Impact of Istradefylline on Levodopa Dose Escalation in Parkinson's Disease: ISTRA ADJUST PD Study, a Multicenter, Open-Label, Randomized, Parallel-Group Controlled Study.

INTRODUCTION: A higher levodopa dose is a risk factor for motor complications in Parkinson's disease (PD). Istradefylline (IST) is used as adjunctive treatment to levodopa in PD patients with off episodes, but its impact on levodopa dose titration remains unclear. The objective of this study was to investigate the effect of IST on levodopa dose escalation in PD patients with wearing-off. METHODS: This was a multicenter, open-label, randomized, parallel-group controlled study (ISTRA ADJUST PD) in which PD patients experiencing wearing-off (n = 114) who were receiving levodopa 300-400 mg/day were randomized to receive IST or no IST (control). Levodopa dose was escalated according to clinical severity. The primary endpoint was cumulative additional levodopa dose, and secondary endpoints were changes in symptom rating scales, motor activity determined by a wearable device, and safety outcomes. RESULTS: The cumulative additional levodopa dose throughout 37 weeks and dose increase over 36 weeks were significantly lower in the IST group than in the control group (both p < 0.0001). The Movement Disorder Society Unified Parkinson's Disease Rating Scale Part I and device-evaluated motor activities improved significantly from baseline to 36 weeks in the IST group only (all p < 0.05). Other secondary endpoints were comparable between the groups. Adverse drug reactions (ADRs) occurred in 28.8% and 13.2% of patients in the IST and control groups, respectively, with no serious ADRs in either group. CONCLUSION: IST treatment reduced levodopa dose escalation in PD patients, resulting in less cumulative levodopa use. Adjunctive IST may improve motor function more objectively than increased levodopa dose in patients with PD. TRIAL REGISTRATION: Japan Registry of Clinical Trials: jRCTs031180248.

Multimodal treatment, including extracorporeal shock wave therapy, for refractory chronic tension-type headache: a case report.

BACKGROUND: Few reports have described multidisciplinary treatment, including extracorporeal shock wave therapy, for patients with refractory chronic tension-type headache. In this study, we conducted multidisciplinary treatment for a patient with chronic tension-type headache who suffered from chronic headache refractory to treatment. CASE PRESENTATION: The patient was a 45-year-old Japanese male suffering from 20 years of headache. As his headache had worsened recently, he visited a local clinic. With the diagnosis of suspected tension-type headache, its treatment was unsuccessful and he was referred to our hospital. The neurology department confirmed the tension-type headache and prescribed another medication, but he showed no improvement. Then, the patient was referred to the rehabilitation medicine department for consultation. At the initial visit, we identified multiple myofascial trigger points in his bilateral posterior neck and upper back regions. At the initial visit, he was prescribed 10 mL of 1% lidocaine injected into the muscles in these areas. In addition, he received 2000 extracorporeal shock wave therapy into bilateral trapezius muscles, and was instructed to take oral Kakkonto extract granules, benfotiamine, pyridoxine hydrochloride, and cyanocobalamin. Cervical muscle and shoulder girdle stretches and exercises were also recommended. At follow-up treatment visits, we used extracorporeal shock wave therapy to bilateral trapezius muscles, which led to immediate pain relief. After 11 weeks, he was not taking any medication and his headache was subjectively improved and his medical treatment ended. CONCLUSION: A patient with chronic tension-type headache refractory to regular treatment was successfully treated with a multimodal approach including extracorporeal shock wave therapy in addition to standard treatment. For patients with tension-type headache accompanied by myofascial trigger points, it may be recommended to promptly consider aggressive multimodal treatment that includes extracorporeal shock wave therapy.

Evaluating the impact of adjunctive istradefylline on the cumulative dose of levodopa-containing medications in Parkinson's disease: study protocol for the ISTRA ADJUST PD randomized, controlled study.

BACKGROUND: Levodopa remains the most effective symptomatic treatment for Parkinson's disease (PD) more than 50 years after its clinical introduction. However, the onset of motor complications can limit pharmacological intervention with levodopa, which can be a challenge when treating PD patients. Clinical data suggest using the lowest possible levodopa dose to balance the risk/benefit. Istradefylline, an adenosine A2A receptor antagonist indicated as an adjunctive treatment to levodopa-containing preparations in PD patients experiencing wearing off, is currently available in Japan and the US. Preclinical and preliminary clinical data suggested that adjunctive istradefylline may provide sustained antiparkinsonian benefits without a levodopa dose increase; however, available data on the impact of istradefylline on levodopa dose titration are limited. The ISTRA ADJUST PD study will evaluate the effect of adjunctive istradefylline on levodopa dosage titration in PD patients. METHODS: This 37-week, multicenter, randomized, open-label, parallel-group controlled study in PD patients aged 30-84 years who are experiencing the wearing-off phenomenon despite receiving levodopa-containing medications ≥ 3 times daily (daily dose 300-400 mg) began in February 2019 and will continue until February 2022. Enrollment is planned to attain 100 evaluable patients for the efficacy analyses. Patients will receive adjunctive istradefylline (20 mg/day, increasing to 40 mg/day) or the control in a 1:1 ratio, stratified by age, levodopa equivalent dose, and presence/absence of dyskinesia. During the study, the levodopa dose will be increased according to symptom severity. The primary study endpoint is the comparison of the cumulative additional dose of levodopa-containing medications during the treatment period between the adjunctive istradefylline and control groups. Secondary endpoints include changes in efficacy rating scales and safety outcomes. DISCUSSION: This study aims to clarify whether adjunctive istradefylline can reduce the cumulative additional dose of levodopa-containing medications in PD patients experiencing the wearing-off phenomenon, and lower the risk of levodopa-associated complications. It is anticipated that data from ISTRA ADJUST PD will help inform future clinical decision-making for patients with PD in the real-world setting. TRIAL REGISTRATION: Japan Registry of Clinical Trials, jRCTs031180248 ; registered 12 March 2019.

Lewy pathology of the submandibular gland in Lewy body disease: A report of autopsy cases.

Accumulation of phosphorylated α-synuclein in the central and peripheral nervous systems is a histological hallmark of Lewy body disease (LBD), including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and LB-related pure autonomic failure. The submandibular gland is employed as a biopsy site for detecting Lewy pathology; however, the incidence of Lewy pathology in this region in autopsy-proven LBD cases at all stages from an aged Japanese cohort remains unclear. To validate the utility of Lewy pathology of the submandibular gland as a diagnostic biomarker for LBD, we investigated the submandibular gland Lewy pathology in autopsied patients. To determine the specificity, we prospectively evaluated the submandibular gland in 64 consecutive autopsied patients. To determine the sensitivity, we retrospectively assessed the submandibular gland in 168 consecutive autopsied patients who had prodromal or clinical LBD. In the prospective study, Lewy pathology was found in 21 of 64 patients, and nine of those 21 patients had the submandibular gland Lewy pathology. No Lewy pathology was found in 43 patients without CNS Lewy pathology, giving a specificity of 100%. In the retrospective study, Lewy pathology of the submandibular gland was detected in 126 of 168 patients. The sensitivity was 89.1% in PD and 75.4% in DLB. The sensitivity increased with disease progression. These findings support the utility of the submandibular gland biopsy for the pathological diagnosis of LBD.

Monoamine Oxidase B Binding of 18F-THK5351 to Visualize Glioblastoma and Associated Gliosis: An Autopsy-Confirmed Case.

An 86-year-old woman with cognitive impairment and left hemiparesis underwent F-THK5351 PET 4 months before her death. In addition to "normal" off-target binding in the basal ganglia, abnormal accumulation was observed along the pyramidal tract and around the right basal ganglia as ring-shaped uptake that overlapped a gadolinium-enhanced lesion. Postmortem pathological examination revealed that she had glioblastoma multiforme with associated gliosis, in which monoamine oxidase B (MAO-B) activity is increased. In vitro autoradiography of the corresponding lesion demonstrated specific binding of F-THK5351, which was blocked by an MAO-B-selective ligand. Thus, F-THK5351 PET may reflect glioblastomas and associated gliosis by binding to MAO-B.

Effect of istradefylline on mood disorders in Parkinson's disease.

Depression is the most common psychiatric complication in patients with Parkinson's disease (PD). Istradefylline, a new anti-parkinsonian agent with completely different mechanism, improves depression-like symptoms in an experimental disease model; however, there is no report of its effects in PD patients. In this study, the effectiveness of istradefylline for treatment of mood disorders in patients with PD was examined in an open-label trial. Thirty PD patients were enrolled. All patients had scores of higher than cut-off level in at least one of the following batteries: Snaith-Hamilton Pleasure Scale Japanese version (SHAPS-J), Apathy scale, or Beck Depression Inventory-2nd edition (BDI). Following study enrollment, all patients received 20 mg of istradefylline, and the dose was increased to 40 mg after 4 weeks. Results from these 3 batteries and the Unified Parkinson's Disease Rating Scale (UPDRS) score were assessed every 2-4 weeks until 12 weeks and the changes in these scores were analyzed. Following administration of istradefylline, the scores of SHAPS-J, Apathy scale, and BDI were significantly improved over time. Significant improvement was also found in the UPDRS score; however, no significant correlation was observed between the score change in these 3 batteries and UPDRS motor function. This is the first study to show the effectiveness of istradefylline for treatment of mood disorders in PD independent of improvement of parkinsonian motor symptoms. In the future, this should be confirmed in a double-blind placebo-controlled trial.

PML Nuclear Bodies Are Altered in Adult-Onset Neuronal Intranuclear Hyaline Inclusion Disease.

Neuronal intranuclear hyaline inclusion disease (NIHID) is a neurodegenerative disorder characterized by the presence of eosinophilic nuclear inclusions (NIs) in diverse cell lines in systemic organs. Adult-onset NIHID typically manifests with dementia associated with leukoencephalopathy. The detection of NIs in skin biopsies is useful for an antemortem diagnosis. A previous analysis suggested that NIs in NIHID originated from nuclear bodies (NBs), an important nuclear domain related to the ubiquitin-p62-mediated protein degradation system. In this study, we analyzed skin samples from 5 NIHID and 5 control cases immunohistochemically and electron microscopically. In the control cases, small but significant amounts of ubiquitin- and p62-positive intranuclear structures were found. These structures were consistently colocalized with promyelocytic leukemia protein (PML), an essential component of NBs, in particular when activated. The p62- and PML-positive structures were more frequently found in NIHID cases. Activated NBs, having a core and a shell, were observed by electron microscopy in control but not in NIHID cases. Instead, immature and mature filamentous NIs were found only in the NIHID cases. Our results indicate that NBs could not be normally activated in the NIHID, and an abnormal alteration of NBs might be related to the pathogenesis of NIHID.

Malignant Middle Cerebral Artery Infarction Resulting from Dissection of Middle Cerebral Artery.

A 30-year-old man presented with headache, left hemiparesis, and uncal herniation. Magnetic resonance imaging showed acute infarction in the right middle cerebral artery (MCA). Lifesaving craniotomy proceeded because of the uncal herniation. Assessment of brain tissue led to a diagnosis of MCA dissection. His skin biopsy showed ultrastructural abnormalities of dermal connective tissue. This is the unique case that dissection was diagnosed from both a biopsy specimen of the MCA and the dermal connective tissue.

¹¹C-PiB PET imaging of encephalopathy associated with cerebral amyloid angiopathy.

We herein report that the clinical, laboratory, and radiographic features and positron emission tomography (PET) imaging may provide valuable clues to the pathogenesis of cerebral amyloid angiopathy (CAA)-associated encephalopathy, which currently remains unclear. We herein describe two cases of encephalopathy with CAA, with an emphasis on PET imaging with (11)C-Pittsburgh compound B ((11)C-PiB) and (18)F-fluorodeoxyglucose ((18)F-FDG). One case of Alzheimer's disease for which a brain biopsy was performed showed CAA-related inflammation. Another case that had developed sudden sensory aphasia presented with posterior reversible encephalopathy syndrome-like vasogenic edema in the left temporal region with (11)C-PiB uptake and microhemorrhages. (11)C-PiB and (18)F-FDG PET are useful for detecting CAA-associated encephalopathy, including atypical CAA cases.

[A case of isolated mycobacterial focal meningitis diagnosed on brain and meningeal biopsy].

A 76-year-old woman was admitted to our hospital because of convulsions that developed after a 1-month history of progressive right-leg palsy. MRI showed thickening of the meninges with gadolinium enhancement in the left parietal lobe and it revealed pia-subarachnoid space pattern. A lumbar puncture was performed, and cerebrospinal fluid analysis revealed no abnormality. Her serum adenosine deaminase level was elevated (28.7 IU/l). The results of serum cultures were normal. To differentially diagnose collagen disease, infection, malignancy, and inflammation of uncommon causes, we conducted brain and meningeal biopsies on the 15th hospital day. Histopathological examination of the brain tissue showed mainly necrosis and inflammation. There was severe pachymeningeal thickening without necrosis. Although it was difficult to reach a definitive diagnosis, a tissue sample taken from under the leptomeninges tested positive for mycobacterium on Ziehl-Neelsen staining. The results of polymerase chain reaction for mycobacterium were negative in the meningeal tissue. The patient received anti-tuberculous drugs, anti-nontuberculous mycobacteriosis drugs, and corticosteroids to treat Mycobacterium tuberculosis and nontuberculous mycobacterium. After starting treatment, the findings on magnetic resonance imaging improved dramatically, and no convulsions occurred during hospitalization. She was discharged on the 153rd hospital day without any neurological deficit. Because previous studies have reported that isolated mycobacterium meningitis is a diagnostically challenging condition, brain and meningeal biopsies should be considered in patients with gadolinium enhancement in the meninges.

[An advanced case of myopathy and dementia with a new mutation in the valosin-containing protein gene].

We report a 51-year-old man with myopathy and dementia probably caused by a novel mutation of the valosin-containing protein (VCP) gene, in the form of a p.Ala439Pro substitution. At 43 years old, he presented at least 2-year history of weakness of right ankle dorsiflexion. Findings from muscle biopsy suggested distal myopathy with rimmed vacuoles. However, no mutation in the GNE gene was identified. He complained of giving way of the knee, and muscle imaging study showed adipose tissue infiltration in the quadriceps. Ten years later, he was confined to a wheelchair and became reticent and antisocial with slightly impaired memory. A muscle CT revealed atrophy or replacement by adipose tissue in the muscles of neck, trunks and extremities muscles with laterality and variation of the degree. The magnetic resonance imaging of the brain showed bilateral frontal and temporal lobe atrophy with left dominance. Findings were compatible with inclusion body myopathy with Paget's disease of bone and frontotemporal dementia.

[Beneficial effects of rituximab in a case of anti-myelin antibody-associated neuropathy].

We report here in a 61-year-old woman in whom sensory disturbance predominantly affecting the distal portion of the limbs progressed over the course of 1 year. Blood tests showed IgM monoclonal gammopathy as well as the presence of anti-myelin-associated glycoprotein (MAG) antibody. Nerve conduction studies revealed significant prolongation of distal latency, and sural nerve biopsy showed IgM deposition on the myelin sheath. She was diagnosed as suffering anti-MAG neuropathy. High-dose intravenous immunoglobulin therapy proved to be ineffective and her symptoms progressed. Therefore, rituximab was administered and the sensory disturbance improved. Although no detailed studies on rituximab therapy for anti-MAG neuropathy have been reported in Japan, the present findings suggest that rituximab may be more effective than immunoglobulin therapy and other conventional therapies that have been used for autoimmune neuropathies.

Incidence and extent of Lewy body-related alpha-synucleinopathy in aging human olfactory bulb.

We investigated the incidence and extent of Lewy body (LB)-related alpha-synucleinopathy (LBAS) in the olfactory bulb (OB) in 320 consecutive autopsy patients from a general geriatric hospital (mean age, 81.5 +/- 8.5 years). Paraffin sections were immunostained with anti-phosphorylated alpha-synuclein, tyrosine hydroxylase, phosphorylated tau, and amyloid beta antibodies. LBAS was found in 102 patients (31.9%) in the central nervous system, including the spinal cord; the OB was involved in 85 (26.6%). Among these 85 patients, 2 had LBAS only in the anterior olfactory nucleus, 14 in the peripheral OB only, and 69 in both areas. In 5 patients, Lewy bodies were found only in the OB by hematoxylin and eosin stain; 3 of these patients had Alzheimer disease, and all had LBAS. Very few tyrosine hydroxylase-immunoreactive periglomerular cells exhibited LBAS. All 35 LBAS patients with pigmentation loss in the substantia nigra had LBAS in the OB. LBAS in the amygdala was more strongly correlated with LBAS in the anterior olfactory nucleus than with that in the OB periphery. LBAS did not correlate with systemic tauopathy or amyloid beta amyloidosis. These results indicate a high incidence of LBAS in the aging human OB; they also suggest that LBAS extends from the periphery to the anterior olfactory nucleus and results in clinical manifestations of LB disease.

Lewy body pathology involves cutaneous nerves.

Involvement of the peripheral autonomic nervous system is a core feature of Lewy body (LB) diseases, including Parkinson disease (PD), PD with dementia, and dementia with LBs. To investigate the potential use of skin biopsy for the diagnosis of LB diseases, we assessed anti-phosphorylated alpha-synuclein immunoreactivity in peripheral nerves in samples of skin from the abdominal wall and flexor surface of the upper arm in 279 prospectively studied consecutively autopsied patients whose data were registered at the Brain Bank for Aging Research between 2002 and 2005. Positive immunoreactivity was demonstrated in the unmyelinated fibers of the dermis in 20 of 85 patients with LB pathology in the CNS and the adrenal glands, the latter representing a substitute for peripheral autonomic nervous system sympathetic ganglia; no reactivity was seen in 194 patients without CNS LB pathology. In 142 retrospectively studied patients autopsied from 1995 onward who had subclinical or clinical LB disease, the sensitivity of the positive skin immunoreactivity was 70% in PD and PD with dementia and 40% in dementia with LBs. Skin immunoreactivity was absent in cases of multiple-system atrophy, progressive nuclear palsy, and corticobasal degeneration. We demonstrate for the first time that the skin is involved and may be a highly specific and useful biopsy site for the pathological diagnosis of LB diseases.

[Skin collagen abnormalities in a Japanese patient with extracranial internal carotid artery dissection followed by extracranial vertebral artery dissection].

A 41-year-old man with hypertension and hyperlipidemia who complained of left hemiparesis after a temporal headache was admitted to our hospital. A cervical MRI with gadolinium enhancement revealed an intramural hematoma is compatible with right extracranial internal carotid artery dissection. Two weeks later, he complained of sudden onset of pain in the right side of his neck. The right extracranial internal carotid artery dissection followed by the right extracranial vertebral artery dissection was diagnosed. Spontaneous cervical artery dissection (SCAD) is one of the causes of stroke in young adults. The pathogenesis of SCAD remains unknown. Minor trauma like an excessive sneeze, migraine, and connective tissue disorders such as fibromuscular dysplasia and Ehlers-Danlos syndrome are well-known as risk factors for SCAD. Pathologically skin collagen abnormalities have been seen in German patients with SCAD without clinical evidence for any specific connective tissue disorder. We examined the ultrastructural morphology of the Japanese patient's dermal connective tissue components by electron microscopy. The patient's collagen fibers contained fibrils with highly variable diameters, and there were other ultrastructural abnormalities, including flower-like fibrils and large-diameter composite fibrils. This is the first report of a case of ultrastructural abnormalities of dermal connective tissue in a Japanese patient with SCAD.

[A case of aphasia with preserved repetition due to anterior choroidal artery territory infarction].

A 55-year-old right-handed male patient with atrial fibrillation was admitted to our hospital because of a sudden disturbance of consciousness and right hemiparesis. Neurological examinations revealed left conjugate deviation of the eyes, aphasia, right hemianopsia without macula sparing using a Goldmann perimeter, right hemianesthesia, and right hemiparesis. Magnetic resonance imaging showed low intensity areas (left posterior limb of internal capsule, left cerebral peduncle of middle brain, a part of left substantia nigra, left amygdala, ventral posterior lateral nucleus and ventral anterior nucleus of left thalamus, left lateral geniculate body, and left occipital lobe) in T1 weighted image, due to the infarct in the left anterior choroidal artery territory. Aphasia in this case was accompanied with non-fluent speech, good repetition, naming deficits, and perseveration. We suggest that aphasia with anterior choroidal artery syndrome cannot be classified using the conventional system, and emphasize the importance of accurate descriptions of the symptoms characteristic of aphasia with anterior choroidal artery.

[A case of cardiac myxoma presenting with multiple cerebellar hemorrhages and elevation of interleukin-6 in the cerebrospinal fluid].

We report a 25-year old man with cardiac myxoma presenting with multiple cerebellar hemorrhages and elevation of interleukin-6 (IL-6) in the cerebrospinal fluid (CSF). The patient was first admitted to our hospital because of cerebral infarctions at the age of 23. After systemic exploration he was diagnosed as cardiac myxoma. In this patient, the serum level of IL-6 was elevated. The cardiac myxoma was resected and the serum IL-6 level returned to normal. His neurological symptoms improved almost to normal and he was discharged. The patient had been well for two years until he developed headache at the age of 25. Brain MRI revealed multiple cerebellar hemorrhages that overlaid old infarctions. The hemorrhages enlarged in a three months period and his headache became worse, and then he was admitted again. The IL-6 value was normal in serum at that time, but it was elevated in the CSF. The CSF IgG index was also elevated. Cerebral angiograms showed no abnormal vessel in the infratentorium, while multiple fusiform aneurysms were found in both middle cerebral arteries. A transesophageal echocardiography revealed no recurrence of cardiac myxoma. Craniotomy was performed and intracerebellar hematomas were removed. Histopathological examination showed only old and recent bleedings; no metastatic myxoma tissue was found. Although no myxoma tissue was found in biopsy specimen, it seemed reasonable that an elevated level of IL-6 in the CSF was due to metastasized intracranial myxoma, which caused cerebellar embolism, and then invaded the vessel walls and continued to grow. In reviewing the literature we have found no reported case of cardiac myxoma with analysis of IL-6 value in the CSF. We speculate that the level of IL-6 in the CSF might be a good marker for the neurological manifestations of cardiac myxoma.