamma-secretase and that the effects of PS1 mutations and gamma-secretase inhibitors on the specificity are mediated through a common mechanism.

Nucleolar characteristics of reducing bodies in reducing body myopathy.

Reducing body myopathy is a rare muscle disease defined by abnormal inclusions in affected muscle fibers that can be stained with menadione-nitroblue tetrazolium. The origin of these inclusions has not been determined. Here we show that reducing bodies bear characteristics of nucleoli. Ultrastructurally, muscle biopsy specimens of a patient with adult-onset reducing body myopathy showed granular structures of reducing bodies with features similar to the granules of nucleoli, which consisted of pre-ribosomes. In addition, reducing bodies were positive for histochemistry of argyrophilic nucleolar organizer regions (a method for detecting the areas where ribosomal RNA is actively transcribed in the nucleolus), and for antibodies against nucleoli and nuclear ribonucleoprotein. The current findings suggest that reducing bodies contain pre-ribosomes and their associated proteins of the nucleolus and that formation of reducing bodies may result from defects of processing and assembly of ribosomes.