Patients with amyotrophic lateral sclerosis (ALS) develop progressive generalized skeletal muscle atrophy, weakness, and die on average 3–4 years from onset or require permanent ventilation. Even now, we have no curative treatment for ALS, but there is much to do in medical care. As standard care, we will administer progression inhibitors, manage nutritional and respiratory status, provide symptomatic treatments, introduce rehabilitation, support communication disorder and build a multidisciplinary support team. The clinical courses and prognoses of ALS patients are shown to be very diverse, and the treatment and care plan for each patient should be determined according to the status and progress of the individual patient.
The development of disease–modifying treatments that alter the pathophysiology of neurodegeneration in ALS patients is being vigorously carried out. The background is that many genes and molecules related to the pathogenesis of ALS have been identified since the 2000s. Therapeutic development of ALS is approaching the stage of developing disease–modifying therapy by elucidating pathogenic genes and molecular pathogenesis. There has been great progress in elucidating the molecular pathogenesis of ALS, and it is expected to become an active area of drug discovery.
Autoimmune encephalopathies are clinically and immunologically heterogeneous disorders. Many different types of autoimmune encephalopathy have been discovered, and most common type may be Hashimoto encephalopathy in it. We often recognize that patients with autoimmune encephalopathy are often misdiagnosed as functional psychogenic movement or somatoform disorders. We have reported 63 patients with autoimmune encephalopathy. Two–thirds of patients showed motor disturbance mostly with unsustained or give–way weakness. About 70% of patients showed sensory abnormalities that was not explainable anatomically. 27% of patients exhibited involuntary movements such as tremor entrainment, dystonia, or coarse involuntary movement. Although give–way weakness, anatomically unexplainable pain, and strange involuntary movements were thought to be psychogenic, the presence of one of these three symptoms was indicative of autoimmune encephalopathy. As autoimmune encephalitis exhibits diffuse involvement with the whole brain, these symptoms were entirely understandable. Except for the presence of organic disease, most patients were classified into somatoform disorders or functional movement disorders. Without first excluding autoimmune encephalopathy, physicians should not diagnose somatoform disorders.
The new guideline for epilepsy entitled “The clinical practice guidelines for epilepsy 2018” (Guideline 2018) was published in 2018, it updated “The clinical guidelines for the treatment of epilepsy in 2010”, aiming at standard treatments of epilepsy for all clinicians who treat epilepsy patients even if not epileptologists. The guidelines consist of two parts, the first part including the various summary of diagnosis, medical and surgical therapy, related conditions such as the status epilepticus, the psychogenic non epileptic seizures and the acute symptomatic seizures, the information providing for epilepsy patients. Second part includes systematic reviews prepared by GRADE system.
The major points of updated medical treatments are as follows : (1) Although the timing of initiation of therapy is basically after two unprovoked seizures, it may start in cases of neurological abnormality, abnormal finding of EEG, epileptogenic lesion of neuroimages, family history or elder patients. It can also start according to the social status or the willing of patients. (2) The first line treatment of generalized tonic–clonic seizures is sodium valproate, other new drugs such as lamotrigine and levetiracetam are recommended in women fitting the child–bearing age. The first line treatments of focal onset seizures are carbamazepine, lamotrigine and levetiracetam, following zonisamide and topiramate. Second line treatments for focal onset seizures are other drugs including gabapentin, lacosamide and perampanel. (3) In the elder patients with co–mobidity, lamotrigine, levetiracetam and gabapentin are recommended. In women fitting the child–bearing age, the comprehensive counseling, family planning and selection of appropriate treatment are recommended before pregnancy.
Current standard managements for epilepsy are established in Guideline 2018. In the near feature, it will be updated by the evidences of efficacy and tolerability of new drugs, such as lacosamide and perampanel, provided after 2016.
Achieving complete stable remission (CSR) may be an ideal goal, but it is uncommon for MG patients, and the rate of CSR cannot be increased at least by presently available treatment. Early achievement of minimal manifestations (MM) or better status on prednisolone at ≤5mg/day (MM–or–better–5mg) is now proposed as a practical and initial goal, and which is another way to say “early return to a normal lifestyle without complications from steroids”. However, the percentage of patients who achieved this goal was not high in our subjects of surveys in 2010 and 2012, and they were treated mainly by chronic oral immune therapies based on corticosteroids. It was also shown that longer treatment with a higher dose of oral steroids does not ensure better outcome. These indicate that changes in treatments are needed to further increase treatment success.
To achieve MM–or–better–5 mg status early, it is better to use steroid–sparing agents, such as calcineurin inhibitors, during the early stages of treatment. To reduce the steroid dose and achieve early improvement of symptoms, non–oral fast–acting treatment such as high–dose methylprednisolone, plasmapheresis and/or IVIG can be more aggressively used. They can be repeated as needed during both the early stages and chronic stages of treatment to achieve early improvement with sparing oral steroids. If the MM status cannot be maintained, a fast–acting treatment can be repeated as maintenance therapy to avoid dose–up of oral steroids. Such treatment approaches are now proposed in the Japanese guidelines and named as early fast–acting treatment strategy (EFT). It is shown that EFT can promote early achievement of MM–or–better–5mg lasting more than 6 months. In an attempt to achieve early goal by EFT, dosing regimens of oral steroids (low–dose or high–dose) produce no difference in the outcome. If the frequency of fast–acting treatment is too high and not decreased for years or if the effects are insufficient, molecular target therapies (new arms) now can be an effective next step.
Multiple system atrophy (MSA) is a refractory neurodegenerative disease and at present no fundamental therapeutic method has been found, but due to the progress of research in recent years, development of new therapeutic regimens is expected in the future. Treatment methods that can be selected in Japan as of 2018 are symptomatic treatments such as TRH analogs, drugs for treating Parkinson's disease, vasopressors, drugs for dysuria disorder etc. Non–medication therapy includes treatment such as rehabilitation, non–invasive ventilation therapy, tracheostomy, ventilation, and gastrostomy. Clinical trials targeting humans have failed to demonstrate the inhibitory effect on progression, but as a future treatment, COQ10 treatment, mesenchymal stem cell transplantation, treatment targeting α–synuclein, etc. are expected. In future clinical trials, it is important to set up an appropriate clinical trial plan with the precise pathological condition modifying mechanism as the background, and appropriate clinical study plan such as severity, evaluation index, biomarker, treatment start time, drug dose setting etc.
Lower urinary tract dysfunction (LUTD) is common and one of the biggest problems in patients with neurodegenerative disease and the family. Thus accurate diagnosis and sufficient management should be provided for these patients and families. LUTD is usually calcified into storage disorder and voiding disorder. Storage disorder is easily noticed by patients and directly results in impairment of quality of life, whereas voiding disorder is less noticeable to the patients and subclinically results into impairment of hearth condition. Therefore the management of voiding disorder is more important than that of storage disorder for the management of LUTD in patients with neurodegenerative disorder. Thus it is so important to detect the presence and severity of voiding disorder. Polyuria and nocturnal polyuria are also important to know the cause of daytime and night time urinary frequency. For the diagnosis of LUTD in patients with neurodegenerative disorder, detail questionnaire, bladder diary and measurement of residual urine volume (RU) are needed at least and these should be done routinely. The management of LUTD in these patients is according to the severity of voiding disorder. If voiding disorder is severe (RU > 100–200ml), the management of voiding dysfunction is preferred. If voiding disorder is moderate (RU 100–200ml >50–100ml), the management of voiding dysfunction is preferred. In the cases with mild or no voiding disorder (RU < 50–100ml), the management of storage dysfunction is done. In parallel, if polyuria or nocturnal polyuria is recognized, the management of polyuria or nocturnal polyuria is done. In cases with nocturnal polyuria, sleep apnea syndrome failure from being overlooked.
Japanese clinical practice guideline for Parkinson's disease was released in 2018. In this guideline, the importance of levodopa therapy during both early and advanced stage of PD is stressed. Further, MAO–B inhibitors became a one of first–line treatment for the early stage of PD. It is also mentioned about the characteristics of Device Aided Therapy. To state recommendations of each therapy, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was employed. The recent development of devices which is used in Deep brain stimulation enable us to control PD symptoms more precisely. From 2016, Levodopa–carbidopa intestinal gel therapy became available in Japan. We have many therapeutic options for PD treatment, however, we must start to consider the cost and benefit of each therapy in the future.
Movement disorders are defined as neurological states presenting with abnormal speed, fluency, quality, and ease of movement. To categorized patients with abnormal involuntary movements, movement disorders should be divided into those with too little movement, hypokinetic and those with too much movement, hyperkinetic. Mainly six movement disorders are recognized and include parkinsonism, chorea/ballismus, tremor, dystonia, myoclonus and tic. However, some movement disorders show very similar, e.g. dystonic tremor v.s. tremor, and some patients may have mixed movement disorders, e.g. dystonia with myoclonus. For understanding the movement disorders, neurologist should be aware need to focus on the speed, frequency, rhythm and localization of involuntary movements. In this chapter, we review how to diagnosis the movement disorders.
Monocular eye movement abnormalities and strabismus are caused by a lesion involving brainstem ocular motor nucleus (such as the oculomotor nucleus and abducens nucleus) and/or its afferent/efferent fibers (such as the medial longitudinal fasciculus). On the other hand, conjugate eye movement abnormalities are explained by a disorder of the saccadic or vestibular neural system. The horizontal saccadic system consists of the frontal eye field, and contralateral paramedian pontine reticular formation and abducens nucleus, and the horizontal vestibular system consists of the vestibular nucleus (lateral semicircular canal), cerebellum, and contralateral abducens nucleus. The vertical saccadic system originates from the rostral interstitial nucleus of medial longitudinal fasciculus, and the vertical vestibular system originates from the vestibular nucleus (anterior and posterior semicircular canals). Torsional eye movements are always involved in the vertical saccadic and vestibular systems.
The role of imaging in diagnosing neurodegenerative disorders have been increasing its importance. By combing the results of brain magnetic resonance image (MRI) and nuclear images, clinicians can not only increase the diagnostic assurance, but may also trigger alternative diagnosis when the result was an unexpected one.
In brain MRI, ischemic change, hemorrhagic regions as well as local atrophy are visually assessed. Single case voxel–based morphometry can be performed by VSRAD® as for adjunct diagnostic tool. Diffusion weighted images may be able to diagnose Creutzfeldt–Jakob disease and Neuronal intranuclear inclusion disease, and Adult–onset leukoencephalopathy with axonal spheroids and pigmented glia. Nigrosome–1 can be visualized by susceptibility weighted image and may help diagnose parkinsonian disorders.
Perfusion images may reflect local ischemia, atrophy and neuronal activities and should be visually assessed with corresponding brain MRI. It is useful diagnostic tool for dementia and parkinsonian disorders. Neurotransmitter images such as dopamine transporter image which captures nigrostriatal presynaptic dopaminergic function and sympathetic myocardiac image may each give a clue to certain diagnosis of neurodegenerative disorders, and should be tested for narrowing down the estimated differential diagnoses, not for routine screening purpose.
Thanks to the advance of the treatment strategy, such as an introduction of early fast–acting treatment (EFT), the rate of myasthenic crisis has reduced recently. However, we still encounter this condition occasionally. The result of Japanese multicenter study shows that the overall rate of crisis is 10.2% among all myasthenia gravis (MG) patients and that thymoma–associated MG has especially high incidence. Those who received EFT revealed lower rate of crisis compared to those without EFT. There are some risk factors of myasthenic crisis. Patients showing bulbar palsy or difficulty breathing are vulnerable to crisis when the certain condition such as infection, surgery, stress or intravenous methyl prednisolone pulse therapy were added. Once patients developed crisis, intubation has to be performed promptly, and anti–cholinesterase should be discontinued. Plasma exchange is the most effective procedure to treat myasthenic crisis. Intravenous methyl prednisolone pulse therapy is also recommended.
After the discovery of new class of autoantibodies against neuronal cell surface antigens or synaptic proteins (NSA), the concept of acute encephalitis has dramatically changed. Encephalitis can be divided into infectious and autoimmune encephalitis (AE). AE may have autoantibodies against intracellular onconeuronal antigens (e.g. Hu, Yo, Ri, CRMP5, Ma2), intracellular synaptic proteins (e.g. amphiphysin, GAD65) or NSA (e.g. NMDAR, AMAPAR, GABAaR, GABAbR, LGI1, Caspr2, DPPX).
Most of the classic paraneoplastic anti–neuronal antibodies are less likely pathogenic but IgG NSA antibodies are more likely pathogenic, and the presence of the NSA antibodies implies that patients may respond to immunotherapy. Although early initiation of immunotherapy is often emphasized in AE, antibody testing is not readily accessible in most situation, thus initiation of immunotherapy may be delayed. In 2016, a practical diagnostic approach to AE was published as a position paper in Lancet Neurology to achieve prompt immunotherapy at 3 levels of evidence for AE (possible, probable, and definite) with several new diagnostic criteria including possible AE, probable AE, probable and definite anti–NMDAR encephalitis, autoimmune limbic encephalitis, ADEM, and Hashimoto encephalopathy.
In this lecture, I focus on recent progress in antibody–mediated encephalitis, stiff–person spectrum disorder, and cryptogenic new–onset refractory status epilepticus (C–NORSE) with development of a clinically–based score that predicts C–NORSE.
Endocrine or metabolic diseases can be major causes of neurological disorders such as disturbance of consciousness, psychosis, epilepsy, involuntary movements, and cerebellar ataxia. Such endocrine diseases widely vary among impairments of subthalamus/pituitary gland, thyroid/parathyroid, adrenal gland, and pancreas. Metabolic diseases, including unusual blood sugar, hyperammonemia, and electrolyte abnormalities, also cause neuropsychiatric disorders. Particular neurological signs, e.g. mounding phenomenon in hypothyroidism or Trousseau's sign in tetany, can be a key for the early–diagnosis of endocrine/metabolic diseases. The basic laboratory findings, e.g. hyponatremia, or radiological findings, hyperintensity in the basal ganglia in hyperammonemia are also helpful in making a different diagnosis. As delays in the diagnosis and treatments of these neurological patients associated with endocrine/metabolic diseases may cause irreversible brain damage, it is imperative for clinicians or medical staffs to carefully exclude the possibility of latent endocrine/metabolic diseases.
Encephalitis and meningitis are severe neurological infections, and the neurologic manifestations of these conditions include fever, headache, altered mental status, convulsions, and psychiatric symptoms. It is critical that the clinician considers a broad range of causes, such as bacteria, virus, tuberculosis, fungus, and autoimmune or paraneoplastic diseases. Since treatment is more efficient if given early, these conditions of encephalitis/meningitis should represent as a life–threatening neurological emergency. For patients with suspected encephalitis/meningitis, therefore, empiric treatments should be initiated promptly based on the history, physical examination, and cerebrospinal fluid (CSF) findings. In this article, the author describes the characteristic clinical findings, magnetic resonance imaging and spinal fluid analysis of bacterial meningitis, tuberculous meningitis, cryptococcal meningitis, herpes simplex encephalitis, and anti–NMDA receptor encephalitis, and discusses the choice of empirical treatments until the cause of infection is determined. Also the differential diagnosis of encephalitis/meningitis is reviewed, with an emphasis on infectious etiologies.
Parkinson's disease (PD) exhibits motor symptoms such as resting tremor, bradykinesia, and rigidity for which levodopa is successful, but often needs to be differentiated from other PD–related disorders resistant to levodopa. In PD, non–motor symptoms including autonomic symptoms such as constipation, hyperhidrosis, orthostatic hypotension, REM sleep behavior disorder (RBD), psychological symptoms such as depression and apathy, and olfactory dysfunction are merged at a high rate. Since non–motor symptoms develop before the onset of motor symptoms in PD, most of the PD cases are judged from the initial symptoms, however, atypical cases often encountered. Although conventional MRI do not show any abnormalities in PD, disappearance of nigrosome 1 can be confirmed by high magnetic field MRI susceptibility weighted images. Further, dopamine transporter scintigraphy (DaT–SPECT) is a sensitive for parkinsonism and iodine–123–metaiodobenzylguanidine (123I–MIBG) has higher specificity of PD diagnosis myocardial scintigraphy. However, the advanced stage of PD involves dementia with overlapping Aβ and tau pathology, leading to the mixed pathology of PDD/DLB which are clinically problematic. Differentiation from DLB, AD, PSP, CBD is also enabled by brain SPECT. Progress of these diagnostic tools is improving the correct diagnosis of PD, but quite a few familial PD and atypical cases exist. In this lecture, the tips as the clinical and pathological discrimination points of PD and other parkinsonian syndromes are outlined with specific cases. Further, not only various pathological background but also trauma and inflammation of the brain are required to consider the modifying factor for the diagnosis and treatment of PD.
Muscles produce contraction and relaxation to make force and motion of animals, and function as one of major energy storage. Thus, “muscle disease” is defined as disorders of muscle resulting in motor impairment with dysfunction of contraction or relaxation.
Electrodiagnostic studies are most important to confirm the presence of muscle diseases ; electromyography (EMG) to identify a decrement of motor units in myopathy, and repetitive nerve stimulation studies and single fiber EMG to identify instability of neuromuscular transmission in neuromuscular junction disorders.
It is easy to understand the pathogenesis of muscle diseases to classify as follows ; exogenous, systemic, immune–mediated, dysfunction of membrane excitability, dysfunction of energy metabolism, structural abnormality.
Recently, treatable myopathy identified among patients with chronic progressive weakness. Improvement of patient care and development of therapies are in progress. It is important to diagnose properly to provide accurate management and therapy for patients with muscle disease.
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system, causing demyelination and neurodegeneration in most patients. Clinical symptoms of MS vary. In recently diagnosed or benign course patients, the incidence of cognitive impairment ranges from 20–40% of RRMS. Secondary progressive course is more common ; roughly 50–60% of patients are affected. The Brief International Cognitive Assessment for MS (BICAMS) battery includes tests of mental processing speed and memory. BICAMS has been recently internationally validated and can be useful in Japan. Diagnostic criteria of MS has been changing as the evolution of technology. Poser criteria were diagnostic criteria for MS. They had replaced the older Schumacher criteria ; defining Laboratory supported definite MS, showing oligoclonal bands. McDonald criteria intended to replace these two criteria. McDonald criteria were revised first in 2005 to clarify exactly what an “attack”, “dissemination” and a “positive MRI” mean. Later they were revised again in 2017 as follows : patients with a typical clinically isolated syndrome and clinical or MRI demonstration of dissemination in space, the presence of CSF–specific oligoclonal bands allows a diagnosis of multiple sclerosis. Informed consent is needed in decisions involving high risk. Patients should nonetheless be informed about the benefits and risks of the treatments, and they are free to refuse it. Shared decision making is appropriate for situations in which 2 or more medically reasonable choices exist, regardless of whether the degree of risk is high or low.
Immunosuppressive agents are administered to neuro–immunological diseases such as multiple sclerosis, myasthenia gravis, neuromyelitis optica, vasculitic neuropathy. Attention should be paid to the complication and exacerbation of infection due to the immunosuppressive action of these drugs. Monitoring of the concentration in blood of the drugs is also useful as a countermeasure against side effects.
Neuro–immunological diseases are prevalent in women of childbearing age, and administration of immunosuppressive agents must always consider risks to mothers and fetuses. In June 2018, the Ministry of Health, Labor and Welfare in Japan approved the use of 3 drugs such as tacrolimus, azathioprine and ciclosporin for pregnant women, “Contraindication to pregnant women” was removed from the package insert.
In recent years, fulminant hepatitis with hepatitis B virus due to administration of immunosuppressive agents or sudden withdrawal has attracted attention and “Guidelines” has been prepared in Japan. It had described the screening methods and countermeasures and it is necessary to be informed.
In clinical practice, if patients treated with immunosuppressive drugs complain of unusual symptoms, it is required to deal with side effects of this drug in a timely manner.
Guillain–Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) are representative inflammatory diseases affecting peripheral nerves. Recently autoantibodies against proteins located in nodes of Ranvier and paranodes, such as neurofascin (NF)186, moesin, NF155, contactin–1 (CNTN1) and contactin–associated protein 1 (caspr1), have been reported in a fraction of GBS and CIDP. Although clinical manifestations of CIDP are heterogeneous, CIDP with anti–NF155 or CNTN1 antibodies shows unique features. The common features include sensory ataxia, severe demyelination on nerve conduction study, very high cerebrospinal protein levels and poor response to intravenous immunoglobulin. Analysis of IgG subclasses of both antibodies has clarified predominant elevation of IgG4 subclass. Because IgG4 lacks complement binding and activating capabilities, IgG4 antibodies are regarded to directly interfere with the functions of the relevant antigens. Blocking the interaction between NF155 and CNTN1 results in detachment of terminal myelin loops from the axolemma, which is frequently recognized in longitudinal sections of sural nerves from patients with anti–NF155 or CNTN1 antibodies. Younger age at onset, higher frequency of tremor, hypertrophic nerve roots and strong association with HLA–DRB1*15, have been reported as characteristic features of anti–NF155 antibody–positive CIDP. By contrast, anti–CNTN1 antibody–positive CIDP patients present more advanced age of onset, higher frequency of concurrent nephrotic syndrome and an occasional acute to subacute onset with subsequent aggressive course. Because of rarity of patients with anti–NF186, moesin or caspr1 antibodies, clinical significance of these antibodies is not conclusive. This review summarizes autoantibodies against protein antigens in GBS and CIDP.
Antibodies to glycolipid are detected in approximately 60% of Guillain–Barré syndrome (GBS) patients. Localizations of those antigens in human peripheral nerves are well correlated with clinical phenotypes of GBS. Campylobacter jejuni and Mycoplasma pneumoniae as antecedent infectious agents in GBS have carbohydrate structures mimicking glycolipids. Thus, anti–glycolipid antibodies, which are produced by antecedent infections, bind to glycolipids localized in human peripheral nerves and can cause GBS. By contrast to GBS, positive rate of anti–glycolipid antibodies is low in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Among glycolipids, LM1 is predominantly localized in human peripheral nerve myelin. LM1–related antibodies are detected in approximately 10% of CIDP patients. CIDP patients with those antibodies frequently present ataxia but rarely have cranial nerve deficits ; these features are possibly associated with the localization of LM1, which is more abundant in the dorsal root than the cranial nerves. Those findings suggest an involvement of anti–glycolipid antibodies–mediated mechanism in GBS and CIDP.
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired peripheral neuropathy characterized by demyelination triggered by autoimmune–responses that targets the myelin sheath or paranodal molecules. Clinically, it has monophasic, relapsing, not only slowly progressive course, and causes motor sensory dysfunction in each limb. The disease is characterized by its diversity in the distribution of disorders and therapeutic responses, etc. Although the pathogenesis of both cellular and humoral immunity is presumed to be involved, it is not a uniform immunological background, but diverse. It is considered as a syndrome in which various pathological conditions co–exist. Therefore, understanding of the diversity and understanding of the characteristics of each subtype are essential from the viewpoint of therapeutic intervention as well as elucidation of the pathological condition.
According to the conventional criteria (EFNS/PNS criterion), CIDP is broadly classified into typical CIDP and non–typical CIDP, and the former has good responsiveness to existing first–line therapeutics. On the other hand, atypical CIDPs are important for differentiation from other diseases, and generally include many intractable cases showing resistance to first–line therapeutics. treatment, there are also subtypes whose pathogenesis is becoming clear. Since IgG4 itself is considered to be essential factor for IgG4–subclass autoantibody positive CIDP, its removal can be expected as a therapeutic. From this, the efficacy of rituximab, which selectively injures B cells, is underway as a doctor–initiated trial in Japan. In addition, even if treatment response is good in the typical clinical picture of CIDP, treatment–dependent cases that repeat recurrence may shift to irreversible axonal degeneration if the proper therapeutic intervention is missed, which may be a prognostic case. Thus, for cases in which frequent relapses occur and where a single initial treatment alone is considered inadequate, the introduction of maintenance therapy should be considered.
The international league against epilepsy (ILAE) classification of the epilepsy was updated in 2017. An etiological diagnosis was considered in this classification, i.e. structural, genetic, infection, metabolic, immune and unknown. The concept of immune epilepsy is that it results directly from an immune disorder in which seizures are a core symptom of the disorder. An immune etiology was conceptualized as where there is evidence of autoimmune–mediated central nervous system inflammation. Although autoimmune encephalitis has been under–diagnosed because of the difficulty to find responsible antibodies, increasing number of antibodies have been recognized as the causes of autoimmune encephalitis. Epileptic seizures evoked by autoimmune encephalitis should be treated by immunotherapies instead of conventional antiepileptic drug therapies. The clinical features of autoimmune–mediated encephalitis frequently manifest those of limbic encephalitis, since amount of patients often encounter complex partial seizures (seizures with loss of awareness) accompanied with memory disturbance, abnormal behaviors and psychosis. In case of progressive psychosis or neurological disorder with undetermined etiology, we should pay attention to the possibility of immune–mediated encephalitis and consider the indication of immunotherapy. The representative antibodies are anti–NMDA (N–methyl–d–aspartate) receptor or anti–VGKC (voltage–gated potassium channel), which are considered to have direct relation with induction of epileptic seizure. Therefore, it would be necessary to elucidate the mechanism how autoantibodies induce epilepsy or how immunotherapy is effective.
Approximately 90% of babies of women with epilepsy are reported to be normal, however, women with epilepsy have a 10–fold risk of death during delivery hospitalization. Upon commencement of therapy with antiepileptic medication in women of childbearing age, patients and their family should be advised whether they can practically carry out pregnancy and delivery, considering seizure severity, viability, and family cooperation. In adjusting ‘minimum maintenance dose’ for pregnancy, while generalized tonic–clonic seizures should be suppressed in order not to cause critical events as hypoxemia, acidosis, abortion, etc., milder seizures are permissible. Full consideration is needed of social life, driving, and business description. Dose of antiepileptic drugs should be in ‘minimum maintenance dose’ therapy with low risk of teratogenicity. Patients and their family members should be cautioned upon possible risk of developing severer seizures during dose reduction. New–onset epileptic seizures, or epileptic seizures whose types are different from habitual ones, various etiologies causing to acute symptomatic should be evaluated.
Status epilepticus (SE) is a common neurological emergency with high morbidity and mortality. Prompt and appropriate diagnosis and treatment of SE lead to a good outcome. We outline in this review the definition and classification, diagnosis, and treatment of SE according to the up–to–date knowledge. The International League Against Epilepsy's new definition and classification of SE in 2015 are explained. Although the diagnosis of convulsive SE is mostly easy, there are some pitfalls (e.g., psychogenic non–epileptic seizure). As the symptoms of nonconvulsive SE (NCSE) are various and nonspecific, electroencephalography findings are essential for its diagnosis. The Salzburg criteria are now widely used as the diagnostic criteria for NCSE, and its high diagnostic accuracy and excellent inter–rater agreement were reported. Although a number of treatment guidelines for convulsive SE have been published in recent years, the basic concept of treatment strategy is similar : benzodiazepines as the first–line, intravenous antiepileptic drugs as the second–line, and anesthetics as the third–line drugs. However, evidence for the second and third–line drugs is insufficient to date. Furthermore, only an expert opinion is available for the treatment of NCSE.
Amyotrophic lateral sclerosis (ALS) is a lethal degenerative disease of motor neurons that results in progressive muscle weakness. At present, riluzole and edaravone have been approved in Japan, but its effect on the progression of symptoms is limited, and development of more effective treatments is desired.
Hepatocyte growth factor (HGF) is an in–vivo substance discovered by Nakamura et al., and cell proliferation promoting/cell death suppressing activity of HGF has been reported in many cells including hepatocytes. Also, neurotrophic factor–like effects of HGF have been shown in neurons, and from that point HGF has been used to study the disease–suppressing effects on ALS in Tohoku University. Human recombinant HGF (hrHGF) showed about 63% prolongation of morbidity by administration into the cerebrospinal fluid from the onset of the disease in mutant superoxide dismutase 1 (SOD1) overexpressing rats. Next, a phase I study of 15 patients with mild ALS was conducted in Tohoku University Hospital from 2011 to 2014 to confirm the safety and pharmacokinetics of intrathecal administration of hrHGF in humans. Based on this result, a placebo–controlled double–blind phase II study in 48 patients with ALS was started in Tohoku University Hospital and Osaka University Hospital from May 2016.
Patients who show a mild to moderate symptom progression after 12 weeks of pre–registration are enrolled, and after catheter implantation surgery in the spinal cord cavity, the drug is administered once every two weeks for a total of 24 weeks. Patients who desire to continue are given the active drug for up to 24 weeks. As of the end of September 2018, 22 cases have been enrolled. No serious adverse events have been seen to date.
We will further promote recruitment of candidate patients and aim to complete the clinical trial sooner. If the clear efficacy of HGF to ALS patients is confirmed in this clinical trial, ALS treatment based on a novel mechanism of action using neurotrophic factors becomes possible, and the effects on other neurodegenerative diseases are also expected.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects the upper and lower motor neurons. Only riluzole and edaravone are approved as drugs for ALS in the world, and new agents with larger effect size are warranted. Our previous study (E0302–J081–761) has suggested that high–dose mecobalamin (E0302) prolonged the overall survival and suppressed progression in ALS patients with a disease duration less than 12 months in exploratory analyses.
The Japanese Early–stage Trial of high dose methylcobalamin for ALS (JETALS) is a prospective, multicenter, placebo–controlled, double–blind, randomized phase III study conducted at 25 neurology centers and is funded by the Japan Agency for Medical Research and Development.
A total of 128 ALS patients within 1 year from onset were randomized at a 1:1 ratio to receive intramuscular injection with E0302 50mg or placebo twice a week for 16 weeks. The primary endpoint is changes in the ALS Functional Rating Scale Revised (ALSFRS–R) total score at 16 weeks. If the patients expect to receive E0302 50mg after double–blind administration period, E0302 will be provided to those who wish to receive by March 2020 in the continuous administration period.
This study was started in November 2017. The patient enrollment period is scheduled to end on October 2019 and the follow–up is scheduled to end on March 2020. Respectively, 133 and 71 patients were registered for observation and treatment period until Jan, 2019. The number of the patients registered for treatment period has been above the goal.
Perampanel, a selective non–competitive AMPA receptor antagonist, has been reported to prevent the progression of the model mouse for sporadic amyotrophic lateral sclerosis (ALS) (AR2 mice), in which an RNA editing enzyme adenosine deaminase acting on RNA2 (ADAR2) is conditionally knocked out in the motor neurons. Because of therapeutic potency of perampanel for sporadic ALS, we planned to perform a clinical trial with perampanel for sporadic ALS to investigate the safety and the efficacy of perampanel in patients with sporadic ALS. We designed a multicenter randomized, double–blinded, placebo–controlled, parallel–group phase 2 clinical trial (CrinicalTrials.gov. ID NCT03019419, UMIN ID UMIN000025614).
The patients eligible for inclusion criteria and not applicable for exclusion criteria will be enrolled for the interim registration. After 12 weeks of observation period, the patients with the progression on score of ALS functional rating scale–revised (ALSFRS–R) between −2 and −5 will proceed to the registration. Then the patients will be allocated into three groups : placebo (n＝20), 4mg of perampanel (n＝20), and 8mg of perampanel (n＝20). The patients will take placebo or perampanel once daily before bedtime with dose–escalation method. The primary outcome measure is change in ALSFRS–R after 48 weeks of the treatment. This research is supported by the Project Promoting Clinical Trials for Development of New Drugs and Medical Devices (Japan Medical Association) from Japan Agency for Medical Research and development, AMED. This study was started in April 2017, and the recruiting ALS patients was completed in October 2018. The open–labeled continuation study will follow after the phase 2 study. The results of the phase 2 study will be available in early 2020.
There is an urgent needs for us, neurologists in Japan, to increase the presence in the clinical practice, education, and research of neuroemergency and neurointensive care. In this Keynote Address, current status and advances in critical care neurology was presented with perspectives.
Status epilepticus (SE) is a common neurological emergency with high morbidity and mortality, and its incidence is especially high in elderly people. As Japanese population is rapidly aging, SE in the elderly is increasingly becoming an important clinical problem. We outline in this review the epidemiology, clinical characteristics, and treatment of SE in the elderly. Epidemiological studies in the United States and Europe showed the incidence of 15–86/100000/year, and the mortality of 22–38%, in elderly people. Compared to younger SE, elderly SE more frequently occurs de novo ; is less likely to be tonic–clonic but more likely to be focal motor or nonconvulsive ; and is more frequently refractory, particularly refractory nonconvulsive. Cerebrovascular disease and dementia are the major etiologies. As nonconvulsive SE is common in elderly people, electroencephalography must be performed when they have acute impaired consciousness without known causes. Although SE in the elderly should be treated basically according to the treatment guidelines, the characteristics of elderly persons (individual differences in pharmacokinetic and pharmacodynamic parameters, comorbidities, and medications) also must be taken into account. Moreover, adverse effects and underlying disease severities should be carefully balanced, particularly in elderly nonconvulsive SE.
In ER, prevalence of neurological illnesses which require neurocritical care is estimated to account for 40–60% of the patients. However, neuromonitoring is very limited compared to circulatory, respiratory, and other systems. Ideally, real–time neuromonitoring is needed, which is able to evaluate the brain function like blood pressure and blood oxygen saturation, regardless of time, place, specialty and condition of patients. The main goals of neuromonitoring in neurological illness and neurocritical care are to provide early detection of neurological worsening or cerebral dysfunction to avoid progression to irreversible neurological injury, better understand a patient's cerebral pathophysiology, and evaluate the effect of treatment. Evaluation of the pathophysiology of the critically ill patients with single monitoring is still difficult, thus combination of serial neurological examinations, neuroimaging studies, and continuous monitoring different neuropathophysiological parameters are inevitable. In this short review, we describe advances of neuromonitoring which include noninvasive intracranial pressure monitoring by transorbital ultrasonography, continuous and fast electroencephalogram monitoring with a novel electrode and headset, quantitative electric pupillometer, and endtidal CO2 monitoring by capnometer.
In the emergency settings, rapid identification of stroke is critically important. Furthermore, uncommon causes of strokes also share the clinical significance either in the emergency room or in the general hospital.
Uncommon causes of stroke contains arteriopathy (cervicocephalic artery dissections, Ehlers Danlos type IV, moyamoya disease, RCVS/PRES, etc), hematological disorders (Trousseau syndrome, antiphospholipid syndrome, etc) and cerebral venous thrombosis. Recently, some uncommon causes of strokes gain some progress in understanding its evaluation and management such as Fabry disease, PRES, artery dissections, and Moyamoya disease.
On behalf of the neurologists' roles in the neurological emergency settings symposium, this article tried to disclose the road map for the era of the uncommon stroke. Uncommon causes of stroke will take neurologists to the new stage for the future stroke clinics with appropriate diagnosis and management.
This review explains the following : First, it demonstrates that functional impairment of the prefrontal cortex leads to chronic pain due to improper functioning of the descending pain modulatory system. In addition, patients with chronic pain often develop “learned–nonuse,” a condition in which affected limbs are not used because of misinterpretation (distorted cognition) that movements cause pain. When learned–nonuse occurs, cerebral cortical areas associated with the execution of movement and sensation are reduced in size, which leads to functional impairments associated with these areas. If nonuse of the affected limbs is prolonged, the self–perception of the body is decreased as in neglect–like symptoms, and this decrease in cognitive ability may result in chronic pain or pain exacerbation. Neglect–like symptoms associated with the development of chronic pain is caused by the collapse in the perception–movement loop, particularly by the disturbed mechanism of the comparator model. The comparator model is involved in the embodied brain system. In the end, this review explains the hypothesis for the mechanism of how functional disturbances can occur in the embodied–brain systems of patients with chronic pain at all levels, from sensorimotor representation to propositional representation and meta–representations.