The Japanese POEMS syndrome with Thalidomide (J–POST) Trial is a phase II/III multicenter, double–blinded, randomized, controlled trial that aims to evaluate the efficacy and safety of a treatment with thalidomide in POEMS (crow–Fukase) syndrome. In this editorial, thoughts, opinions, and efforts to perform this investigator–lead clinical trial are described. A clinical trials are tough work, requiring a large amount of time, effort, and money, but it also give a great achievement for patients with intractable disease, and doctors and medical staffs involved in the trial. The advantage for the investigators includes expanding motivation for better and update understanding of the disease, as well as growing as a physician. The idea for novel treatments is more likely to be arising from young neurologists. Definitely this approach is necessary for rare diseases. The Japanese Society of Neurological Therapeutics should play an important role in the spread of clinical trial with novel treatments.

After the report of 5 major randomized controlled trials (ESCAPE, EXTEND–IA, SWIFT–PRIME, MR–CLEAN, REVASCAT), adding mechanical thrombectomy on the t–PA therapy was thought to be acceptable. Mechanical thrombectomy might come back to the front page of the acute stroke therapy guidline. With the elongation of t–PA therapy to 4.5 h after onset of the ischemic stroke, the new era started for the acute stroke therapy. Although the study showed good results for mechanical thrombectomy, it should be emphasized that those studies were built on the conditions of 1) the use of stent type device, 2) selection of the patients with MRI or CT, 3) shortening of the time to apply devices.

The Japanese guidelines for the management of stroke 2015 was published. It involved important evidences, searched from more than 23000 references for the stroke therapy. The classification of evidence levels were also improved.

Dementia affects over 35 million people in the world with a rapidly increasing prevalence. Alzheimer's disease (AD) is the most common form of dementia.

No fundamental treatment for AD has been established, and novel therapeutic strategies are pursued extensively. This progress has led to the development of numerous therapeutic strategies in the clinical testing. A long–term randomized controlled trial suggested the beneficial effects of multidomain lifestyle–based interventions to maintain cognitive functioning, Although humanized monoclonal antibodies that bind amyloid b failed to improve cognition in patients with AD, several other promising trials are currently ongoing. In patients with dementia with Lewy bodies, it has been reported that lack of interferon–β signaling causes α–synuclein pathology. In addition, new therapeutic strategies have been reported in prion disease and Huntington disease. This review overviews recent advances in basic and clinical research in dementia.

Recent advances in the treatment of neurological infections are described based on reports published in 2014.

Cochrane Database Systemic Review reported the effect of adjuvant corticosteroid therapy in acute bacterial meningitis. Corticosteroids significantly reduced hearing loss and neurological sequelae, but did not reduce overall mortality. It recommended the use of adjunctive dexamethasone in patients with suspected or proven community–acquired bacterial meningitis, but only in high–income countries. The European research group reported causative pathogens, clinical characteristics, and outcome of adult community–acquired bacterial meningitis after the introduction of adjunctive dexamethasone treatment and nationwide implementation of paediatric conjugate vaccines. The incidence of adult bacterial meningitis has decreased substantially, which is partly explained by herd protection by paediatric conjugate vaccines. Adjunctive dexamethasone treatment was associated with substantially improved outcome.

Following standard treatment with intravenous acyclovir for PCR–confirmed herpes simplex encephalitis (HSE), Effect of an additional 3–month course of oral valacyclovir therapy was evaluated as measured by neuropsychological testing 12 months later. However, they did not show a benefit of long–term valacyclovir therapy. Recent reports showed that some patients with herpes simplex encephalitis (HSE) developed autoantibodies against NMDAR, in especially relapsing HSE. The clinical and immunologic features of patients with immune–mediated relapsing symptoms post–herpes simplex encephalitis were assessed. The teenage and adult patients developed severe psychiatric/behavioral symptoms or refractory status epilepticus, however, all younger children developed choreoathetosis. As immunotherapy can be highly effective, prompt diagnosis is important.

Microbiological confirmation cannot be obtained in approximately two–third patients with tuberculous meningitis. The epidemiological, clinical, cerebrospinal fluid, and imaging parameters among patients with tuberculous meningitis were assessed. Among 118 cases of tuberculous meningitis, there were 36% of definite, 50% of probable, and 14% of possible cases. Severe disability, cerebrospinal fluid cells >100 mm³, and basal exudates were significantly related to definite diagnosis of tuberculous meningitis. Microbiologically confirmed tuberculous meningitis is associated with poorer outcome.

Earlier antiretroviral therapy (ART) initiation in cryptococcal meningitis resulted in higher mortality compared with deferred ART initiation. The immune pathological study showed that early ART initiation in cryptococcal meningitis increased CSF cellular infiltrate, macrophage/microglial activation, and T helper 2 responses within the central nervous system. An increased mortality from early ART would be immunologically mediated.

The triple combination therapy interferon–α, valproic acid, and prednisolone in patients with HTLV–I–associated myelopathy/tropical spastic paraparesis (HAM/TSP) was evaluated. As the data showed that the triple therapy improved motor dysfunction of the lower extremities as well as reduced HTLV–I provirus levels in peripheral blood, it could be a potential as a new therapeutic tool for HAM/TSP patients.

Recent advances and new evidences related to treatment for multiple sclerosis (MS) were reviewed. In year of 2015, glatiramer acetate has been approved in Japan. New biological reagents have been developed in these several years, however, it seems very important to reconsider self injection agents such as interferon beta 1a/1b, or glatiramer acetate. They are still working well and very valuable.

From such point of view manuscripts especially regarding optimization of disease modifying therapy for MS were reviewed.

We review reports published in 2015 providing new information on management of Parkinson's disease (PD) and related disorders.

We report here the outcome of this new medical management of PD. Coenzyme Q10 improved motor symptoms in PD patients with wearing–off phenomenon. Pioglitazone, which is shown to have a neuroprotective effect in pre–clinical study, and neurturin, a neurotrophic factor, did not show symptom relieve nor inhibit the disease progression. Multidisciplinary rehabilitation, multi–dimensional balance programme and repetitive transcranial magnetic stimulation improved balance, gait performance and motor function. For treatment of motor fluctuation, ADS–5102, an amantadine extended release capsule, and eltoprazine, a 5–HT1A/B agonist, reduced levodopa–induced dyskinesia. Opicapone, a catechol–O–methyltransferase inhibitor, reduced off time.

In studies aimed at improvement of non–motor functions in PD, transcutaneous tibial nerve stimulation reduced lower urinary tract symptoms such as urgency and nocturia. Droxidopa improved orthostatic hypotension, but efficacy lasted only one week. Injection of botulinum toxin type A into the parotid glands was effective in reducing drooling. Patients with chronic pain reported significant relief with prolonged release, oral formulation oxycodone combined with naloxone. Meta–analysis for treatment of cognitive impairment in PD showed cholinesterase inhibitors, aside from memantine, were effective. Exercise training such as modified Fitness Counts (mFC) and Progressive Resistance Exercise Training (PRET) improved attention and working memory.

For treatment of parkinsonian type multiple system atrophy, rasagiline ― shown to have neuroprotective effects in preclinical studies ― did not show clinical effectiveness for multiple system atrophy.

We reviewed the recent advances in therapeutics of spinocerebellar degeneration and multiple system atrophy that were published in 2015. Various clinical trials were carried out in 2015. However, the therapeutic reports did not provide much evidence. Some interesting clinical trials were reported, and further developments are expected. The therapeutic studies investigating a new pathomechanism were reported in animal and/or cell culture studies. We expect that these results will be translated to patients with these disorders.

Amyotrophic lateral sclerosis (ALS) is the most rapidly progressive motor neuron disease (MND) in adults, characterized by the selective death of motor neurons in the motor cortex, brainstem and spinal cord. Only supportive care and riluzole are available worldwide to date. This review provides a general overview of preclinical and clinical advances in 2015 and summarizes the literature regarding emerging therapeutic approaches. The topics include research using next–generation sequencing, progress in the pathomechanism of C9ORF72–mutated ALS, therapeutic strategies on mitochondrial pathology, novel investigation of therapies from Japan, strategies focusing on growth factors and neuro–inflammations, therapeutic strategies using iPS cells. We also discuss about the biomarkers and the problems of the design of clinical trials.

The aim of this paragraph is to introduce recent advances in the studies of gliomatosis cerebri, intravascular lymphoma, lymphomatoid granulomatosis and neurosarcoidosis to neurological clinicians based on reports published in 2015. Any four are very rare, and their neurological manifestations are non–specific, hence they are difficult to diagnose, in early phases.

Regarding gliomatosis cerebri, younger patients showed good performance scores before therapy, underwent combined chemotherapy and had good survival outcomes. Diagnosing intravascular lymphoma requires considerable labor because it does not form a mass. In 2015, cases where successfully detected by endoscopic biopsy and nasal biopsy, were reported. Both biopsies are minimally invasive and can be recommended hereafter. A rare case of a patient with primary cerebral lymphomatoid granulomatosis which caused various neurological symptoms and progressed to methotrexate–associated lymphoproliferative disease, suggests that clonal analysis of the specimens are of importance to plan a treatment strategy. In diagnosing neurosarcoidosis, analysis of angiotensin converting enzyme from serum or cerebrospinal fluid did not show accurate results even though they were much anticipated. In the treatment of neurosarcoidosis, immunosuppressannts, monoclonal antibodies and intravenous immunoglobulin therapy were proposed as part of a combination therapy or second line therapy.

In 2015, several studies about CIDP with antibodies to paranodal proteins were reported. Of the 533 patients with CIDP, 13 (2.4%) had IgG4 antibody to contacin–1. Three of 13 patients showed subacute symptom onset. All of the patients presented with sensory ataxia. Six of 10 anti–contactin–1 antibody–positive patients had poor response to IVIg, whereas 8 of 11 antibody–positive patients had good response to corticosteroids. The clinical features of CIDP with anti–neurofascin–155 antibody were reported. Anti–neurofascin–155 IgG4 antibodies were detected in 18% (9/50) of CIDP patients. Anti–neurofascin–155 antibody–positive CIDP patients had younger onset age (p＜0.0001), higher frequency of drop foot (p＝0.0242), tremor (p＝0.03), and DADS phenotype (p＝0.0014). Greater cervical root diameter on MRI neurography (p＝0.002) and higher CSF protein levels (p＜0.0001) were observed. Improvement of polyneuropathy following autologous stem cell transplantation (ACST) for sixty patients with POEMS syndrome was reported. After ACST, the Neuropathy Impairment Score improved from 66 to 48 points at 12 months and to 30 points at most recent follow–up (p＜0.0001). The mRS score improved from 3 to 1.5 (p＜0.0001). VEGF levels decreased from 452 to 63.5pg/mL (p＜0.0001). The ulnar CMAP improved from 4.3 to 7.6mV (p＜0.0001) and CV improved from 34 to 51m/s (p＜0.0001). The clinicopathologic features of 18 patients with folate–deficiency neuropathy were reported. Those patients presented with low serum folate levels but normal blood thiamine and serum cobalamin levels in the absence of chronic alcoholism. Folate–deficiency neuropathy was characterized by slowly progressive polyneuropathy with predominant involvement of the lower extremities, with a tendency to manifest as sensory rather than motor neuropathy and predominant deep rather than superficial sensory loss, which was different from thiamine–deficiency neuropathy.

Articles in 2015 on treatments for autonomic nervous system disorders were reviewed.

1. Orthostatic hypotension (OH) : Droxidopa had an improvement in some clinical symptoms due to OH in patients with Parkinson's disease, multiple system atrophy, pure autonomic failure and nondiabetic autonomic neuropathy.

2. Constipation : Polyethylene glycol and lubiprostone were effective for the constipation due to slow colonic transit in PD. Management of constipation secondary to defecatory dysfunction due to pelvic floor dyssynergia could be done by levodopa or apomorphine injections, botulinum toxin type A injection into the puborectalis muscle.

3. Postural tachycardia syndrome : Inspiratory resistance through an impedance threshold device improved heart rate control in patients with postural tachycardia syndrome during upright posture.

4. Vasovagal syncope : Non–pharmacologic treatments including physical counterpressure maneuver and tilt–training and pharmacologic treatments with beta–blocker, fludrocortisone, midodrine and serotonin transporter inhibitors were effective in patients with vasovagal syncope.

5. Urinary disturbance : β₃–adrenoceptor agonist mirabegron improved the symptoms of overactive bladder (OAB). Antimuscarinics such as solfenacin, imidafenacin, fesoterodine or oxybutynin patch, provided an improvement of OAB. Treatment with solifenacin plus tamsulosin improved the storage and voiding symptoms. Combination treatment with mirabegron and solifenacin improved OAB symptoms. Accupuncture was safe with significant improvements of overactive bladder symptoms. BoNT/A and A/Ona showed benefits in treatment of refractory OAB. Percutaneous tibial nerve stimulation and sacral nerve stimulation showed effectiveness for treatment of OAB.

6. Hyperhidrosis : Oxybutynin for treating plantar hyperhidrosis and topical glycopyrrolate for treatment of facial hyperhidrosis were effective. A combination of BoNT/A, B and anticholinergics improved compensatory hyperhidrosis after sympathectomy. Video–assisted thoracic sympathicotomy for the treatment of palmar and axillary hyperhidrosis showed the long–term effectiveness. Sympathotomy by clamping at T3 was less effective in reducing the primary symptom of postoperative palmar sweating, but induced less compensatory sweating than did sympathotomy by cutting at T3. Tumescent suction curettage was an effective and safe treatment for axillary hyperhidrosis.

We reviewed major bibliographic references pertaining to headache (migraine and cluster headache) and epilepsy treatments, which were predominantly published in 2015.

Calcitonin gene–related peptide (CGRP) plays a major role in the pathophysiology of migraine headaches. In 2014, the results of phase II clinical studies of two CGRP antibodies, LY2951742 and ALD403, were reported, and both antibodies demonstrated efficacy. TEV–48125, administered by subcutaneous injection every 28 days, seemed to be tolerable and effective, thus supporting its further development for preventive treatment of chronic migraine in a phase III trial. As these CGRP antibodies have high tolerability and cause few serious adverse reactions, they are expected to serve as the next generation of prophylactic drugs for migraine. A study demonstrated that simvastatin plus vitamin D was effective for preventing headaches in adults with episodic migraines. Given the ability of statins to repair endothelial dysfunction, this economical approach may also reduce the increased risk of vascular diseases among migraineurs. An open–label observational cohort study included patients with cluster headaches (11 chronic, 8 episodic), including 7 who were refractory to drug treatment. A device, known as the gamma–core, was used to treat and prevent individual attacks. Ten patients reduced their acute use of high–flow oxygen therapy by 55% and 9 reduced their triptan use by 48%. The prophylactic use of the device resulted in substantial reduction in the estimated mean attack frequency from 4.5/24h to 2.6/24h after treatment.

Over the last year, several epilepsy studies published might soon influence our clinical decisions. A unique study this year was a clinical trial of bumetanide for the treatment of seizures in neonates with hypoxic–ischemic encephalopathy. Fourteen infants were included in the study ; they received bumetanide doses of 0.05mg/kg to 0.3mg/kg, together with phenobarbital. Eleven survived, but none had outcomes that met efficacy criteria.

A 60–year–old man was admitted to our hospital with a diagnosis of pneumococcal meningitis. Even though his meningitis had become less severe with antibiotic administration, the results of echocardiography indicated severe aortic regurgitation and prolapse. The progress of his recovery was considered good, but on the 13th day of his hospitalization, he experienced a relapse with worsening of inflammatory findings. Subsequently, his respiratory condition deteriorated and his symptoms rapidly progressed in a manner consistent with heart failure. We diagnosed his condition as valvular damage and acute heart failure caused by infectious endocarditis. Aortic valve replacement and aortic root angioplasty were performed on the 22nd day of hospitalization, and he was discharged from the hospital on 57^th day of hospitalization.

Despite receiving appropriate treatment, pneumococcal pneumonia and meningitis are sometimes complicated by infectious endocarditis. Classically, the association of pneumococcal meningitis, pneumonia and infectious endocarditis is known as Austrian syndrome. It is thought that heavy users of alcohol and hosts with compromised immunity tend to be at risk for this syndrome, but this patient had no such risk factors. In patients with pneumococcal infection, even those with no risk factors, if symptoms worsen it is necessary to keep this triad in mind and conduct physical examination carefully such as auscultation of heart murmur as for a thorough evaluation.

A 69–year–old female experienced higher brain dysfunction, including impaired visuospatial and constructional function and disorientation, 2 years after the onset of Parkinson's disease (PD). After 4 weeks of cognitive rehabilitation (CR), rivastigmine patch therapy was administered along with CR for an additional 4 weeks. After the initial 4 weeks of CR, her attention/executive function and visuospatial and constructional function were improved，as evidenced by her trail making test – B score and her ability to capture the size of three–dimensional objects measured by the behavioural inattention test (BIT). After the full 8 weeks of treatment, including rivastigmine, her visuospatial and constructional function were further improved along with the ability to capture shapes, as measured by BIT and the Alzheimer's Disease Assessment Scale. We concluded that an improvement in attention/executive function achieved by the CR along with the additional improvement in visuospatial and constructional function achieved through the addition of rivastigmine patch therapy led to an improvement in activities of daily living.

Chronic headache is often comorbid with obstructive sleep apnea syndrome (OSAS). We investigated the prevalence of primary headaches and also evaluated the effect of continuous positive airway pressure (CPAP) on the primary headaches. A total of 235 patients with OSAS (190 M, 45F ; mean age 54.8±11.6 years) receiving CPAP therapy were participated in this study. Primary headaches were diagnosed according to the International Classification of Headache Disorders, 2nd edition (ICHD–2). Sleep apnea headache was diagnosed based on ICHD–3 beta. Of 235 OSAS patients, chronic headaches were observed in 105 (44.7%) : 18 migraines (7.7%) ; 55 tension–type headaches (23.4%) ; 1 cluster headache (0.4%) and 31 unclassified headaches (13.2%). Patients with chronic headache showed higher scores for sleep disturbances, daytime sleepiness and depressive symptoms compared with patients without chronic headache. Of 105 patients with chronic headaches, 39 (37.1%) had sleep apnea headache. CPAP treatment was effective in reducing headaches in 12 patients with migraine (8 with comorbid sleep apnea headache, 66.7%) and in 33 patients with tension–type headache (16 with comorbid sleep apnea headache, 48.5%). Among OSAS patients with chronic headaches after exclusion of patients with sleep apnea headache (n＝66), CPAP–responsive headache group (n＝36) had a significant longer daily CPAP use compared to CPAP–non responsive headache group (n＝30). In patients with OSAS, chronic headache was frequently observed. Our study results showed that CPAP therapy can ameliorate concomitant primary headaches not fulfilling the diagnostic criteria of sleep apnea headache in patients with OSAS.

[Objectives]

A randomized single blinded, placebo–controlled study was conducted to evaluate the efficacy of Zonisamide (ZNS) for treating the Behavioral Psychological Symptoms of Dementia (BPSD) in patients with Dementia with Levy bodies (DLB).

[Subjects]

Thirteen patients with probable DLB diagnosed by the criteria of the Consensus Guidelines for the clinical and pathologic diagnosis of DLB revised by the Consortium on DLB International Workshop in 2005 : 6 assigned to the treatment group with ZNS and 7 assigned to the control group.

[Methods]

The subjects in the treatment group were medicated with ZNS 100mg/day. The primary efficacy endpoints were changes from baseline in the Neuropsychiatric Inventory (NPI) scores over the 2–week and 4–week treatment periods. The secondary endpoints were changes in Mini Mental State Examination (MMSE), The NPI– Brief Questionnaire Form (NPI–Q), and the Unified Parkinson's Disease Rating Scale (UPDRS) ; MMSE and NPI–Q were assessed at 2 and 4 weeks after the start of dosing, while UPDRS was assessed once at 4 weeks after the start of dosing.

[Results]

There were no significant differences in the baseline assessment between the two groups. As the clinical trial results, no significant differences were demonstrated in both the primary and secondary endpoints. However, NPI total scores showed the tendency toward improvement in the treatment group, and regarding the adverse events, hallucination and anorexia were reported in one subject.

[Conclusion]

Statistically significant differences were not demonstrated due to the small sample size. It is required to conduct a dose finding study with larger number of subjects.