[Historical Review of Hemifacial Spasm].

Facial spasm is a disorder characterized by mostly unilateral(hemifacial)involuntary facial muscle contractions, usually caused by vascular compression of the facial nerve. It has been known since ancient times and we can currently find both old medical and artistic presentations. Charles Bell has described at least one definite case(No. IV)with hemifacial spasm in his textbook published in 1830 as did the following physicians like Romberg, Hammond, Gowers, and Brissaud. Babinski coined the name hemispasme facial in 1905 and its English term "hemifacial spasm" appeared in the article by Ehni et al. in 1945. Neurovascular or microvascular decompression surgery was applied to treat this disease in the 1960s and remains a curative therapeutic procedure. Therapy with botulinum toxin appeared as a less invasive procedure in the 1980s and is currently the preferred treatment because of its high safety and efficacy. Secondary facial spasms may occur as a consequence of facial paresis or space-occupying lesion along the facial nerve pathway.

[Focal or Segmental Dystonia Resistant to Botulinum Toxin: Re-Evaluation, Surgery, and Botulinum Again].

Botulinum toxin is effective in most patients with focal/segmental dystonia. A minority of these patients show primary or secondary resistance to this therapy. After excluding technical reasons, such as inappropriate dosage or injection sites, neutralizing antibodies against the toxin may be suspected. If the patient tests positive for the anti-toxin antibody, changing the toxin type may be effective. The next step in treatment is local surgical approaches or stereotactic surgery, depending on the type of dystonia. Stereotactic surgery can be the first-line treatment for some types of dystonia because of its high efficacy or because of the absence of official approval for botulinum toxin treatment in Japan. If the clinical efficacy of surgery is insufficient, retreatment with botulinum toxin should be considered for remaining symptoms when the patient is negative for the anti-toxin antibody. Adjunctive therapies include oral medication, rehabilitation, or the use of devices that alleviate symptoms via sensory tricks or other mechanisms. Any of these may be applied simultaneously with the main procedure. The shortage of expert doctors providing botulinum toxin therapy is the most urgent issue in Japan, as this limits patients' access to therapy and potentially undermines the quality of disease management.

Jacqueline du Pré and her alternative diagnosis.

JacquelineduPré (26 January 1945-19 October 1987) is one of the greatest cellists in the 20th century. Her musical career was terminated at age 28, allegedly due to multiple sclerosis (MS). MS is an immune-mediated demyelinating disease of the central nervous system with axonal involvement, characterized by the dissemination in time and space of the lesions (plaques). Diverse neurological symptoms may occur in MS, and a variety of symptoms relentlessly accumulated in her case after the diagnosis in 1973, which is concordant with primary progressive rather than relapsing-remitting form of MS. No radiological confirmation was however possible in her days and the diagnosis should be reconsidered, because her symptoms had some unusual features in MS. First, her principal symptoms, aside from transient visual and urological problems noticed earlier, began in the upper and lower limbs, often only in the upper limbs, then followed by the involvement of lower cranial nerves, and by the cognitive decline with changes in character. Hence the pattern of progression was ascending from the cervical spinal cord to the brainstem and to the cerebrum, which is not the pattern of dissemination in space typical of MS. Her clinical status appeared steroid-dependent temporarily in the early stage of the disease, which is also unusual in MS and some different etiology deserves consideration. We suppose that Uhthoff phenomenon, i.e. worsening of symptoms by the elevation of body temperature, may have been negative contrary to the previous interpretation, and if we are correct the absence of this sign does not support the demyelinating pathophysiology of her disease. Now that there is no objective medical information sufficiently disclosed, another scenario may be hypothesized, although MS is still a likely possibility. We discuss that syringomyelia/syringobulbia associated with Chiari malformation type I and obstructive hydrocephalus can be an alternative diagnosis.

Phenotype variability and allelic heterogeneity in KMT2B-Associated disease.

BACKGROUND: Mutations in Lysine-Specific Histone Methyltransferase 2B gene (KMT2B) have been reported to be associated with complex early-onset dystonia. Almost all reported KMT2B mutations occurred de novo in the paternal germline or in the early development of the patient. We describe clinico-genetic features on four Japanese patients with novel de novo mutations and demonstrate the phenotypic spectrum of KMT2B mutations. METHODS: We performed genetic studies, including trio-based whole exome sequencing (WES), in a cohort of Japanese patients with a seemingly sporadic early-onset generalized combined dystonia. Potential effects by the identified nucleotide variations were evaluated biologically. Genotype-phenotype correlations were also investigated. RESULTS: Four patients had de novo heterozygous mutations in KMT2B, c.309delG, c.1656dupC, c.3325_3326insC, and c.5636delG. Biological analysis of KMT2B mRNA levels showed a reduced expression of mutant transcript frame. All patients presented with motor milestone delay, microcephaly, mild psychomotor impairment, childhood-onset generalized dystonia and superimposed choreoathetosis or myoclonus. One patient cannot stand due to axial hypotonia associated with cerebellar dysfunction. Three patients had bilateral globus pallidal deep brain stimulation (DBS) with excellent or partial response. CONCLUSIONS: We further demonstrate the allelic heterogeneity and phenotypic variations of KMT2B-associated disease. Haploinsufficiency is one of molecular pathomechanisms underlying the disease. Cardinal clinical features include combined dystonia accompanying mild psychomotor disability. Cerebellum would be affected in KMT2B-associated disease.

Dystonia as a patterned motor malflow.

The definition of dystonia has been renewed repeatedly but always within the context of overactive muscle contractions. In dystonia the muscles unnecessary for a motion fail to be adequately suppressed because of the loss of central motor control, resulting in inappropriate movements or abnormal postures ("overflow phenomenon"). This represents, however, only one side of the disrupted motor control. Some patients complain of the inability to activate muscles necessary for the intended task despite the lack of motor paresis, as best exemplified by the apraxia of eyelid opening. The author has ever coined the term "negative dystonia" for this phenomenon, which occurs hypothetically as a result of failed central motor flow and is often co-existent with overflow. Negative dystonia has a fixed pattern and sensory trick may be effective to ameliorate the symptom just as in the case of conventional dystonia. Hence we can speculate that the overflow and flow failure are the two sides of the same coin, both being caused by the loss of motor control. The current hypothesis is that dystonia is a representation of the patterned motor malflow (malicious flow) due to the loss of motor control.

Are multifocal motor neuropathy patients underdiagnosed? An epidemiological survey in Japan.

INTRODUCTION: Our objective was to do an epidemiologic survey of patients with multifocal motor neuropathy (MMN) in comparison with those with amyotrophic lateral sclerosis (ALS) in Japan. METHODS: In this retrospective study, we examined 46 patients with MMN and 1,051 patients with ALS from major neuromuscular centers in Japan from 2005 to 2009. Diagnosis was based on the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) and the revised El Escorial criteria. The efficacy of intravenous immunoglobulin (IVIg) was also taken into consideration in the diagnosis of MMN. RESULTS: The ratio of MMN to ALS patients (0­0.10) varied among the centers, but mostly converged to 0.05. The prevalence was estimated to be 0.29 MMN patients and 6.63 ALS patients per 100,000 population. CONCLUSIONS: The frequency of MMN patients was around 1 out of 20 ALS patients, and MMN was possibly underdiagnosed in some centers.

[Dystonia as a common status against a common belief].

Primary dystonia is believed to be rare, and its estimated prevalence is roughly around 10-20 per 100,000 in the general population. In middle-aged or elderly people, the prevalence is much higher, reported to be over 700 per 100,000. Dystonia also occurs secondarily in various conditions, as drug-induced (acute or tardive) dystonia or in association with neurological disorders. Reported prevalence values may be underestimate. The diagnosis of dystonia tends to be delayed for several years after the onset of symptoms, or the symptoms may be left unrecognized or misinterpreted. "Dry eye" is common in the modern society and is a frequent misdiagnosis of blepharospasm. "Stiff sensation of the neck", a ubiquitous symptom among Japanese, may actually be a phenotype of cervical dystonia. A subset of "essential tremor" and tremor in SWEDDs (Scans Without Evidence of Dopaminergic Deficits) reportedly have similar pathophysiology to dystonia. Occupational dystonia is common within a specific population. About 1% of musicians may suffer from musician's dystonia, and about one-third of professional or highly skilled golfers may have "yips", possibly a representation of dystonia. Dystonia is common against a general belief, and should be included among the differential diagnosis in patients with muscular hyperactivity and impaired voluntary movements.

[Clinical characteristics and treatment of dystonia].

Dystonia is defined as a syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements, or abnormal postures. Its diagnosis is based on clinical characteristics. In dystonia, the pattern of abnormal posture or movement tends to be constant during the short term even if its severity fluctuates. This stereotypy often helps differentiate dystonia from psychogenic reaction. Dystonia may appear only during some specific task (task specificity) especially in its early phase, although it often becomes obscure during the long clinical course, resulting in persistent dystonic posture. Sensory trick or geste antagoniste means the change of severity triggered by some sensory input Overflow phenomenon is the activation of muscles unnecessary to a task, hampering purposeful movement. Symptoms tend to be milder in the morning, with large individual variation of its duration (morning benefit). Symptoms of dystonia may abruptly appear or disappear (flip-flop phenomenon). Cocontraction, believed as an essential feature of dystonia, reflects a loss of reciprocal inhibition of muscle activities, causing involuntary simultaneous contractions of agonists and antagonists. "Negative dystonia," still an unaccepted feature of dystonia, is defined as non-paretic loss of central driving of muscle activities necessary to a task. Apraxia of lid opening/closure, paretic form of hand dystonia, dropped head syndrome, camptocormia, Pisa syndrome, cervical dystonia with limited range of head movement, or mandibular dystonia without cocontractions of masticatory muscles, can be explained with this concept at least in a subset of cases. Treatment of dystonia includes medication, botulinum toxin injection, intrathecal baclofen, surgical intervention, acupuncture and other alternative therapies, rehabilitation, and psychotherapy. Oral medication is usually an adjunct to more potent therapeutic options except for some specific indications like dopa-responsive dystonia. Botulinum toxin is usually the treatment of choice for focal dystonia. Deep brain stimulation can be considered for both focal and non-focal phenotypes of dystonia.

[Clinical application of botulinum toxin].

The clinical application of botulinum toxin (BoNT) was first proposed by Justinus Kerner in 1822. BoNT was formally accepted as a therapeutic agent in the 1970s, and currently, it is used worldwide for treating diseases as well as for cosmetic conditions. In Japan, Botox® is the only type A formulation that has been officially approved for the treatment of blepharospasm, hemifacial spasm, cervical dystonia, pes equinus of cerebral palsy, adult spasticity of upper and lower limbs, and Botox Vista® is applied for glabellar frown lines. Its effect is symptomatic, but long-lasting remission is noted after treatment in more than 30% of cases with cervical dystonia. Ultrasound guidance is useful and may be even superior to electromyographic monitoring, especially when the obliquus capitis inferior muscle is targeted in rotatocollis, because the vertebral artery or upper cervical nerve root(s) may be injured when the needle penetrates the muscle. BoNT alleviates pain or glandular secretion besides causing a neuromuscular block. After being transported to the axons, BoNT is carried centrally and even to the adjacent neurons via synapses (toxin jump). A direct central action has also been postulated. BoNT is generally safe, but serious adverse reactions may occur very rarely. Individual differences in toxin sensitivity may be considerably greater than assumed, and even the routine clinical dose may be too high in some patients. The future strategy includes clinical application of other types of toxin or chimera toxins, or the use of the toxin as a cargo ("Trojan Horse") carrying some bioactive molecules into the cell. A non-injection procedure for mucosal application or cosmetic use is currently under clinical trials.

Rippling is not always electrically silent in rippling muscle disease.

Rippling muscle disease (RMD) is a myopathy with hyperirritability, the pathophysiology for which is uncertain.We report electromyographic findings in a 30-year-old man with RMD. Clinical features included muscle rippling and percussion-induced rapid muscle contractions. Both were associated with bursts of short-duration, low-amplitude spikes, which resembled single muscle fiber discharges. Our case stands in contrast to previously reported cases, which showed either electrical silence or motor unit potential discharges associated with rippling, and may represent muscle fiber hyperexcitability.

Impairment of the cortical GABAergic inhibitory system in catatonic stupor: a case report with neuroimaging.

We report the case of a 32-year-old patient who presented with catatonic stupor during the course of acute aseptic encephalitis involving the right frontotemporal area. Flumazenil-PET performed during the stupor indicated decreased benzodiazepine receptor binding in the right frontotemporal area where glucose metabolism was preserved as revealed by FDG-PET. An injection of diazepam immediately ameliorated catatonic symptoms and reduced widespread high amplitude slow EEG activities with right frontotemporal predominance. Compared with a SPECT study performed a week earlier, there was no abnormal right-sided anteriorly predominant cerebral hyperperfusion after injection of diazepam. While neither flumazenil- nor FDG-PET could be repeated, and with the caveat that generalized convulsions occurred initially and epilepsia partialis continua was present for two weeks starting on the 23rd day after illness onset, these findings suggest that in our case the presentation with catatonic stupor may be related to impairment of the cortical GABAergic inhibitory system.

Dystonic frowning without blepharospasm.

We report on two cases who presented with involuntary facial grimacing and frowning. Blepharospasm has never been documented in one, and the other case showed difficulty in lid opening only in the early phase of the disease. Botulinum toxin was effective for both. This is a hitherto unreported presentation of upper facial dystonia without interference of eyelid motor control.

Dystonia redefined as central non-paretic loss of control of muscle action: a concept including inability to activate muscles required for a specific movement, or 'negative dystonia'.

Dystonia is defined as a syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements, or abnormal postures. Although this definition comprises an essential feature of dystonia, the clinical observation indicates that there is an additional aspect of dystonia; failure to adequately activate muscles required for specific movement, exemplified by the lack of contractions of the levator palpebrae superioris muscles in apraxia of lid opening, as well as by inability to activate appropriate muscles in cervical dystonia or in the paretic form of writer's cramp, and possibly by dropped head syndrome or camptocormia seen in parkinsonian patients without apparent truncal dystonia or rigidity. Taking this "negative dystonia" into consideration, the author proposes a revised definition of dystonia as a symptom characterized by the central non-paretic loss of voluntary control of muscle activities, which may result in either excessive or deficient contractions of muscles, frequently causing twisting and repetitive movements, limitation of movements, or abnormal postures.

Dynamic change of proximal conduction in demyelinating neuropathies: a cervical magnetic stimulation combined with maximum voluntary contraction.

OBJECTIVE: To evaluate conduction abnormalities in the nerves innervating the proximal muscles in demyelinating neuropathies (DN) using cervical magnetic stimulation. METHODS: We applied cervical root magnetic stimulation in the biceps brachii muscles and examined its activity-dependent conduction changes produced by maximal voluntary contraction (MVC) in 12 DN patients (seven chronic inflammatory demyelinating polyradiculoneuropathy and five multifocal motor neuropathy), six motor neuron disease (MND) patients, and 12 healthy volunteers. RESULTS: Defining the upper normal limit of motor threshold (31%) and latency (6.7 ms) of the compound muscle action potential (CMAP) as mean+2SD, most DN patients revealed an abnormality in motor threshold (10/12) and latency (11/12) in contrast to MND patients (motor threshold (1/6) and latency (0/6)). These parameters contribute to the differentiation of DN from MND (P<0.01). Furthermore, the MVC maneuver transiently decreased the CMAP amplitude ratio (after MVC/before MVC x 100) in DN (83+/-18 %) compared with MND (P<0.01). Two of three DN patients who showed normal motor threshold or latency as in MND were successfully differentiated from MND by the MVC maneuver. CONCLUSIONS: In DN patients, conduction abnormality in the nerves innervating the proximal muscles was revealed by cervical magnetic stimulation combined with the MVC maneuver. SIGNIFICANCE: Our results suggested that conduction abnormalities in the proximal nerves innervating the proximal muscles could be evaluated by this method.

[A survey about the accessibility to botulinum toxin therapy for dystonia].

We investigated the accessibility of the therapy with botulinum toxin for blepharospasm or cervical dystonia in Japan. Based on the administration sheet for Botox sent to the Japan Branch of Allergan Co. Ltd. (Tokyo, Japan), the survey was performed about how many institutions treated 3 or more patients with botulinum toxin in each of February, 2003, and February, 2005, for each disease entity. Among 369 secondary medical zones covering all the areas of Japan, 73 zones had 103 institutions that met our criteria for blepharospasm in 2003, and the number slightly increased to 77 zones and 109 institutions in 2005. For cervical dystonia, 25 zones had 32 institutions in 2003, and the number increased to 36 zones and 48 institutions in 2005. Although medical zones with larger population tended to have more institutions, there was great inequality in the accessibility of patients among medical zones. Besides, the number of institutions was thought to be quite insufficient especially for cervical dystonia in most areas of Japan. Larger number of institutions in any region of Japan should be preferably able to treat focal dystonia with botulinum toxin in order to improve patients' accessibility, because this safe and effective therapy can be now regarded as the first line for both blepharospasm and cervical dystonia.