Masago Tsukaguchi

Abnormalities of rate-corrected QT intervals in Parkinson's disease—a comparison with multiple system atrophy and progressive supranuclear palsy

A number of patients with Parkinsons disease (PD) and multiple system atrophy (MSA), in whom sudden death does occur occasionally, have QT or rate-corrected QT (QTc) interval prolongation on electrocardiogram (ECG). Although these QT or QTc interval abnormalities are likely related to autonomic dysfunction, the pathophysiology remains unknown. The aim of this study was to compare the degree of QTc interval prolongation among akinetic-rigid syndromes, namely PD and related disorders, and to evaluate the relationship between QTc prolongation and severity of autonomic dysfunction. Thirty-four patients with PD, 22 with MSA, 11 with progressive supranuclear palsy (PSP) and 30 healthy controls underwent standard autonomic function tests, and electrocardiography variables (RR, QT and QTc intervals) were measured by an ECG recorder with an automated analyzer. The relationship between QTc interval and cardiovascular reflex tests were also analyzed. Orthostatic hypotension and decreased heart rate in response to respiratory stimuli were prominent in MSA, while these were relatively mild in PD. Unlike the RR and QT intervals, the QTc interval significantly differed among all groups (p<0.01). The QTc interval was significantly prolonged in PD (409+/-17 ms; p<0.001) and MSA (404+/-14 ms; p<0.05) compared with healthy controls (394+/-19 ms). Neither autonomic dysfunction nor QTc interval prolongation was evident in PSP. QTc intervals and cardiovascular reflexes did not correlate, except for Valsalva ratio. The QTc interval was obviously prolonged in PD patients to an extent that could not be accounted for simply by autonomic dysfunction levels. MSA patients showed slightly prolonged QTc intervals in spite of marked cardiovascular autonomic dysfunction. Abnormalities of the QTc may reflect the degeneration of cardioselective sympathetic and parasympathetic neurons that cannot be fully captured by cardiovascular autonomic function tests.

Effects of daily water drinking on orthostatic and postprandial hypotension in patients with multiple system atrophy.

ObjectiveIt has been demonstrated that the increased blood pressure (BP) caused by a single dose of water alleviates orthostatic hypotension (OH) and postprandial hypotension (PPH) in patients with autonomic failure (AF). The aim of this study was to evaluate the practical effect of daily water drinking on OH and PPH in the morning when patients with AF are usually most affected.MethodsIn five patients with multiple system atrophy (MSA) characterized by intractable OH and PPH, we measured seated, standing and postprandial BP in the morning without and with ingestion of 350 ml tap water at 07.30 hours for seven successive days. The changes from the basal BP level at 07.30 hours (ΔBP) were assessed as an index of the effect of water drinking.ResultsWater drinking elicited a rapid pressor response in all patients. The ΔBP during sitting, standing and after a meal following water drinking (day 1 and day 7) was significantly higher than without water drinking (day 0). The effects of reducing OH and PPH on day 7 were equivalent to those on day 1. No adverse effects associated with daily water drinking were observed, except later diuresis, which occurred in one patient.ConclusionsDaily water drinking demonstrated constant pressor effects in the morning with no severe adverse effects in MSA patients. This finding suggests that water drinking should be tried as a practical measure to prevent or reduce OH and PPH.

Painful legs and moving toes syndrome associated with herpes zoster myelitis

A 75-year-old woman developed painful legs and moving toes syndrome (PLMT) 16 months after the onset of herpes zoster (HZ) myelitis. Although the scattered extensive lesions due to HZ myelitis were observed to be eccentric near the posterior horn on MRI, these changes had disappeared upon the development of PLMT. Combined median and tibial nerve somatosensory evoked potentials demonstrated abnormal findings only in the tibial nerve stimuli, suggesting that a severe alteration occurred in the somatosensory fibers coming selectively from the lower legs. These findings suggest plasticity in the ascending somatosensory pathway including the posterior horn cells, probably involving the interneuron networks, for the lower legs may underlie the development of PLMT associated with HZ myelitis.

Absence of orbito-ocular signs in dural carotid–cavernous sinus fistula with a prominent anterior venous drainage

A 55-year-old woman developed an intractable right orbitofrontal headache. The symptoms subsided spontaneously 2 months after onset, but diplopia due to right abducens nerve palsy had occurred, and gradually worsened. Orbito-ocular signs were never observed throughout the clinical course. Brain MRI and MR angiography demonstrated abnormal signal changes corresponding to the right cavernous sinus. Angiography confirmed a dural carotid-cavernous sinus fistula (CCF) with three directional drainage routes in the arterial phase. Although the most prominent draining vein was the superior ophthalmic vein (SOV), an outflow with a high flow rate into the angular facial vein prevented prolonged enhancement of the SOV in the venous phase. These findings suggest that the absence of orbito-ocular signs in dural CCF with an anterior venous drainage could be attributed to the relief of venous hypertension of the SOV.

Paraneoplastic necrotizing myelopathy in a patient with advanced esophageal cancer : An autopsied case report

We report the first autopsied case of paraneoplastic necrotizing myelopathy associated with esophageal cancer in the literature. The patient had acute flaccid paraplegia and urinary retention, and had a good recovery of strength of both legs in response to corticosteroids. MRI showed a characteristic lesion with post-gadolinium enhancement of the cervical to mid-thoracic spinal cord at the onset, which has never been reported. Taken together, these results suggest that there is an underlying autoimmune mechanism in paraneoplastic necrotizing myelopathy.

Improvement of cardiovascular autonomic dysfunction following anti–copper therapy in Wilson’s disease

Sirs: Detailed autonomic function tests (AFTs) have recently revealed significant abnormalities in almost one-third of patients with Wilson’s disease (WD) [1–4]. However, the time course and reversibility of the autonomic dysfunction in WD are unknown [5]. In addition, it remains unclear whether or not the autonomic dysfunction results from central nervous system lesions. We report a patient with WD who underwent AFTs before and after anti-copper therapy. A 47-year-old woman was referred to our outpatient clinic because of tremors in her right arm and leg, which developed at 43 years of age. She had had a history of transient liver damage of unknown origin at 27 years of age. She had no family members with neurological and/or hepatic problems. She was alert, oriented and cooperative. The neurological examination revealed slight dysarthria and resting, postural and intention tremor involving the head and upper and lower extremities. A full-scale IQ on the Wechsler Adult Intelligence Scale-Revised Version (WAIS-R) was 78 (verbal, 89; performance, 68). A KayserFleischer (K-F) ring was found by slit lamp examination. Laboratory investigations showed decreased serum copper (20 μg/dl) and ceruloplasmin (3.0 mg/dl), and elevated urinary copper excretion (868 μg/day). The liver enzymes were normal. A liver biopsy confirmed the diagnosis of WD. T2-weighted magnetic resonance imaging (MRI) showed an increased signal in the thalamus, hypothalamus, midbrain and pons, and a decreased signal intensity in the putamen and globus pallidum (Fig. 1). Apart from lightheadedness upon standing, no clinical features of autonomic dysfunction were observed. AFTs revealed orthostatic hypotension upon a 60° head-up tilt, decreased pressor responses to isometric exercise and mental arithmetic and decreased heart rate responses to deep breathing and the Valsalva maneuver. A pressure “overshoot” during phase IV of the Valsalva maneuver was absent (Table 1). She had no other causes of autonomic dysfunction. Since she found treatment with penicillamine was intolerable, triethylene tetramine dihydrochloride (trientine) was administered alternatively at 2000 mg/day as a maintenance dose. Consequently, her tremor nearly disappeared within 24 months. A follow-up MRI made 36 months later revealed that the increased signal intensity lesions had disappeared (Fig. 1). The WAIS-R showed marked improvement (full-scale, 100; verbal, 99; performance, 101). Reassessment of AFTs no longer revealed orthostatic hypotension, and cardiovascular responses to pressor and respiratory stimuli were normal or increased toward the normal levels. The phase IV of the Valsalva maneuver showed a slight pressure “overshoot” (Table 1). In this case, AFTs before the anti-copper therapy revealed the latent sympathetic and parasympathetic dysautonomia, similar to previous reports [1–4]. In addition, this case showed for the first time LETTER TO THE EDITORS

Low-dose tacrolimus for two cases of myasthenia gravis with invasive thymoma that relapsed shortly after thymectomy.

Two patients with myasthenia gravis (Ossermann IIb) involving invasive thymoma who underwent extensive thymectomy manifested myasthenic crisis shortly after the procedure; however, both patients were treated with intravenous immunoglobulin and recovered from myasthenic crisis that had been deteriorating for about 1 week. Subsequently, the patients were administered a low-dose of tacrolimus (3 mg/day) in addition to prednisolone. Several months later, tacrolimus continued to control fluctuations of myasthenic symptoms and maintained remission in these patients. The serum titer of anti-Ach-receptor antibodies decreased in parallel with clinical improvement due to tacrolimus, and we accordingly reduced the dosage of prednisolone. Tacrolimus is a new immunosuppressive agent acting through the selective inhibition of helper-T-cell activation that can be reduced dosage of steroids and can maintain remission of myasthenia gravis with invasive thymoma.

Impaired novelty P3 potentials in multiple system atrophy--correlation with orthostatic hypotension.

Although neuropsychological tests demonstrate frontal lobe dysfunction in multiple system atrophy (MSA), assessment of frontal function using event-related brain potentials (ERPs) has not been sufficiently performed in MSA. The correlation between frontal lobe dysfunction and orthostatic hypotension (OH), which is known to cause frontal hypoperfusion, remains unclear. Our objectives were to assess frontal lobe dysfunction in MSA patients using ERPs and to elucidate the relevance of OH to changes in ERPs. Nine consecutive patients with MSA and nine age- and gender-matched healthy controls were compared by performance in the Wisconsin Card Sorting Test (WCST) and somatosensory ERPs to target and novel stimuli, namely, parietal maximal P3 (target P3) and fronto-central P3 (novelty P3), respectively. The correlation between novelty P3 and OH was evaluated in the MSA group. The MSA group showed a poorer performance in categories achieved (CA), total errors (TE) and perseverative errors by Nelsons (PEN) method in the WCST compared with the control group (CA and PEN: p<0.01; TE: p<0.02). Novelty and target P3s in the MSA group showed significantly prolonged latency (novelty: p<0.05; target: p<0.01) and reduced amplitude (novelty: p<0.02; target: p<0.01) compared with the control group. There was a significant negative correlation between novelty P3 latency and a drop in systolic blood pressure (r=0.76; p<0.02). Abnormalities of novelty P3 in the MSA group might reflect frontal lobe dysfunction, namely failure of attentional set-shifting, that was identified by the WCST. OH may play a role in the development of frontal lobe dysfunction in MSA.

The close relationship between life-threatening breathing disorders and urine storage dysfunction in multiple system atrophy

Survival of multiple system atrophy (MSA) depends on whether a variety of sleep-related breathing problems as well as autonomic failure (AF) occur. Since the brainstem lesions that cause respiratory and autonomic dysfunction overlap with each other, these critical manifestations might get worse in parallel. If so, the detection of AF, which is comparatively easy, might be predictive of a latent life-threatening breathing disorder. In 15 patients with MSA, we performed autonomic function tests composed of postural challenges and administered a questionnaire on bladder condition, as well as polysomnography and laryngoscopy during wakefulness and under anesthesia. Polysomnographic variables such as the apnea-hypopnea index (AHI) and oxygen saturation (SpO2) and the findings of laryngoscopy were compared with the degree of cardiac and urinary autonomic dysfunction. AHI, mean SpO2 and the lowest SpO2 showed significant correlations with urine storage dysfunction. In addition, patients with vocal cord abductor paralysis (VCAP) or central sleep apnea (CSA) contributing to nocturnal sudden death had more severe storage disorders than those without. On the other hand, no significant relationship between polysomnographic variables and orthostatic hypotension was observed except in the case of mean SpO2. These results indicate that life-threatening breathing disorders have a close relationship with AF, and especially urine storage dysfunction. Therefore, longitudinal assessment of deterioration of the storage function might be useful for predicting the latent progress of VCAP and CSA.

Assessment of autonomic dysfunction of multiple system atrophy with laryngeal abductor paralysis as an early manifestation

Laryngeal abductor palsy (LAP) is common in the advanced stages of multiple system atrophy (MSA). However, occurrence of LAP in the early stages might make a diagnosis of MSA difficult. To search for a clue to diagnosis of MSA with LAP as an early manifestation, we assessed the clinical features of autonomic dysfunction and the central cardiovascular control circuits in two MSA patients who had LAP as a cardinal symptom in the early stages. Development of autonomic dysfunction was preceded or followed by LAP. The autonomic symptom occurring predominantly in the earliest stages was urinary disturbance rather than orthostatic hypotension. Although screening cardiovascular autonomic function tests did not conclusively indicate a diagnosis of MSA, vasopressin release in response to head-up tilt and growth hormone response to clonidine administration demonstrated inappropriate responses, suggesting that the noradrenergic neurons of the caudal ventrolateral medulla were impaired. Diagnosis of atypical MSA with LAP in the early stages might be accelerated by a detailed investigation focused on urinary symptoms and neuroendocrine approaches.