Domperidone effective in preventing rivastigmine-related gastrointestinal disturbances in patients with Alzheimer's disease.

OBJECTIVE: While acetylcholinesterase inhibitors, such as donepezil, galantamine, and rivastig-mine, are beneficial in treating behavioral symptoms of patients with Alzheimer's disease (AD), their dose-limiting effects include gastrointestinal disturbances, such as nausea, vomiting, and diarrhea. We aimed to predict the occurrence of these gastrointestinal disturbances with rivastigmine therapy for optimal drug choice and improved compliance. MATERIALS AND METHODS: Thirty patients with mild-to-moderate AD (scores 10-22 on the MiniMental State Examination) were administered a rivastigmine 18 mg patch with domperidone 30 mg (RWD) and without domperidone (RWOD; n = 15 each) for 20 weeks. Gastrointestinal disturbances were evaluated using a frequency scale for symptoms of gastroesophageal reflux disease (FSSG), Bristol stool form scale, laboratory data (hemoglobin, albumin, total cholesterol), body weight, and amount of food intake. RESULTS: After 12 weeks, FSSG scores were higher in the RWOD group compared to baseline scores; however, no significant differences were noted between the RWD and RWOD groups. We then subdivided each group based on high and low baseline scores; the RWOD high-score (≥4) subgroup showed increased FSSG after 12 weeks compared with the baseline score. In both RWD and RWOD groups, the low-score (≤3) subgroups showed no changes during the dose-escalation phase. CONCLUSION: For AD patients with higher FSSG scores at baseline, domperidone was effective in preventing rivastigmine-related gastrointestinal disturbances.

Clinically meaningful treatment responses after switching to galantamine and with addition of memantine in patients with Alzheimer's disease receiving donepezil.

Clinical trials have shown the benefits of acetylcholinesterase inhibitors, such as donepezil and galantamine, and an N-methyl-D-aspartate receptor antagonist, memantine, in patients with Alzheimer's disease (AD). However, little is known regarding the effects of switching from donepezil 5 mg/day to galantamine 16 or 24 mg/day, or regarding the effects of adding memantine to established therapy compared with increasing the dose of donepezil. This report discusses two studies conducted to evaluate treatment with galantamine and memantine with respect to cognitive benefits and caregiver evaluations in patients with AD receiving donepezil 5 mg/day for more than 6 months. Patients with mild or moderate AD (scores 10-22 on the Mini-Mental State Examination) were enrolled in the Galantamine Switch study and switched to galantamine (maximum doses 16 mg versus 24 mg). Patients with moderate to severe AD (Mini-Mental State Examination scores 3-14) were enrolled in the Donepezil Increase versus Additional Memantine study and either had their donepezil dose increased to 10 mg/day or memantine 20 mg/day added to their existing donepezil dose. Patients received the study treatment for 28 weeks and their Disability Assessment for Dementia, Mental Function Impairment Scale, Cohen-Mansfield Agitation Inventory, and Neuropsychiatric Inventory scores were assessed with assistance from their caregivers. For the Galantamine Switch study after 8 weeks, agitation evaluated by the Cohen-Mansfield Agitation Inventory improved in both the 16 mg and 24 mg groups compared with baseline. However, there were no significant differences between the two galantamine groups. Agitation was also less in patients in the additional memantine group than in the donepezil increase group. In summary, switching to galantamine from donepezil and addition of memantine in patients with AD receiving donepezil were both safe and meaningful treatment options, and particularly efficacious for suppression of agitation.

Limb-onset amyotrophic lateral sclerosis patients visiting orthopedist show a longer time-to-diagnosis since symptom onset.

BACKGROUND: There have been several reports concerning the survival time after symptom onset in patients with amyotrophic lateral sclerosis (ALS). However, little is known about how the choice of physician (i.e., general practitioner, neurologist, etc.) may affect the time it takes for a diagnosis of ALS to be made. METHODS: We conducted a retrospective study, covering a 20-year period, comparing the type of physician first consulted by an ALS patient at the time of initial symptoms and the amount of time that elapsed to the final diagnosis of ALS. A total of 202 patients were diagnosed and stratified according to the onset of ALS symptoms (bulbar onset [BO] and limb onset [LO]). We noted the type of physician first seen by the patient. The diagnostic interval was calculated as the time between onset of symptoms and the final diagnosis of ALS. RESULTS: A total of 202 ALS patients were examined. Clinical BO and LO was observed in 78 (36.6%) and in 124 (61.4%) of these patients, respectively. The type of physician examining these patients at the first symptoms of disease was as follows (BO and LO): neurologist (38.5% and 25.8%), general practitioner (14.1% and 35.5%), orthopedist (12.8% and 35.5%), otolaryngologist (15.4% and 0%), and neurosurgeon (14.1% and 3.2%). Mean diagnostic interval (standard deviation) for patients with either set of symptoms was 13.1 (6.5) months; the diagnostic interval of patients with BO and LO was 9.2 (4.5) and 15.2 (7.7) months, respectively. ALS diagnosis in LO patients was delayed by more than 10 months when the patient first consulted an orthopedist rather than a neurologist. CONCLUSION: More than 50% of the ALS patients included in this study did not visit a neurologist at the first symptoms of disease onset. The diagnosis of ALS was prolonged in LO patients visiting an orthopedist. We speculate that this increase in the diagnostic interval in LO patients visiting an orthopedist was due to a lack of bulbar symptoms in the early stages of this disease.

Influenza-associated monophasic neuromyelitis optica.

Neuromyelitis optica (NMO) is an inflammatory demyelinating disorder characterized by optic neuritis and acute myelitis. A parainfectious pathogenesis may play a partial role in the development of this disorder. Several viral infections are known to cause NMO. Here we report the case of a 15-year-old girl diagnosed with postinfluenza monophasic NMO. The patient developed sudden fever and chills, and the rapid diagnostic test for influenza was positive. She was diagnosed as influenza A and was treated with zanamivir hydrate (10 mg/day, inhalation). Three days later, she complained of dysuria and dysesthesia in the lower extremities. After nine days, she experienced blurred vision bilaterally. Neurological examination revealed visual disturbance, dysuria, dysesthesia and hyperreflexia in the lower extremities. Her visual acuity was counting fingers in OD and 2/100 in OS. Pupillary size was 4.0 mm and light reflexes were sluggish on both sides. Ophthalmoscopy showed marked edema of the optic discs. Serum influenza immunoglobulin M antibodies were elevated and serum anti-aquaporin 4 (AQP4) antibodies were undetectable. Spinal cord magnetic resonance imaging (MRI) displayed longitudinally extensive lesions in the thoracic cord. Brain MRI disclosed three subcortical lesions. The patient fulfilled the revised diagnostic criteria for NMO (2006). After methylprednisolone pulse therapy followed by oral administration of prednisolone, visual dysfunction, dysuria, limb dysesthesia and hyperreflexia were improved. Subsequently, she experienced no attacks for 3 years. This is the first case report of influenza A-associated NMO with such features of postinfectious NMO as a pediatric onset, monophasic course and anti-AQP4 antibody-seronegative status.

Repeated non-enhancing tumefactive lesions in a patient with a neuromyelitis optica spectrum disorder.

A 51-year-old woman had developed fever and consciousness disturbance at 47 years of age. Brain magnetic resonance imaging (MRI) revealed acute disseminating encephalomyelitis (ADEM)-like lesions without gadolinium enhancement (GDE). One year later, she had an episode of bilateral optic neuritis and cerebellar ataxia. Speech deficit and right hand weakness occurred at the age of 51 years. Neurological examination showed motor aphasia, finger agnosia, right-left disorientation, and right hand paresis. Neuromyelitis optica (NMO)-IgG was seropositive. Cerebrospinal fluid examination showed negative results for myelin basic protein and oligoclonal IgG band. The IgG index was normal. Brain MRI revealed a tumefactive lesion in the left temporo-parietal region and conglomerate ovoid lesions in the pericallosal regions. No GDE was found in the brain lesions. Visual evoked potential test showed bilateral prolongation of P100 latencies. She was treated twice with methylprednisolone pulse therapy followed by oral prednisolone, but the motor aphasia did not respond to steroid treatment. She had no prior history of myelitis and was diagnosed as NMO spectrum disorder (NMOSD). Similar to previous studies of NMO-IgG seropositive extensive brain lesions, this patient with NMOSD indicated no GDE in tumefactive lesions at two episodes of encephalopathy. Compared to multiple sclerosis (MS), a high frequency of non-enhancing tumefactive lesions is reported in patients with NMO or NMOSD. The absence of GDE in tumefactive lesions could help to differentiate between NMO and MS.

Serological profiles of urate, paraoxonase-1, ferritin and lipid in Parkinson's disease: changes linked to disease progression.

BACKGROUND: Oxidative stress plays a role in the pathogenesis of neuronal death. Serum levels of urate or lipid were associated with the incidence of Parkinson's disease (PD). OBJECTIVE: We compared urate, paraoxonase-1 (PON1), iron, ferritin and lipid in sera of 119 PD patients and 120 healthy controls matched by age, sex and body mass index. We aimed to elucidate whether those serological data are correlated with disease progression. RESULTS: Mean age (SD) of PD patients was 73.4 (8.7) years. Mean Yahr stage (SD) was 3.2 (0.9). Mean disease duration (SD) was 6.9 (5.1) years. Mean dose of L-DOPA (SD) was 355 (157) mg/day. As compared to controls, serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), urate and PON1 activity were significantly reduced, and serum ferritin levels were significantly increased in male and female PD patients. Serum urate levels and PON1 activities were inversely related, and serum ferritin levels were correlated with Yahr stage and PD duration in men and women. Serum levels of TC and LDL-C were inversely related to Yahr stage or PD duration in female patients. CONCLUSIONS: Our studies indicated serological profiles of urate, PON1, ferritin, TC and LDL-C in PD patients. These serological changes were linked to PD progression. Metabolism of lipid, oxidant- and antioxidant-related substances may contribute to the pathogenesis and the progression of PD.

Cheiro-oral syndrome associated with lateral medullary infarction.

A 62-year-old man was admitted to our department because of the sudden onset of dysaesthesia in the right perioral region of the face and right hand. Neurological examination demonstrated a loss of pain and temperature sensation in both the right perioral region and in the fingers of the right hand. These findings suggested damage to parts of the ipsilateral spinothalamic and trigeminothalamic ascending tracts, producing restricted sensory impairment of the perioral region and ipsilateral hand. This is the first reported case of a medullary lesion causing cheiro-oral syndrome.

Rheumatoid leptomeningitis: radiological alteration of cerebral hypoperfusion and subarachnoid lesions.

A 56-year-old man with rheumatoid arthritis developed emotional lability and myoclonic seizure in the left arm, followed by fever and generalized convulsion. Brain magnetic resonance imaging (MRI) revealed leptomeningeal lesions with abnormal enhancement. MRI lesions were localized predominantly in the right cerebral subarachnoid spaces. Electroencephalogram showed epileptogenic focus at the right frontal and central points. After administration of valproate sodium improved convulsion and myoclonus, single photon emission computed tomography (SPECT) using N-isopropyl-p-(123)I-iodoamphetamine was performed. Brain SPECT displayed hypoperfusion predominantly in the right cerebral hemisphere. Cerebrospinal fluid (CSF) disclosed mild pleocytosis and marked elevations of interleukin-6 levels. Repeated CSF analyses showed cytology of class I and negative results for infectious pathogens. Methylprednisolone pulse therapy (1 g for 3 days, iv) and subsequent prednisolone administration (daily 50 mg, po) ameliorated neurological symptoms dramatically. Prednisolone was tapered to 20 mg/day for 5 months. Leptomeningeal MRI lesions were attenuated gradually followed by restoration of cerebral hypoperfusion on SPECT. He was diagnosed as rheumatoid leptomeningitis (RLM). Although clinical features of RLM exhibited variable deficits of the central nervous system (CNS), MRI failed to detect the corresponding CNS lesions. We first highlighted neuroradiological changes of cerebral hypoperfusion and leptomeningeal lesions in RLM. These neuroimages of our patient supported that leptomeningeal inflammation and the adjacent cerebrocortical ischemia could cause encephalitis-like symptoms in RLM patients.

A distinct phenotype of leg hyperreflexia in a Japanese family with Gerstmann-Sträussler-Scheinker syndrome (P102L).

Gerstmann-Sträussler-Scheinker Syndrome (GSS) is an inherited prion disease characterized by midlife onset and slowly progression of cerebellar ataxia and dementia. We report a distinct phenotype of leg hyperreflexia in a Japanese family with GSS. A 38-year-old woman noticed unsteady gait at 33 years of age. Afterwards, dysarthria and writing difficulty were appeared. Her family history revealed that her grandfather and her mother had a clinical history of unsteadiness and mental changes. At 1 year after clinical onset, neurological examination showed cerebellar ataxia and leg hyperreflexia. At 4 years after onset, she suddenly developed insomnia and nocturnal howling. Her mental status disclosed marked disorientation, anxiety and irritability. Muscle stretch reflexes were increased in four extremities with Babinski's signs. Remarkable dysarthria and cerebellar ataxia were presented. Brain diffusion weighted imaging showed extensive hyperintensity signal areas in the cerebral cortex. A point mutation of the prion protein gene (PRNP) at codon 102 resulting in the substitution of proline by leucine (P102L) was identified. PRNP polymorphism exhibited homozygous methionine at codon 129 and homozygous glutamate at codon 219. She had verbal perseveration, somnolence and myoclonus of lower limbs, leading to akinetic mutism at 4 months after neuropsychiatric events. Phenotypic hallmark of our patient indicates leg hyperreflexia from an early disease course. This neurological sign differs from the previously reported clinical expression of Japanese and foreign patients with GSS (P102L). Thus, physicians should pay more attention to phenotypic heterogeneity in this prion disease.

Familial amyotrophic lateral sclerosis with a novel G85S mutation of superoxide dismutase 1 gene: clinical features of lower motor neuron disease.

Amyotrophic lateral sclerosis (ALS) is a devastating disease characterized by upper and lower motor neuron damage. Mutations of Cu/Zn superoxide dismutase gene (SOD1) account for 20% of familial ALS (FALS). We report a unique clinicogenotype of a Japanese family with a novel SOD 1 mutation. A 37-year-old woman (the proband) noticed muscle weakness in the left lower limb. Her mother had developed progressive lower motor neuron signs in four extremities at 38 years of age. Subsequently she was diagnosed as ALS and died of respiratory failure at 15 months after clinical onset. Neurological examination of the proband showed absent muscle stretch reflexes in the left knee and the left ankle without Babinski signs. Mild to moderate degree of muscle weakness existed in the left lower extremity. Muscle atrophy was presented in the left thigh. Initial pulmonary function revealed forced vital capacity of 91.1%. Electromyography disclosed ongoing denervation muscle potentials in the left lower extremity. SOD1 analysis demonstrated amino acid substitution of glycine by serine at codon 85 (G85S) in exon 4. Six months later, marked muscle weakness and atrophy expanded to four extremities. All muscle stretch reflexes were absent. Three months later, ventilator support with a tracheostomy was needed. The patient died at 18 months after clinical onset. Clinical hallmarks of this FALS family indicate that G85S mutation of SOD1 may cause rapidly progressive form of pure lower motor neuron signs.

Scopolamine-induced migraine like headache.

OBJECTIVE: Scopolamine butylbromide (SB), a muscarinic receptor antagonist, is used commonly in gastric X-ray examination in the physical check-up in Japan. This study describes clinical features of SB-induced headache. PATIENTS AND METHODS: SB-induced headache was defined as headache that started within 20 minutes after intramuscular administration of SB (20 mg/body). The Primary and the secondary headaches were diagnosed according to the ICHD-II criteria. SB-induced headache was classified as headache induced by acute substance use or that due to exposure (ICHD-II code 8.1). Clinical features and background of subjects with SB-induced headache were analyzed. We also estimated the frequency of SB-related headache between migraineurs and non-migraineurs. RESULTS: A total of 54 subjects (39 women and 15 men) experienced SB-induced headache. All subjects had the present history of migraine. Nine subjects had > or =2 times of the headache. Mean age (SD) was 46.2 (9.7) years [46.2 (9.7) for women and 46.3 (10.0) for men]. Clinical hallmarks of headache showed that pulsating / throbbing pain occurred in diffuse or bilateral head sites. Headache worsened at 20-30 minutes from the onset and persisted for 6-18 hours, and ameliorated gradually 8 hours later. All subjects had repeated nausea and vomiting. Severity of headache revealed severe degree requiring complete bed rest in 50 subjects (92.6%). SB-induced headache had similar characteristics as migraine without aura (MO) attacks. Liver and renal functions were normal in all SB-related migraineurs. They had no allergic history of medication and food. In 1,865 non-migraine controls, one healthy subject had a mild degree of migraine like headache triggered by SB injection. CONCLUSION: SB triggers a severe degree MO like headache or worsens pre-existing migraine in some migraineurs. SB-induced headache could contribute to disequilibrium between acetylcholine and other neuropeptides. We should use SB more carefully as it can be an aggravating drug of migraine.

Beneficial effect of pramipexole for motor function and depression in Parkinson's disease.

We examined whether pramipexole (PPX) can influence depressive scale in normal and mild depressive parkinsonian patients. In an open study of PPX as an add-on to L-dopa therapy or single administration, 36 nondemented outpatients with Parkinson's disease (PD) were entered first. All were in the stage II or III of Hoehn and Yahr scale (H&Y). PPX were started at 0.125 mg/day and daily doses were increased to 1.5 mg/day. At 3 months after PPX treatment, patients were re-evaluated. Hamilton Depression Rating Scale (HAM-D), Unified Parkinson's Disease Rating Scale III, H&Y stage, and freezing of gait questionnaire were compared in patients before and after PPX treatment. These scores were significantly improved after PPX administration. There were no correlations between HAM-D and those motor functions. We suggest that PPX treatment has antidepressant effects in depressive PD patients and also ameliorates HAM-D score in nondepressive PD patients in addition to motor function.

[Clinicoradiological studies and frequency of incidental meningiomas on brain check-up].

The purpose of this study is to evaluate clinico-radiological findings and to estimate frequency of incidental meningiomas detected by brain check-up (BC). A total of 12,258 healthy adults (8,515 men and 3,743 women) had BC, using physical check-up, brain magnetic resonance imaging (MRI) and MR angiography. Mean age (SD) was 52.6 (11.4) years, 52.7 (11.2) in men and 52.5 (11.8) in women. Duration of this study was between April 2004 and March 2007. BC subjects were divided into the first BC and the repeated BC group. The number of the first BC subjects was 5,056 (3,284 men and 1,772 women). In the repeated group defined that they had the first BC before April 2004 in our center, there were 7,202 subjects (5,231 men and 1,971 women). Fifteen subjects (7 men and 8 women) were diagnosed as meningiomas. Fourteen cases were detected by the first BC and one case by the repeated BC. The percentage of incidental meningiomas in the first BC group was calculated as 0.28, 0.18 in men and 0.45 in women. The sex ratio of women/men was 2.5. The mean age of those cases was 55.2 (10.1), 54.6 (12.9) in men and 55.8 (7.7) in women. Incidental rate of meningioma in the repeated BC group was calculated as 0.01% and 0.02% in men. No subjects had meningioma at age < or = 30 years. Asymptomatic meningiomas were seen in 14 cases (93.3 %) and they expected BC to ascertain healthy and normal brain by themselves. The size of tumors was ranged 10 to 46 mm and mean (SD) was 21.3 (10.2) mm. The locations of meningiomas were variable. Three cases had surgical removal. Twelve cases were under investigation on MRI. In middle-aged working subjects, incidental rates of asymptomatic meningiomas detected by BC are not uncommon in Japan. We should pay more attention to incidental meningioma when brain MRI is performed in 40-60 years women.

Different variables between patients with left and right hemispheric ischemic stroke.

We studied whether some variables differ between patients with right and left hemispheric ischemic stroke. A total of 383 cases were obtained from our department-based records between April 2003 and March 2006. Age distribution, sex, intracranial localization of anterior (carotid artery distribution) or posterior (vertebrobasilar artery distribution) circulation, mechanism subtypes according to Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria, cerebrovascular risk factors, and time from clinical onset to admission were analyzed between the right and the left hemispheric ischemic stroke groups. In all, 200 patients had left hemispheric stroke and 183 patients had right hemispheric stroke. Age, sex, vascular risk profile, stroke subtypes, and mechanism subtypes were not statistically different between patients with right- and left-sided ischemic stroke. Time interval from neurologic onset to admission within 6 hours was significantly associated with left hemispheric cerebral infarction. Furthermore, patients with left-sided small-vessel occlusion visited our hospital earlier, up to 6 hours as compared with patients with right-sided small-vessel occlusion (P < .05). We suppose that patients with right-sided small-vessel occlusion may take time to be aware of neurologic deficits because of nondominant language or hand function. Our data indicate that different medical attention exists between patients with right and left hemispheric ischemic stroke. We should pay more attention to the difficulty in recognizing the neurologic deficits in patients with right hemisphere ischemic stroke, so that those patients delay hospital visit.

Reversible cerebellar lesions induced by metronidazole therapy for helicobacter pylori.

Metronidazole is widely used for chronic or refractory infection and has recently also been used for the treatment of Helicobacter pylori. The authors report the case of a Japanese patient presenting with reversible cerebellar lesions induced by prolonged administration of metronidazole for treatment of H pylori with magnetic resonance imaging findings. Although rare, prolonged and high-dose administration of metronidazole may induce cerebellar lesions. Increased awareness of this phenomenon is important, as these lesions are reversible with discontinuation of this drug.