It is thought to be the most important theme for neurogenic disease is the neurotherapeutics not only now but also in the future.
Our department of neurology of Dokkyo Medical University have done mainly clinical research for developing the neurotherapeutic in many field. We found many new results and published using neurophysiological and neuro–immunological technic and field work in sleep disorders, a migraine headache, cerebrovascular disease, cognitive impairment and neurologic immune disorders. We have done also many promotion to prevent stroke and other disease.
However, there are still some intractable neurological disorders with unknown causes that have a progressive clinical course still now. In addition, we are facing on the super low birthrate and aged society in the present. Moreover, it will be continued and spread till around 2040. Therefore, looking for the future it must be important to develop new treatments for such neurological disorders.
First of all, new drug for the neurological disorder should be approved more effectively using so called delayed–start study design.
Furthermore, gene therapy, innovative drug development such as disease modifying drug using iPS cell, genome information and big data analysis will be important. In addition, progress of nerve stimulation and new rehabilitation technic will be necessary. Promotion of brain machine interface (BMI) and the regenerative therapy for function reproduction is required. Probably contribution of the AI will be important.
On the other hand, JSNT have to be focusing on preventive health care with a medical practitioner, nurses and other medical stuffs.
Education for young doctors, nurses and medical staff sabout the treatment of neurological disorders are also important. JSNT is preparing some educational programs every year and publishing guidelines for the treatment of neurological disorders.
As activity that we pay more attention to the world, JSNT is involved in exchanges with the American Society for Experimental Neuro Therapeutics (ASENT). The mission of ASENT is to facilitate cooperation between academia, government, industry, the clinical community and advocacy groups to enable and advance the discovery, translation, and development of neurotherapeutics. An ongoing partnership between ASENT and JSNT are successful and productive.
Thus, JSNT is contributing to progress in the treatment of neurological disorders and a role and the importance of JSNT will increase more in future.
Until recently, neurotherapeutics has been based on the medical empiricism, which has given us many still very useful medications, such as digitalis, opium or aspirin. But these empirical treatments without sound scientific background are mere medical technology and do not deserve to be called science. In 1934, the first scientific treatment in the history of neurological therapeutics was done by an Irish neurologist Mary B Walker. She successfully treated myasthenia gravis with physostigmine, assuming that the basic pathology of myasthenia gravis is common to that of curare poisoning which can be treated with physostigmine. The door to the scientific neurotherapeutics was opened by Isamu Sano who found in 1959 that dopamine concentration was extremely high in the human striatum. Sano's discovery lead to the investigations of striatal dopamine in Parkinson disease patients which revealed the decrease of dopamine in Parkinsonian striatum. Immediately followed by these basic studies, levodopa therapy was initiated in 1961 and won a great therapeutic success.
Although marked development of neurotherapeutics has been recently realized by scientific background, we have to remember that the important therapeutic discoveries have been done by serendipity. Therapeutic efficacy of β–blocker to essential tremor, prevention of migraine attacks with botulinum toxin, the efficacy of amantadine to Parkinson disease, and the discovery of zonisamide as an anti–parkinsonian agent, all of these are the product of serendipity which was fortunately picked up by excellent clinical neurologists having keen eyes enough to notice the unexpected effects of the medications.
Scientific approach to the neurotherapeutics is getting more and more important, but the keen eyes not to miss the serendipity in daily clinical practices are the most important points to the further development of neurotherapeutics.
It has been 14 years since the comprehensive medical care evaluation system (DPC/PDPS) has been introduced to medical practice. However, I feel that my understanding of this system is not enough in medical practice. In this talk, I would like to describe the basic idea of the DPC system, and to mention the revision of the medical service fee.
The causes of strokes in young adults differ from older patients whose main causes are atherothrombosis and non–valvular atrial fibrillation. It's very important to understand the specific cause with young adults. According to “Strategies against Stroke Study for Young Adults in Japan” (SASSY–Japan), 8.9% of all stroke patients are under 50 years of age. Arterial dissection, moyamoya disease, and antiphospholipid syndrome are the most common three causes of ischemic strokes in young adults. Arteriovenous malformation and moyamoya disease are the most common two causes of hemorrhagic strokes.
Arterial dissection is the most common disease in young adults. Most causes are unknown, but sometimes slight trauma is the cause. Dissection causes not only ischemic strokes but also subarachnoid hemorrhage (SAH). The mechanisms of ischemic strokes are artery–to–artery mechanisms and/or hemodynamic mechanisms. The therapies are blood pressure control and anti thrombotic agency. When patients suffer SAH, open surgery and endovascular therapy are considered.
In these days, strokes accompanied with pregnancy are studied. Changes in cardiovascular hemodynamics and in the coagulation mechanisms of pregnancy increase the risk of ischemic and hemorrhagic stroke, SAH, and venous thrombosis. Reversible posterior leukoencephalopathy syndrome (RPLS) and reversible cerebral vasoconstriction syndrome (RCVS) are also reported. RPLS's main symptoms are headaches, visual abnormalities, and epilepsy. In a MRI, the main disease location is parieto–occipital lobe's white matter and where brain edemas occur. If blood pressure is decreased, symptom and image abnormalities disappear. RCVS's main symptom is a headache called thunderclap headache. Cerebral artery temporary becomes vasoconstriction but after anti hypertension therapy, the artery returns to normal.
Otherwise, cryptogenic stroke, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) are important stroke causes.
In this paper, I summarized causes of strokes which occur in young adults.
Fabry disease is caused by deficiency of a lysosomal enzyme, α–galactosidase, leading to accumulation of its substrate globotriosylceramide in various tissues such as vascular endothelial cells and ganglion cells. Due to the multiple organ involvement, various symptoms such as burning extremity pain, anhidrosis, skin lesion called angiokeratoma, renal failure, and heart failure develop progressively. In addition, one in five patients develop cerebrovascular disorder with the average onset of 40 years for males and 45 years for females. Fabry disease is therefore an important cause of juvenile cerebral infarction. Since the α–galactosidase A gene is on the long arm of the X chromosome, the genetic form is X–linked with men exhibiting severe symptoms as hemizygotes. However, 86% of heterozygous women also become symptomatic due to random X chromosome inactivation. Fabry disease can be ruled out for males with normal α–galactosidase activity in leukocytes, but not for females with the normal enzyme activity. Urine sediment analysis shows a grayish white or transparent spiral structure called mulberry body which may be helpful for the diagnosis of Fabry disease. As women develop left ventricular hypertrophy and cerebral infarction later than men but show cumulative incidence curve similar to men, enzyme replacement therapy should be started as soon as possible. The median age of the initial occurrence of the composite endpoint (kidney, heart, or stroke event, or death) can be delayed by about 10 years with enzyme replacement therapy. Therefore, the importance of early diagnosis of Fabry disease cannot be emphasized enough.
Migraine is a common and debilitating neurological disorder. Currently, triptans are used to abort migraine attacks, while medical preventive therapy is carried out using centrally–acting calcium blockers, antiepileptic agents, and tricyclic antidepressants. Nevertheless, alternative therapy is required to treat those who are intractable to these medications. Calcitonin gene–related peptide (CGRP) is abundantly expressed in trigeminal ganglion neurons. Blood CGRP concentrations are increased in some migraine patients, and intravenous administration with CGRP has been shown to induce delayed migraine–like headache attacks almost exclusively in migraineurs. Hence, attempts have been made to develop CGRP–based migraine therapy. Initially, an injectable small–molecule CGRP receptor antagonist termed BIBN 4096 BS (Olcegepant) was found to abort migraine attacks. Oral CGRP receptor antagonists are now being developed for abortive and preventive treatment. Recently, monoclonal antibodies against CGRP or its receptor have been shown to be effective in migraine prophylaxis with minimal side effects. Moreover, it has been made clear that these antibodies are able to ameliorate chronic migraine, which is extremely disabling and generally drug–resistant. In this article, recent advance in CGRP–based migraine therapy and its perspective are discussed.
Sleep disorders are common in neurological diseases but are still underrecognized and undertreated. Different brain lesions related to neurological diseases result in altered sleep–wake rhythm and sleep structure. Additionally, insomnia is caused by sensorimotor symptoms related to neurological diseases, medication use and comorbid primary sleep disorders, such as sleep apnea syndrome, restless legs syndrome and rapid eye movement sleep behavior disorder. In headache disorders, headache can be caused by sleep disturbances. For further understanding of the relationship between neurological diseases and sleep disturbances, this review addresses 1) sleep and wakefulness disorders due to focal brain lesions, 2) sleep disturbances in Parkinson's disease and related disorders, 3) sleep disturbances in dementia disorders and 4) sleep disorders and headache disorders.
There are various pitfalls for the electrodiagnostic tests including nerve conduction studies (NCS) and needle EMG. Failure to recognize them would easily lead us to misdiagnosis.
Regarding motor–nerve conduction studies (MCS), one of the most important facts is that the amplitude of the compound muscle action potential (CMAP) is supposed to be proportional to the muscle power, i.e. manual muscle testing (MMT). The dissociation between the CMAP amplitude and MMT would become an important clue to the diagnosis. For example, a normal CMAP amplitude in a weak muscle suggests either conduction block (CB) at proximal side, central weakness or other conditions. “MMT is 5, but CB is observed” is always wrong. An insufficient stimulation is a frequent cause of this error, which is especially apt to occur for Erb's point stimulation. If this occurs, a false CB between the Erb's point and arm/axilla would be observed. Unnecessarily strong stimulation at the wrist may cause a spread from the median to ulnar nerve, giving a false impression of CB. Martin–Gruber anastomosis, an anomalous branch from the median to ulnar nerve, is a well–known pitfall, which may give a false impression of CB between the wrist and elbow in the ulnar nerve MCS.
Reagrding needle EMG, correct identification of the spontaneous activities is the most important key to diagnosis. We must be able to distinguish fibrillation potentials and positive sharp waves from the end–plate spikes or voluntary motor unit potentials (MUPs). In voluntary activities, the famous formula that the high–amplitude MUPs suggest neurogenic changes, whereas the low–amplitude MUPs suggest myopathic changes is not always correct. Notably, high–amplitude MUPs are often observed in myopathy. Recruitment pattern is more important for diagnosis.
Nerve conduction study (NCS) is essential for the diagnosis of neuromuscular disorders. NCS is an extended physical examination, and NCS results have only limited value without clinical information. Here I describe “How to read NCS” on a case–by–case basis. 1) When revealing the cause of weakness. NCS is useful, when the origin of the muscle weakness exists in the peripheral nervous system. Abnormality of CMAP in the muscle with weakness suggests that the weakness can be of peripheral nerve origin. Normal CMAP in the muscle with apparent weakness suggests that the origin of the weakness exists in the proximal sites, including central nervous system. 2) When revealing the cause of sensory disturbance. SNAP abnormality in the site with apparent sensory loss supports the idea that the origin of sensory loss is peripheral nerve. If normal SNAP was recorded from site with sensory loss, it suggests that the cause of sensory loss exists in the proximal site of stimulation point (acute phase), or in the proximal site of spinal ganglion including central nervous system (chronic phase). 3) Assessment of unexpected results. In Lambert–Eaton myasthenic syndrome, extremely small CMAP can be recorded from the muscle with normal strength. In the inclusion body myositis, CMAPs from hand muscles are often normal even in patients with weak handgrip. The origin of muscle weakness in inclusion body myositis usually is in forearm muscles, but not in the hand muscles.
In order to provide appropriate treatment for individuals having neurological disorders, understanding neuropathology is essential. However, many clinicians have decreased opportunities to see neuropathologic materials. In this course, I showed neuropathologic findings of some representative cases such as cerebrovascular, infectious and neurodegenerative diseases. I also showed the process from autopsy to microscopic analysis. I highly recommend that young neurologists, neurosurgeons and psychiatrists study across a range of basic aspects of neuropathology.
Neuromuscular ultrasound is useful complementary testing in conjunction with clinical evaluation and neurophysiological testing such as nerve conduction study and electromyography. Two kinds of probe frequencies are commonly used, higher frequency (15–18MHz) for the evaluation of surface regions such as nerve locating at the wrist, on the other hand, lower frequency (11–15MHz) is suitable for deeper structures such as nerve roots and sciatic nerves. To differentiate peripheral nerves from other structures, the color–Doppler technique is useful in identifying blood vessels, and also a long stretching structure can be recognized as a peripheral nerve. For quantitative evaluation, cross–sectional area (CSA) and fascicule diameter (FD) can be measured by the coronal view. In a suspected case of carpal tunnel syndrome, the ratio to compare the CSAs between at the wrist and the elbow. Evaluation of multiple nerves at the different sites enables differential diagnosis of focal vs. diffuse localization as well as axonal vs. demyelinating pathology.
For evaluation of muscles, a linear–type probe is used to check echointensity, fiber arrangement, the presence of characteristic structures intramuscularly, and involuntary movements such as fasciculations and myokymia. Muscular high echointensity may suggest inflammation and fat reposition, that are further differentiated by observing muscle fiber arrangement. Other indications of muscle ultrasound include determination of optimal sites for muscle biopsy, identification of ALS, and other muscle diseases. Muscle ultrasound can detect fasciculation, especially in bulbar muscles at least at the equivalent sensitivity as needle electromyography.
Oral cavity is a reservoir of the microorganisms in human body. If someone have dental caries involving dental pulp or periodontal disease, oral microorganisms easily enter inside the body and might cause bacteremia. If someone have masticatory disturbance and swallowing disturbance (dysphagia), oral microorganisms easily enter the respiratory tract. In order to prevent such disadvantages, it is important to manage the oral function for patients undergone several medical treatments. Medical primary doctors and primary nurses first refer their patients to the dental practitioners. Dental practitioners, such as dentists and/or dental hygienists treat their dental caries, periodontal diseases, masticatory disturbance and swallowing disturbance. Clinical, biological and social effects of the oral management for patients undergone several medical treatments is well recognized. Oral management for patients undergone several medical treatments not only prevent local oral infections but also prevent systemic inflammations and symptoms, reduce the usage of anti–bacterial drugs, and diminish the hospital stay of the patients. Oral management for patients undergone several medical treatments is not a simple action, it is a concept. The concept of oral management is supported by systems and skills. Therefore, medical primary doctors and primary nurses should understand the concept, systems, and skills, and trigger the systems of oral management.
The incidence of dementia and epilepsy in the elderly have increased steadily over the last few decades. Though little is known about the relation between dementia and epilepsy so far, seizure occurrence in Alzheimer's disease (AD) is more common than in the age–matched control in the recent study. On the other hand, of 10–20% of the etiological diagnosis in the elderly with new–onset epilepsy is neurodegenerative diseases, such as AD and Dementia with Lewy bodies. Subclinical epileptiform activity is detected by long–term video–electroencephalography (EEG), and accelerates cognitive deterioration in AD patients.
Sleep apnea was found to be more common among the elderly, and was more prevalent and severe in male than in female. According to the several studies, SA is associated with an earlier age at mild cognitive impairment or AD–dementia onset. Moreover, SA patients showed lower cerebrospinal fluid β–amyloid42 concentration compared to controls and SA treated by continuous positive airway pressure (CPAP). SA may induce cognitive decline early, but is modified by using CPAP in SA patients.
Adverse drug effects causing cognitive impairment are the important problem in the elderly, however, it is not easy to identify the causing drug accurately. The onset of dementia after taking anticholinergic drugs are different between preclinical stage of AD and the elderly. The patients with preclinical stage of AD are exposed to the fewer number of anticholinergic drugs compared with the elderly. We should monitor the drug therapy carefully to minimize this problem.
What should we do if the patient complains of a headache?
In general, it is essential to first check the vital signs, evaluate the level of consciousness, and decide whether or not it is in an emergency. Headache diagnosis will be followed without medical emergent situation. First of all, you should confirm whether it is “a headache that he/she has never experienced before” or “it is a headache that he/she always repeat”. If it is the former, there is a higher probability of a “secondary headache” which has other causes of headache, and if it is the latter, it may be a chronic headache of “primary headache” as the headache itself is a disease.
If you think of a secondary headache, you have to make sure that you don't miss a headache due to an urgent or progressive disease that can not be postponed. According to “Clinical Practice Guideline for Chronic Headache 2013”, in the following cases : (1) headache with sudden onset, (2) headache never experienced before, (3) headache different from the customary headache, (4) headache that has increased in frequency and intensity, (5) headache begins after age 50, (6) headache with neurological deficit, (7) headache in a patient with cancer or immunodeficiency, (8) headache in a patient with psychiatric symptoms, (9) headache in a patient with fever, neck stiffness or meningeal irritation, it is recommended that an aggressive search is necessary in doubt of secondary headache. It is important to keep in mind the characteristics and accompanying symptoms of headaches to search.
When considering primary headache that is a disease itself such as migraine, tension–type headache, and trigeminal autonomic cephalalgias, you should be clear whether the diagnosis is migraine, and if it is migraine, how the influence on daily life is.
One of the most difficult issues at present in daily practice of migraine headaches is to respond chronic headaches. It is necessary to search for chronification promoting factors that can be intervened and to treat migraine with considering the prevention against it.
Although everyone has experienced headaches at least once due to colds, lack of sleep, or hangovers, and headaches are one of the common complaints often encountered in daily practice, there is always the possibility that secondary headaches or severe migraine headaches are included in it. It is hoped that many headache patients will be able to spend their smiles as medical workers deal with appropriate headaches.
Dementia is an acquired cognitive decline in one or more cognitive domains including memory, attention, executive function, learning, language, perception, and social cognition. They interfere significantly with a person's everyday independence in dementia, but not so in mild cognitive impairment (MCI). Evidence of significant cognitive decline from a previous level of performance can be noted by a concern of the individual, knowledgeable informant such as family member, or the clinician. A substantial impairment in cognitive performance, however, may be documented by standardized neuropsychological testing.
Neurophysiological testing is essential to determine incremental improvements or declines in cognitive functioning and to speculate the involved brain regions. Results of the testing can indicate cognitive functioning of a patients, help diagnosing the cause of dementia, and evaluate the effect of therapeutic intervention. The MMSE, HDS–R, and MoCA are brief comprehensive testing used extensively in clinical settings to screen for dementia. ADAS–cog also is a testing to measure cognition, but more thorough than the MMSE, in research studies and clinical trials for new drugs.
Several tests are available to evaluate specific cognitive domains of interest. The frontal assessment battery is a brief testing of six neuropsychological tasks designed to assess frontal lobe function. The Kohs Block Design Test is a non–verbal assessment of executive functioning, useful with the language and hearing impaired. The Rivermead Behavioral Memory Test includes 14 subtests assessing aspects of visual, verbal, recall, recognition, immediate and delayed everyday memory. The Clinical Dementia Rating or CDR is a numeric scale used to quantify the severity of cognitive decline, beneficial for the early diagnosis of dementia and staging. Neuropsychiatric Inventory (NPI) was developed to provide a brief assessment of neuropsychiatric symptomatology in routine clinical practice settings. The NPI includes 12 neuropsychiatric domains and evaluate its frequency, severity, and the severity of caregiver distress of each behavior. Appropriate testing should be selected depending on its purpose, and mental and physical condition of a patient.
Involuntary movements, a collective term for movements occurring without volition, are the hallmark of hyperkinetic movement disorders. The main types of hyperkinetic movement disorders comprise restless leg syndrome, tremor, chorea, dystonia, myoclonus, and tics, along with other symptoms including akathisia, hemifacial spasm, myokymia, stereotypies, periodic limb movement disorder, hyperekplexia, and alien hand syndrome. Variations in movement symptoms termed dyskinesia are often observed in clinical practice in response to levodopa and dopamine agonist treatment. Despite falling outside the narrow definition of involuntary movements, psychogenic involuntary movements that can be temporarily voluntarily suppressed and involuntary movements caused by adverse drug effects also require attention. Most involuntary movements can be diagnosed through observation of clinical characteristics. However, it is important to begin by accurately noting the observed movements without trying to fit them into an existing diagnostic category. The initial focus of observation should be temporal patterns of occurrence, specifically whether movements are irregular or have a constant or periodically recurrent rhythm. Tremors are characterized by constant rhythmic oscillations in contrast with the irregular pattern presented by other types of involuntary movement. In cases where it is difficult to differentiate between tremors and other movement disorders, skin palpation and surface electromyography are useful for diagnosis. The choice of drug therapy among the many available types should be based on the pathophysiology of the hyperkinetic (involuntary) movements or underlying disorder.
Recently, the 2017 Japanese guidelines for multiple sclerosis (MS) and neuromyelitis optica (NMO), as well as the supplement of the 2017 guidelines for dimethyl fumarate have been published. The 2017 guidelines include outlines on MS, NMO, and six other central nervous system demyelinating diseases. Furthermore, they contain 110 clinical questions and general discussion on epidemiological and etiological studies that primarily pertain to MS and NMO. The guidelines also have a detailed discussion section on symptoms, disability measurements, diagnostic tests, diagnostic criteria, clinical course and prognosis. Additionally, they include information on medical economics and social resources. The guidelines further focus on therapeutic approaches. Specifically, they include recommendations on general treatment strategies, acute stage treatment, disease–modifying therapy and symptomatic treatment for sequelae following MS and NMO's relapse. The present review discusses key points of the 2017 Japanese guidelines and their application in the clinical practice. Furthermore, this review discusses additional tasks to focus on in future guidelines.
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system affecting more than two millions people worldwide. Demyelination is a hallmark of MS pathology and remyelination failure is often evident in MS patients. Several candidate remyelination therapies inducing oligodendrocyte maturation are being clinically developed, however the efficacy of these therapies may be compromised by the intrinsic failure in preserved oligodendrocyte precursor cells in MS lesions, a possible species differences between experimental animals and human, and the lack of clinically feasible methods to detect subclinical remyelination. Possible adverse events caused by induced hypermyelination should also be taken into account. In this review, the current status and future perspectives of remyelination medicines in MS will be discussed.
Neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) are the two main autoimmune disorders of the central nervous system (CNS). The discovery of diagnostic biomarkers for NMOSD, aquaporin–4 (AQP4) autoantibodies, provides significant research progresses of NMOSD as follows ; 1) accurate diagnosis and prompt therapeutic option for patients with NMOSD and MS, 2) newly pathomechanistic insights of AQP4 autoantibodies and complements as significant pathogenic immune molecules for NMOSD, resulting in primary damages of astrocytes and ependymal cells, and secondary but severe neuroaxonal damages and demyelination, and 3) future possible developments of new disease–modifying therapies that target aberrant immune systems (e.g. complements, interleukin–6 and B cells) for NMOSD. The NMOSD landscape has been comprehensively transformed by these progresses since the discovery of AQP4 autoantibodies in 2004.
Myelin oligodendrocyte glycoprotein (MOG) is a glycoprotein exclusively expressed on the surface of myelin sheath in the central nervous system (CNS). Although the precise function of MOG is not yet known, it is possibly related to the maintenance of the myelin structure. Although the IgG antibodies against MOG (MOG–IgG) are investigated in various demyelinating diseases, pathogenic antibodies had not been identified in any of the diseases. Using CBA, we are now able to detect a disease–specific MOG–IgG of IgG1 subclass. The specific MOG–IgG was initially reported in a study of pediatric demyelinating diseases, followed by studies of seronegative neuromyelitis optica spectrum disorders (NMOSD) and optic neuritis. However, since the patients with MOG–IgG have various phenotype and are relatively rare compared with multiple sclerosis (MS), it is still yet unknown what a prototypic phenotype of this disease is.
Migraine is a chronic, disabling, and recurrent neurological disorder. The guideline published by Japanese Headache Society, based on evidence–based medicine data, is a useful source of guidance, especially for acute and preventive therapies of episodic migraine (Japanese Guideline for Chronic Headache 2013).
In acute therapy, we give migraineurs NSAIDs or triptans. We have five triptans (sumatriptan, zolmitriptan, eletriptan, rizatriptan, and naratriptan) in Japan. Notably, sumatriptan has three dosage forms (oral tablet, inhalant, and injection). They are used appropriately by the type of migraine attacks. In general, we firstly give an oral tablet. However, when patients have nausea and vomiting, they cannot take oral medicines. At that time, we use inhalant or injection, especially injection for a severe attack. It's important to know the best timing to take a triptan just after the attack to get the most effective treatment.
In preventive therapy, we usually use calcium blockers, anti–epileptic drugs, anti–depressants, and β–blockers. Among them, lomerizine, verapamil, valproic acid, amitriptyrine, and propranolol have insurance adaptations in Japan. When we prescribe those drugs, we should choose an appropriate preventive drug with an individual patient. As for the trick of acute treatment, we sometimes give a migraineur both triptan and NSAIDs when a migraineur has a severe attack.
Both of chronic migraine (CM) and medication–overuse headache (MOH) are common neurological diseases. They have a great detrimental influence on a patient's life, with a severe impact on socioeconomic functioning and quality of life.
One of the most common causes of migraine chronification is acute medication overuse. On the other hand, MOH is an interaction between a therapeutic agent used excessively and a susceptible patient. Among those with a previous primary headache diagnosis, about 80% of MOH patients have migraine.
All patients with CM should be considered for pharmacological prophylaxis, and the behavioral aspects of therapy should be emphasized. The two prophylactic drugs with the best evidence for efficacy in CM are topiramate and onabotulinumtoxinA. But these therapies currently have not been covered by health insurance in Japan. The options to treat patients with CM are valproic acid, propranolol, lomerizine and amitriptyline. The treatment principles for MOH are : (1) discontinue the overused medication, (2) treat the headache after discontinuing the overused medication, and (3) administer prophylactic medications. Clinical evidence shows that the majority of patients with MOH improve after discontinuation of the overused medication, as does their responsiveness to preventative treatment. Simple advice on the causes and consequences of MOH is an essential part of its management and can be provided with success. Initiation of prophylactic medications at the time of withdrawal or even before withdrawal of overused medications is recommended. Since most of the MOH patients have migraine prior to MOH, valproic acid, lomerizine, propranolol, amitriptyline may be considered as prophylactic medications. As for prognosis, the relapse rate is approximately 30%. Even after discontinuation, patients should be given suitable counseling, and headache diary should be used to confirm the frequency of using triptans, ergotamine and analgesics.
Tension type headache (TTH) is the most frequent headache among the primary headaches, and it is often encountered by a doctor in routine practice.
The severity of tension type headache is mild to moderate. However, among patients with chronic or frequent episodic tension type headache it often disturbs their QOL (quality of life) in daily livings.
The most important thing in managing TTH is correct diagnosis. In order to reach the proper treatment, it is important to exclude secondary headache, migraine and other primary headaches.
The first line of acute treatment of TTH is administration of the abortive drugs such as NSAIDs and analgesics. However attention must be paid not to administer them loosely because these drugs sometimes induces medication overuse headache (MOH). As a preventive medication, antidepressants such as amitriptyline and muscle relaxants are recommended. It is also important to combine non–medication therapy such as psyco–behavioural therapy, relaxation or physical therapy. Understanding the stress and environmental factors of each case, and their management according to their condition are another important issues.
Trigeminal autonomic cephalalgias includes cluster headache, paroxysmal hemicrania, short–lasting unilateral neuralgiform headache attacks and hemicrania continua. The trigeminal autonomic cephalalgias share the clinical features of unilateral headache and, usually, prominent cranial parasympathetic autonomic features, which are lateralized and ipsilateral to the headache. However, the responses to the treatment for the headaches are different in each trigeminal autonomic cephalalgias. The present review will discuss the recent findings of the treatments for the trigeminal autonomic cephalalgias.
During the last 10 years, reversible cerebral vasoconstriction syndrome (RCVS) has emerged as the most frequent cause of thunderclap headache (TCH) in patients without aneurysmal subarachnoid hemorrhage, and as the most frequent cause of recurrent TCHs. The typical TCHs of RCVS are multiple, recurring over a few days to weeks, excruciating, short–lived, and brought up by exertion, sexual activities, emotion, Valsalva maneuvers, or bathing, among other triggers. The pathophysiology of RCVS is unknown, though alterations in cerebral vascular tone are thought to be a key underlying mechanism.
Because randomized controlled trials do not yet exist, treatment of RCVS is currently based on empiric treatment. Current treatment recommendations for RCVS include withdrawal of any suspected exogenous triggers, including vasoactive medications, and intensive care unit level care, symptom relief with analgesics, blood pressure control, and seizure prophylaxis. Calcium channel blockers, such as nimodipine, verapamil or lomerizine, have been used in most patients. Glucocorticoid steroids have been administered to patients with RCVS, without improvement in either patient symptoms or sequelae of the disease.
Early diagnosis of RCVS in patients who present with isolated headache enables proper management and might reduce the risk of eventual stroke. Probable RCVS can be diagnosed transiently in patients in whom a repeat angiogram will disclose visible vasoconstriction after a few days, and can also be made in patients who will have no visible vasoconstriction at all. Patients with probable RCVS should be managed as patients with visible vasoconstriction. The syndrome typically follows a benign course ; however, RCVS may result in permanent disability or death in a small minority of patients secondary to complications such as ischemic stroke or intracranial hemorrhage.
We describe the characteristics, triggers, diagnosis, and management of TCH in RCVS.
Migraine is a common neurological disorder, negatively affecting activities of daily living. Patients with migraine frequently show daytime sleepiness and insomnia. Sleep disturbances worsen headache, while sleep ameliorates headache. We have previously reported increased prevalence of restless legs syndrome and dream enacting behavior in migraine patients. Hypersomnia disorders, including narcolepsy and idiopathic hypersomnia, are characterized by excessive daytime sleepiness not caused by disturbed nocturnal sleep or impaired circadian rhythms. Previous studies showed increased prevalence of migraine in patients with narcolepsy compared with healthy controls. In our multicenter study, migraine was more frequently observed in patients with narcolepsy or idiopathic hypersomnia compared with healthy controls. These findings may suggest pathophysiological similarities between migraine and hypersomnia disorders.
Restless legs syndrome (RLS) is characterized by unpleasant leg sensations and irresistible urges to move the lower extremities, mainly at night. The diagnosis of RLS was made using five major items of RLS developed by the International RLS Study Group (IRLSSG). Supported items for RLS were the existence of periodic limb movement, the positive of family history, the effectiveness of dopaminergic agents, and the absence of excessive daytime sleepiness. About twenty percentage of RLS was categorized as secondary RLS such as iron-deficiency anemia and Parkinson's disease. The prevalence of RLS has racial different between western countries and Japan. However, this is no difference on the prevalence of RLS in patients with PD between western countries and Japan. The odds ratio of RLS in PD was reported 2.61 (95%CI 1.96～3.47). The pathophysiology of RLS is supported as dopamine dysfunction in A11 dopamine system. The spinal pathology of PD started after the stage 3 of Braak theory. Many patients with PD had RLS symptoms after the onset of motor symptoms. These findings supported that pathophysiology of RLS origin form spinal dopamine system. However, this issue had not reached a conclusion yet.
A detailed survey to investigate the prevalence, clinical features, associated outcomes, and prognostic factors in adult patients with influenza–associated acute encephalopathy was performed. The estimated annual incidence of adult IAE was 0.98/1,000,000 population in Japan. Baseline patient characteristics were 50% male, median age at onset of 54.5 years, and median hospital stay of 15 days. As initial symptoms, 93% of patients showed disturbance of consciousness. Convulsions and delirious behavior were shown in 26% and 40% of patients, respectively. 65% of patients received pulse corticosteroid therapy with methylprednisolone and 21% of patients received intravenous gamma–globulin therapy. Additionally, 21% of patients required mechanical ventilation. 63% of patients achieved a good recovery, but 7% died. Plasma glucose level was significantly associated with poor outcome. Hyperglycemia might be an independent predictor of poor prognosis in IAE patients and reflect systemic hypercytokinemia in IAE pathogenesis.
Herpes simplex virus encephalitis may have a relapsing course in up to 13–24% of adults and children, despite antiviral treatment. Herpes simplex encephalitis can trigger autoimmune encephalitis that leads to neurological worsening. This review will recapitulate the recent scientific progress.