Nerve Ultrasound, Electrophysiological, and Clinical Changes in Treatment-Naive Chronic Inflammatory Demyelinating Polyneuropathy: A Case Report.

We report the case of a 74-year-old woman with treatment-naive chronic inflammatory demyelinating polyneuropathy evaluated by both nerve conduction studies and nerve ultrasound (NUS) before and after initial treatment. Performing both nerve conduction study and NUS before and after initial treatment seems rare for treatment-naive chronic inflammatory demyelinating polyneuropathy. This case yielded two major findings. First, improvement of nerve swelling as evaluated by NUS correlated well with the improvement of neurological symptoms. Second, NUS improvements were seen right after treatment, whereas electrophysiological improvements were not. Nerve ultrasound might thus allow for judgment of curative effects much more immediately and sensitively than nerve conduction study in treatment-naive chronic inflammatory demyelinating polyneuropathy.

High norepinephrinergic orthostatic hypotension in early Parkinson's disease.

INTRODUCTION: Plasma norepinephrine concentration reflects lesions causing OH. We investigate whether patients with high norepinephrinergic orthostatic hypotension (OH) whose supine plasma norepinephrine concentration (NEsupine) is above the mean value in all patients with Parkinson's disease (PD) have central sympathetic denervation. METHODS: We analyzed data from 110 non-demented patients with early de novo PD who underwent cardiovascular examinations. We divided the patients into three groups according to the presence or absence of orthostatic hypotension and NEsupine: patients without OH, patients with OH+high NEsupine, and patients with OH+low NEsupine. RESULTS: The mean NEsupine in all patients was 251.6 pg/ml. Twelve patients (10.9%) had OH+high NEsupine (≥251.6 pg/ml), and 45 patients (40.9%) had OH+low NEsupine (<251.6 pg/ml). OH was more pronounced in patients with OH+high NEsupine than in those with OH+low NEsupine (p = 0.024). Vasopressin release and percent increase of NE after orthostatic stress were well preserved in patients with OH+low NEsupine, but not in patients with OH+high NEsupine. Cognition was lower in patients with OH+high NEsupine than in patients with OH+low NEsupine (p = 0.019) and was associated with vasopressin release during orthostatic stress on multiple regression analysis. The degree of cardiac sympathetic denervation did not differ between two groups with OH. CONCLUSIONS: Patient with PD and high norepinephrinergic OH are a subset of patients who have early cognitive decline and impaired vasopressin release. Vasopressin release after orthostatic stress was closely related to global cognition in PD.

Predictors of postprandial hypotension in elderly patients with de novo Parkinson's disease.

Postprandial hypotension is one of the most important autonomic disorders in Parkinson's disease. However, its predictors remain unclear. We investigated which variable(s) predict the presence of postprandial hypotension in elderly patients with Parkinson's disease. The subjects were 64 patients with de novo Parkinson's disease who were 70 years or older. Postprandial hypotension was evaluated on a 75-g oral glucose tolerance test. Olfactory function, constipation, cardiac sympathetic or parasympathetic denervation, orthostatic intolerance on head-up tilt table testing, and other baseline characteristics were evaluated. The results showed the presence of postprandial hypotension was associated with severe dysosmia, constipation, orthostatic hypotension (a decrease in systolic blood pressure ≥30 mmHg) and preprandial hypertension at rest. On multiple logistic regression analyses adjusted for age, sex, symptom duration, disease severity, and motor subtype, the odds ratio was 4.02 for severe dysosmia (p = 0.027), 9.99 for constipation (p = 0.006), 6.42 for orthostatic hypotension with alternative definition (p = 0.004) and 7.90 for preprandial hypertension at rest (p = 0.001). Each multiple logistic regression analysis revealed that female sex was also a risk factor for postprandial hypotension. The variables with the highest sensitivity and specificity for postprandial hypotension were constipation (89.6 %) and preprandial hypertension at rest or orthostatic hypotension with alternative definition (both 77.1 %), respectively. Our results suggest that these variables predict the presence of postprandial hypotension in elderly patients with Parkinson's disease, suggesting that postprandial hypotension shares etiologic factors with these potential predictors.

Clinical characteristics of supine hypertension in de novo Parkinson disease.

PURPOSE: Supine hypertension is frequently associated with autonomic failure. However, its clinical characteristics in patients with Parkinson disease (PD) remain unclear. The present study aimed to clarify the characteristics of supine hypertension in patients with de novo PD. METHODS: The subjects were 72 patients with de novo PD. We studied blood pressure and plasma norepinephrine levels after the patients rested for 20 min in the supine position. Changes in blood pressure were also examined on head-up tilt-table testing. RESULTS: The disease duration was 1.7 ± 1.6 years (average ± SD). Thirty-three (45.8 %) patients had supine hypertension (defined as a blood pressure of ≥140/90 mmHg). Supine blood pressure positively correlated with the degree of orthostatic hypotension. Age and the proportion of patients with akinetic-rigid motor subtype or preexisting hypertension were higher among patients with supine hypertension than among those without supine hypertension. The Mini-Mental State Examination score was lower in patients with supine hypertension than in those without supine hypertension. Sex, disease duration, disease severity, and peripheral sympathetic nervous activity as evaluated by the cardiac uptake of (123)I-metaiodobenzylguanidine and the plasma norepinephrine level did not differ between patients with and those without supine hypertension. CONCLUSION: Older age, akinetic-rigid motor subtype, and preexisting hypertension are independent risk factors for supine hypertension. Supine hypertension alone may be associated with milder peripheral sympathetic nervous denervation than orthostatic hypotension alone. As for global cognitive decline, supine hypertension is a far riskier comorbidity of early-stage PD than is orthostatic hypotension.

Thyroid hormone level is associated with motor symptoms in de novo Parkinson's disease.

Sympathetic denervation has been observed not only in the myocardium but also in the thyroid of patients with Parkinson's disease (PD). We investigated whether sympathetic denervation as indicated by decreased cardiac (123)I-meta-iodobenzylguanidine uptake is associated with the levels of thyroid hormones and whether the levels of thyroid hormones affect clinical manifestations in patients with PD. The subjects were 75 patients with de novo PD and 20 age-matched healthy controls. We examined the levels of thyroid-stimulating hormone, free triiodothyronine, and free thyroxine, and evaluated the associations of these levels with cardiac (123)I-meta-iodobenzylguanidine uptake and motor symptoms. The results showed that the free triiodothyronine level was below the normal range in 29 patients (approximately 40 %) and was significantly lower in the patients with PD than in the controls. The decreased free triiodothyronine level was associated with akinetic-rigid motor subtype and washout ratio of cardiac (123)I-meta-iodobenzylguanidine scintigraphy. The free triiodothyronine level negatively correlated with disease severity. Thyroid-stimulating hormone level was within normal range. However, its level was lower in patients with tremor-dominant type or mixed type than in those with akinetic-rigid type. All correlations of these variables with the levels of thyroid hormones remained statistically significant on multiple regression analysis. Our results suggest that the thyroid hormone level, especially the free triiodothyronine level, is closely related to motor symptoms in patients with de novo PD. Further studies are needed to clarify whether the decreased hormone levels have functional roles in motor and non-motor symptoms.

Postprandial hypotension in de novo Parkinson's disease: a comparison with orthostatic hypotension.

BACKGROUND: Postprandial hypotension (PPH) is often associated with Parkinson's disease (PD). However, its mechanism remains to be fully defined. We investigated the mechanism of PPH and compared it with that of orthostatic hypotension (OH). METHODS: The subjects were 37 patients with de novo PD and 10 healthy age-matched controls. We studied changes in blood pressure (BP), plasma norepinephrine concentrations (NE), plasma insulin, plasma glucose concentrations during a 75-g oral glucose tolerance test (75-g OGTT). Changes in BP and NE were also examined with head-up tilt-table testing (HUT). RESULTS: The maximum fall in systolic BP (SBP) on 75-g OGTT (⊿SBPPPH) significantly correlated with that on HUT (r = 0.359, p < 0.05). On 75-g OGTT, ⊿SBPPPH significantly correlated with SBP after 20 min of rest in the supine position (r = 0.394, p < 0.01) and the time in which SBP reached its lowest (r = 0.436, p < 0.01). ⊿SBPPPH did not correlate with NE, plasma insulin and glucose concentrations after glucose loading, but significantly negatively correlated with NE measured after 20 min resting in the supine position (r = -0.347, p < 0.05). Clinical characteristics, including the presence of constipation, did not differ significantly between patients with and those without PPH. CONCLUSIONS: In PD, systemic sympathetic denervation, impaired baroreflex-cardiovagal gain, and insufficiency of compensatory sympathetic nervous activation including lack of baroreflex-sympathoneural gain for postprandial splanchnic vessel pooling seem to be associated with PPH. Systemic sympathetic denervation and baroreflex failure seem to contribute to both pronounced morbidity and the development of PPH and OH.

VPS35 mutation in Japanese patients with typical Parkinson's disease.

Vacuolar protein sorting 35 (VPS35) was recently reported to be a pathogenic gene for late-onset autosomal dominant Parkinson's disease (PD), using exome sequencing. To date, VPS35 mutations have been detected only in whites with PD. The aim of the present study was to determine the incidence and clinical features of Asian PD patients with VPS35 mutations. We screened 7 reported nonsynonymous missense variants of VPS35, including p.D620N, known as potentially disease-associated variants of PD, in 300 Japanese index patients with autosomal dominant PD and 433 patients with sporadic PD (SPD) by direct sequencing or high-resolution melting (HRM) analysis. In addition, we screened 579 controls for the p.D620N mutation by HRM analysis. The p.D620N mutation was detected in 3 patients with autosomal dominant PD (1.0%), in 1 patient with SPD (0.23%), and in no controls. None of the other reported variants of VPS35 were detected. Haplotype analysis suggested at least 3 independent founders for Japanese patients with p.D620N mutation. Patients with the VPS35 mutation showed typical tremor-predominant PD. We report Asian PD patients with the VPS35 mutation. Although VPS35 mutations are uncommon in PD, the frequency of such mutation is relatively higher in Japanese than reported in other populations. In VPS35, p.D620N substitution may be a mutational hot spot across different ethnic populations. Based on the clinical features, VPS35 should be analyzed in patients with PD, especially autosomal dominant PD or tremor-predominant PD.

Reduced cardiac 123I-MIBG uptake reflects cardiac sympathetic dysfunction in de novo Parkinson's disease.

It remains unclear whether cardiac iodine-123-labeled metaiodobenzylguanidine ((123)I-MIBG) uptake is clinically related to autonomic dysfunction on conventional autonomic function testing in de novo Parkinson's disease (PD). We therefore studied the relation between cardiac (123)I-MIBG uptake and cardiovascular autonomic dysfunction in patients with de novo PD. The subjects were 26 patients with de novo PD. The ratio of the average pixel count in the heart to that in the mediastinum was calculated to derive the cardiac (123)I-MIBG uptake. Cardiovascular autonomic function was evaluated on the basis of cardiovascular autonomic response on the Valsalva maneuver (VM), and systolic blood pressure response (SBP) on head-up tilt-table testing (HUT). Patients with de novo PD had significantly reduced cardiac (123)I-MIBG uptake as compared with controls (1.58 ± 0.43 vs. 2.25 ± 0.34, p = 0.0001) and cardiovascular autonomic response on the VM. No significant difference in the fall in SBP on HUT was found between patients with de novo PD and the controls. Cardiac (123)I-MIBG uptake in de novo PD was not significantly related to vasomotor sympathetic function, baroreceptor reflex gain, cardiac parasympathetic function, or the changes in SBP on HUT. Cardiac (123)I-MIBG uptake was, however, significantly related to the blood pressure overshoot in phase IV of the VM (r = 0.648, p = 0.0003). Cardiac (123)I-MIBG uptake began to decrease in association with the reduction in the overshoot of phase IV on the VM. Cardiac (123)I-MIBG uptake clinically reflects cardiac sympathetic dysfunction in de novo PD.

Characterization and localization of side population cells in the lens.

PURPOSE: Side population (SP) cells were isolated and the possibility whether lens epithelial cells contain stem cells was investigated. METHODS: Mouse lens epithelial cells were stained by Hoechst 33342 and then sorted by fluorescence-activated cell sorting (FACS). The expression of stem cell markers in sorted SP cells and the main population of epithelial cells were analyzed by quantitative real-time PCR. Localization of SP cells in the mouse lens was studied by fluorescence microscopy. RESULTS: The sorted cells contained SP cells, which were no longer separable by FACS following treatment with verapamil. The number of SP cells decreased with aging, but the adult mouse lens still contained SP cells. Phase contrast microscopy revealed that SP cells were smaller in size than non-SP cells. SP cells were localized near the equator region in lens epithelial cell layers. SP cells expressed higher levels of the stem cell markers ATP-binding cassette transporter G2 (ABCG2), p75 neurotrophin receptor (p75NTR), nestin (nes), B-cell lymphoma 2 (Bcl2), and cell surface antigen Sca-1 mRNA than the main population cells. These results suggest that SP cells contain a high proportion of stem cells. CONCLUSIONS: The SP cells in the lens contain stem cells, and these stem cells are localized around the germinative zone.

Olfactory dysfunction and cardiovascular dysautonomia in Parkinson's disease.

Several studies have reported that olfactory dysfunction is an early neuropathological manifestation of Parkinson's disease (PD). Reduced cardiac meta-iodobenzylguanidine ((123)I-MIBG) uptake may be one of the earliest signs of PD. We studied the relation of olfactory dysfunction to cardiovascular dysautonomia in patients with PD. The study group comprised 66 patients with PD (70.5 years) and 26 controls (70.3 years) for olfactory assessment, 21 controls (72.1 years) for cardiac (123)I-MIBG scintigraphy and heart rate variability (HRV), assessed using the coefficient of variation for RR intervals (HRV), and 23 controls (69.2 years) for orthostatic blood pressure response. Olfactory function was assessed by the odor stick identification test Japan (OSIT-J), and cardiovascular autonomic function was evaluated by (123)I-MIBG scintigraphy of the heart, the fall in orthostatic blood pressure, and HRV. Patients with PD had a significantly lower OSIT-J score than did the controls (4.1 +/- 3.0 vs. 9.9 +/- 1.7, p = 0.001). The OSIT-J score was unrelated to variables other than gender, including age, disease duration, motor score on the unified Parkinson's disease rating scale, score on the mini-mental state examination, motor phenotype, visual hallucinations, and dopaminergic medication on multiple regression and logistic regression analyses. The OSIT-J score was related to the heart/mediastinum ratio of cardiac (123)I-MIBG uptake, the fall in orthostatic blood pressure, and HRV, after adjustment for other clinical variables. Olfactory dysfunction in PD was, thus, significantly related to both cardiac sympathetic and parasympathetic dysfunction, as well as vascular sympathetic dysfunction. As non-motor symptoms of PD, olfactory dysfunction and autonomic network failure appear to be closely related in PD.

[Maximum phonation time as a tool of screening respiratory muscle weakness in myopathic patients].

UNLABELLED: We examined the relation of maximum phonation time (MPT) and vital capacity (VC) and reviewed the usefulness of MPT as a respiratory function screening. SUBJECTS: 18 healthy adult subjects (8 men and 10 women), and 32 myopathic patients (24 men and 8 women). METHODS: MPT and VC were measured in sitting position. Six patients were tested with and without air stacking by glossopharyngeal respiration. RESULTS: In healthy subjects, MPT was 29.9 +/- 11.8 seconds in men and 21.7 +/- 7.8 seconds in women. Second trials showed good reproducibility. The healthy group had no correlation between MPT and VC. The patient group showed a significant positive correlation between MPT and VC (r2= 0.25, p=0.003). All patients with MPT less than 15 seconds showed VC less than 1.5 l and %VC less than 50%. Air-stacking by glossopharyngeal respiration significantly increased the MPT. CONCLUSIONS: MPT is a useful screening test for respiratory muscle weakness. The patients are easily aware of the effect of air-stacking by glossopharyngeal respiration.

[Palpable orbital subcutaneous masses in chronic inflammatory demyelinating polyneuropathy. MRI and neurophysiological study of multiple peripheral nerve swelling].

We report a 46-year-old woman with chronic inflammatory demyelinating polyneuropathy (CIDP) in whom swelling of the first branch of the trigeminal nerves in the bilateral orbits were observed as subcutaneous masses in the upper eyelids. The disease developed when the patient was 33 years old, and weakness of the four limbs, double vision, unilateral hypoglossal neuroparalysis, and unilateral facial paralysis frequently occurred during the course of the illness. On nerve conduction studies, conduction block was detected in the motor nerves. Steroid therapy and immunoglobulin treatment improved the symptoms. At 43 years old, subcutaneous phymas were noted in the bilateral upper eyelids, and fat-suppressed MRI detected the phymas localized along the upper region of the superior straight muscle in the bilateral orbits, and the muscles were slightly compressed downward. The masses branched in the orbits, and were diagnosed as nerve swelling of the supraorbital nerve, the first branch of the trigeminal nerve. Fat-suppressed MRI also identified nerve swelling of the extracranial maxillary and mandibular nerves. However, the patient had no subjective sensory disturbance in the trigeminal nerve region. Blink reflex did not induce R1 and R2 exhibited low amplitude and delayed latency. MRI confirmed asymmetric nerve swelling in the regions of the bilateral median nerves with motor nerve conduction block. Lumbar MRI detected nerve swelling in the peripheral nerves distant from the lumbar ganglion. MRI detected no nerve swelling in the arachnoid space such as the cervical cord, thoracic cord, or cauda equina. Aggravation of CIDP was treated with steroids and immunoglobulin. Diplopia occasionally appeared, but was not consistent with aggravation of CIDP. The bilateral supraorbital nerves remained unchanged for three years on MRI.