Neurophysiology of cerebellar ataxias and gait disorders.

There are numerous forms of cerebellar disorders from sporadic to genetic diseases. The aim of this chapter is to provide an overview of the advances and emerging techniques during these last 2 decades in the neurophysiological tests useful in cerebellar patients for clinical and research purposes. Clinically, patients exhibit various combinations of a vestibulocerebellar syndrome, a cerebellar cognitive affective syndrome and a cerebellar motor syndrome which will be discussed throughout this chapter. Cerebellar patients show abnormal Bereitschaftpotentials (BPs) and mismatch negativity. Cerebellar EEG is now being applied in cerebellar disorders to unravel impaired electrophysiological patterns associated within disorders of the cerebellar cortex. Eyeblink conditioning is significantly impaired in cerebellar disorders: the ability to acquire conditioned eyeblink responses is reduced in hereditary ataxias, in cerebellar stroke and after tumor surgery of the cerebellum. Furthermore, impaired eyeblink conditioning is an early marker of cerebellar degenerative disease. General rules of motor control suggest that optimal strategies are needed to execute voluntary movements in the complex environment of daily life. A high degree of adaptability is required for learning procedures underlying motor control as sensorimotor adaptation is essential to perform accurate goal-directed movements. Cerebellar patients show impairments during online visuomotor adaptation tasks. Cerebellum-motor cortex inhibition (CBI) is a neurophysiological biomarker showing an inverse association between cerebellothalamocortical tract integrity and ataxia severity. Ataxic gait is characterized by increased step width, reduced ankle joint range of motion, increased gait variability, lack of intra-limb inter-joint and inter-segmental coordination, impaired foot ground placement and loss of trunk control. Taken together, these techniques provide a neurophysiological framework for a better appraisal of cerebellar disorders.

Clinical diagnostic utility of transcranial magnetic stimulation in neurological disorders. Updated report of an IFCN committee.

The review provides a comprehensive update (previous report: Chen R, Cros D, Curra A, Di Lazzaro V, Lefaucheur JP, Magistris MR, et al. The clinical diagnostic utility of transcranial magnetic stimulation: report of an IFCN committee. Clin Neurophysiol 2008;119(3):504-32) on clinical diagnostic utility of transcranial magnetic stimulation (TMS) in neurological diseases. Most TMS measures rely on stimulation of motor cortex and recording of motor evoked potentials. Paired-pulse TMS techniques, incorporating conventional amplitude-based and threshold tracking, have established clinical utility in neurodegenerative, movement, episodic (epilepsy, migraines), chronic pain and functional diseases. Cortical hyperexcitability has emerged as a diagnostic aid in amyotrophic lateral sclerosis. Single-pulse TMS measures are of utility in stroke, and myelopathy even in the absence of radiological changes. Short-latency afferent inhibition, related to central cholinergic transmission, is reduced in Alzheimer's disease. The triple stimulation technique (TST) may enhance diagnostic utility of conventional TMS measures to detect upper motor neuron involvement. The recording of motor evoked potentials can be used to perform functional mapping of the motor cortex or in preoperative assessment of eloquent brain regions before surgical resection of brain tumors. TMS exhibits utility in assessing lumbosacral/cervical nerve root function, especially in demyelinating neuropathies, and may be of utility in localizing the site of facial nerve palsies. TMS measures also have high sensitivity in detecting subclinical corticospinal lesions in multiple sclerosis. Abnormalities in central motor conduction time or TST correlate with motor impairment and disability in MS. Cerebellar stimulation may detect lesions in the cerebellum or cerebello-dentato-thalamo-motor cortical pathways. Combining TMS with electroencephalography, provides a novel method to measure parameters altered in neurological disorders, including cortical excitability, effective connectivity, and response complexity.

[Oculomotor nerve palsy with preserved pupillary reaction in two cases of neurolymphomatosis].

Case 1: A 64-year-old woman with acute ptosis and diplopia was admitted to our hospital. She had right oculomotor nerve palsy with preserved pupillary reaction without any other neurological deficits. MRI showed abnormal enhancement in the right oculomotor nerve. An ovarian tumor was detected on CT examination, and was pathologically diagnosed as diffuse large B-cell lymphoma (DLBCL). Cerebrospinal fluid cytology disclosed malignant lymphoma cells. Based on the above findings, we concluded that she had neurolymphomatosis (NL) of the right oculomotor nerve. Case 2: A 63-year-old woman was admitted to our hospital due to weakness of the bilateral lower extremities and gait disturbance. Lumbar MRI showed enhanced lesions in the cauda equina, and we diagnosed her as having DLBCL based on bone marrow aspiration study. She later developed right oculomotor nerve palsy with preserved pupillary reaction together with the right abducens and hypoglossal nerve palsies, which were caused by NL. Our cases suggest that oculomotor nerve palsy with preserved pupillary reaction can be a clinical feature of NL. Although NL mainly affects the subperinerium, as parasympathetic fibers are located in the periphery of the oculomotor nerve and supplied by pia matar blood vessels, patients with NL may shows this clinical feature.

Rippling Muscle Disease with Irregular Toe Jerks and Anti-acetylcholine Receptor Antibodies: Remission after Extended Thymectomy.

We herein report a 63-year-old rippling muscle disease (RMD) patient who presented with painless stiffness, muscle hypertrophy and muscle contractions elicited by mechanical stimulation. He also showed irregular toe jerks and a slightly elevated level of anti-acetylcholine receptor antibody (AChR-Ab). Since he had a mediastinal mass mimicking thymoma, which was later revealed to be a bronchial cyst, he underwent extended thymectomy. The irregular toe jerks disappeared within a week after the operation. The other muscle symptoms completely remitted 27 months after the onset. This is the first report of a sporadic case of RMD with irregular toe jerks that resolved after extended thymectomy.

A Nationwide Epidemiological Survey of Adolescent Patients With Diverse Symptoms Similar to Those Following Human Papillomavirus Vaccination: Background Prevalence and Incidence for Considering Vaccine Safety in Japan.

BACKGROUND: Since June 2013, Japan has suspended proactive recommendation of human papillomavirus (HPV) vaccination due to self-reported diverse symptoms, including pain and motor dysfunction, as possible serious adverse events following immunization. Although these symptoms may be seen in adolescents without HPV vaccination, their frequency, taking into account disease severity, has not been examined. METHODS: A two-stage, descriptive, nationwide epidemiological survey was conducted in 2016, with a 6-month target period from July 1 to December 31, 2015, to estimate the prevalence and incidence of diverse symptoms among Japanese adolescents without HPV vaccination. Participants were 11,037 medical departments in hospitals selected nationwide by stratified random sampling. Eligible patients had to satisfy four criteria: (1) aged 12-18 years upon visiting hospital; (2) having at least one of four symptoms/disorders (pain or sensory dysfunction, motor dysfunction, autonomic dysfunction, or cognitive impairment); (3) symptoms/disorders persisting for at least 3 months; and (4) both criteria (2) and (3) influence attendance at school or work. We then extracted data of patients with diverse symptoms similar to those after HPV vaccination while considering opinions of doctors in charge. RESULTS: Estimated 6-month period prevalence of diverse symptoms among girls aged 12-18 years without HPV vaccination was 20.2 per 100,000. Annual incidence was estimated to be 7.3 per 100,000. CONCLUSION: Adolescent Japanese girls without HPV vaccination also visited hospitals with diverse symptoms similar to those following HPV vaccination. Our findings predict the medical demands for coincident diverse symptoms, which are temporally associated with but not caused by HPV vaccination of Japanese adolescents.

Perceptual uncertainty modulates auditory statistical learning: A magnetoencephalography study.

Statistical learning allows comprehension of structured information, such as that in language and music. The brain computes a sequence's transition probability and predicts future states to minimise sensory reaction and derive entropy (uncertainty) from sequential information. Neurophysiological studies have revealed that early event-related neural responses (P1 and N1) reflect statistical learning - when the brain encodes transition probability in stimulus sequences, it predicts an upcoming stimulus with a high transition probability and suppresses the early event-related responses to a stimulus with a high transition probability. This amplitude difference between high and low transition probabilities reflects statistical learning effects. However, how a sequence's transition probability ratio affects neural responses contributing to statistical learning effects remains unknown. This study investigated how transition-probability ratios or conditional entropy (uncertainty) in auditory sequences modulate the early event-related neuromagnetic responses of P1m and N1m. Sequence uncertainties were manipulated using three different transition-probability ratios: 90:10%, 80:20%, and 67:33% (conditional entropy: 0.47, 0.72, and 0.92 bits, respectively). Neuromagnetic responses were recorded when participants listened to sequential sounds with these three transition probabilities. Amplitude differences between lower and higher probabilities were larger in sequences with transition-probability ratios of 90:10% and smaller in sequences with those of 67:33%, compared to sequences with those of 80:20%. This suggests that the transition-probability ratio finely tunes P1m and N1m. Our study also showed larger amplitude differences between frequent- and rare-transition stimuli in P1m than in N1m. This indicates that information about transition-probability differences may be calculated in earlier cognitive processes.

Effects of electromagnetic fields from long-term evolution on awake electroencephalogram in healthy humans.

Mobile phones are indispensable for daily life, and the adverse effects of the electromagnetic field (EMF) emitted by mobile phones have been a great concern. We studied the effects of long-term evolution (LTE) -like EMF for 30 min on an awake electroencephalogram (EEG). Thirty-eight healthy volunteers, aged 20-36 years old, participated in this study. The maximum local SAR (specific absorption rate) averaged over 10-g mass was 2.0 W/kg. The EEG was recorded before and after real or sham exposures. The effects of exposure conditions (real or sham) and the recording time (before, during, and after exposure) on each EEG power spectrum of θ, α, and ß frequency ranges were analyzed. The θ and α band waves were enhanced after both exposure conditions. These results may be explained by the participants' drowsiness during the EEG recording in both exposures. We conclude that an LTE-like exposure for 30 min in this study showed no detectable harmful effects on awake EEGs in healthy humans.

A Unique Shape of Brainstem Lesion that Caused Orthostatic Hypotension in Anti-NMDAR Encephalitis.

After experiencing upper respiratory-tract symptoms, a 41-year-old woman developed encephalitis with consciousness disturbance and respiratory failure. She had external ophthalmoplegia and facial diplegia. Magnetic resonance imaging revealed a brainstem lesion with spared longitudinal pontine bundles. Abnormal findings of the brainstem auditory-evoked potentials and blink reflex supported brainstem damage. The patient was positive for anti-N-methyl-D-aspartate receptor (NMDAR) antibodies. Repeated immunological treatments improved her symptoms, but severe orthostatic hypotension emerged. A head-up tilt test revealed no arginine vasopressin response to hypotension. The atypical symptoms of this case highlighted that the brainstem is one of the pivotal regions in anti-NMDAR encephalitis.

Effect of caffeine on long-term potentiation-like effects induced by quadripulse transcranial magnetic stimulation.

Caffeine, an adenosine receptor antagonist, is known to affect sleep-awake cycles, the stress response, and learning and memory. It has been suggested that caffeine influences synaptic plasticity, but the effects of caffeine on synaptic plasticity in the human brain remain unexplored. The present study aimed to investigate the effects of caffeine on long-term potentiation (LTP)-like effects in the primary motor cortex of healthy humans. Twelve healthy participants (six women and six men; mean age: 44.8 ± 1.5 years) underwent quadripulse magnetic stimulation with an inter-stimulus interval of 5 ms (QPS5) to induce LTP-like effects, 2 h after administration of either a caffeine (200 mg) or placebo tablet in a double-blind crossover design. We recorded motor-evoked potentials (MEPs) before and after QPS5. The degree of MEP enhancement was compared between the placebo and caffeine conditions. Neither active nor resting motor thresholds were influenced by caffeine administration. Following caffeine administration, the degree of potentiation significantly decreased in "significant responders", whose average MEP ratios were greater than 1.24 in the placebo condition. The observed reduction in potentiation following caffeine administration is consistent with the A2A receptor antagonistic effect of caffeine. This is the first report of an effect of caffeine on neural synaptic plasticity in the human brain, which is consistent with the caffeine-induced plasticity reduction observed in primate studies. Because we studied only a small number of subjects, we cannot firmly conclude that caffeine reduces LTP in humans. The present results will, however, be helpful when considering further or new clinical uses of caffeine.

[Devotion to painting in a Parkinson's disease patient].

We report a 77-year-old man who suffered from Parkinson's disease for 12 years. Four years after the disease onset, he started to show excessive hobbyism of painting. His painting skills improved along with escalating enthusiasm. He even held a personal exhibition of his paintings. Dopaminergic treatment was increased as he developed wearing-off phenomenon. Six years after the disease onset, he developed dopamine dysregulation syndrome (DDS). In the same year, he underwent surgery for subthalamic deep brain stimulation. DDS did not improve and he did not lose enthusiasm for painting after surgery. Switching from ropinirole to rotigotine improved the DDS, but did not affect the excessive enthusiasm. At the age of 76, he started to have difficulty in completing the paintings. He had an uncontrollable urge to overlay paint strokes until the colors blurred and the paper was torn. In neuropsychological examinations, Mini-Mental State Examination score was above the cutoff, but Frontal Assessment Battery suggested motor perseveration and disinhibition. In summary, the patient's excessive enthusiasm for painting emerged in association with impulse control disorder (ICD) by dopamine agonist therapy, and subsequent change in his painting style appeared to be related with motor perseveration and/or further escalation of ICD.

Pitfalls in clinical diagnosis of anti-NMDA receptor encephalitis.

OBJECTIVES: To report pitfalls in the clinical diagnosis of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. METHODS: We retrospectively reviewed the clinical information of 221 patients with clinically suspected autoimmune neurological disorders who underwent testing for autoantibodies against neuronal cell-surface antigens between January 1, 2007 and September 10, 2017. Forty-one patients met the diagnostic criteria for probable anti-NMDAR encephalitis (probable criteria), but one was excluded because neither serum nor CSF was examined at the active stage. Thus, in 220 patients, sensitivity and specificity of the probable criteria were assessed. RESULTS: NMDAR-antibodies were detected in 34 of 40 patients (85%) with the probable criteria; however, 2 of the 6 antibody-negative patients had ovarian teratoma. The median age at onset was higher in antibody-negative patients than those with antibodies (49 vs. 27 years, p = 0.015). The age at onset was associated with the probability of antibody detection (p = 0.014); the probability was less than 50% in patients aged 50 years or older. NMDAR-antibodies were also detected in 5 of 180 patients who did not fulfill the probable criteria; these patients presented with isolated epileptic syndrome (n = 2), atypical demyelinating syndrome (n = 2; one with aquaporin 4 antibodies), and autoimmune post-herpes simplex encephalitis (post-HSE) (n = 1). Sensitivity and specificity of the probable criteria was 87.2 and 96.7%, respectively. CONCLUSION: The probable criteria are valid, but the diversity of clinical phenotype should be taken into account in diagnosing anti-NMDAR encephalitis particularly in patients aged 50 years or older, or with isolated epileptic syndrome, atypical demyelinating syndrome, or post-HSE.

[A case of leptomeningeal melanomatosis with acute paraplegia and multiple cranial nerve palsies].

A 62-year-old man with acute paraplegia was transferred to our hospital. He had flaccid paraplegia and multiple cranial nerve palsies, such as mydriasis of the left pupil, abduction palsy of the left eye, hoarseness and dysphagia, but no meningeal irritation signs. MRI of the spinal canal showed swellings of the conus medullaris and the cauda equine, and also contrast enhancement of the spinal meninges. The cerebrospinal fluid (CSF) showed pleocytosis and protein increment. The lymph node was swollen in his right axilla. The biopsy specimen from the right axillary lymph node revealed metastasis of malignant melanoma histologically. Careful check-up of his whole body found a malignant melanoma in the subungual region of the right ring finger. Repeated cytological examination revealed melanoma cells in the CSF, confirming the diagnosis of leptomeningeal melanomatosis. His consciousness was gradually deteriorated. His family members chose supportive care instead of chemotherapy or surgical therapy after full information about his conditions. Finally, he died 60 days after transfer to our hospital. This is a rare case of leptomenigeal melanomatosis presenting with acute paraplegia and multiple cranial nerve palsies. Careful follow-up and repeated studies are vital for the early diagnosis of leptomenigeal melanomatosis in spite of atypical clinical presentation.

Evaluation of blood-brain barrier function by quotient alpha2 macroglobulin and its relationship with interleukin-6 and complement component 3 levels in neuropsychiatric systemic lupus erythematosus.

Although quotient of alpha2 macroglobulin (Qα2MG) was previously reported to be useful for the evaluation of blood-brain barrier (BBB) function, it is not commonly used. We therefore evaluated BBB function among the various subsets of neuropsychiatric systemic lupus erythematosus (NPSLE) using quotient Q α2MG. Furthermore, we determined the correlation between Q α2MG and cerebrospinal (CSF) interleukin (IL)-6 level and quotient complement component 3 (Q C3). To determine intrathecal production of C3, the C3 index (Q C3/Q α2MG) was also calculated. Fifty-six patients with SLE were included in this study. Of these, 48 were diagnosed with NPSLE, consisting of 30 diffuse NPSLE patients (acute confusional state (ACS): n = 14, non-ACS: n = 16) and 18 patients with focal NPSLE. CSF IL-6 concentration, and paired serum and CSF levels of α2MG and C3, were measured by enzyme-linked immuno solvent assay (ELISA). The Q α2MG, Q C3, and C3 index were then calculated. Q α2MG, Q C3, and IL-6 concentrations in the CSF were significantly elevated in NPSLE compared with non-NPSLE. Among the subsets of NPSLE, significant increases in Q α2MG, CSF IL-6, and Q C3 were observed in ACS compared with non-ACS or focal NPSLE. There was a positive correlation between CSF IL-6 level and Q α2MG, as well as between Q C3 and Q α2MG, in diffuse NPSLE. There were no significant differences in C3 index between NPSLE and non-NPSLE, as well as among the subgroups of NPSLE. Our study suggests that BBB disruption is present in ACS, and elevated levels of IL-6 and C3 in CSF in diffuse NPSLE, especially in ACS, might result from their entry to the CSF from the systemic circulation through the damaged BBB, as well as increased intrathecal production. Furthermore, Q α2MG might be useful for the evaluation of BBB integrity.

Cryptogenic NORSE: Its distinctive clinical features and response to immunotherapy.

OBJECTIVE: To report the distinctive clinical features of cryptogenic new-onset refractory status epilepticus (C-NORSE) and the C-NORSE score based on initial clinical assessments. METHODS: A retrospective study was conducted for 136 patients with clinically suspected autoimmune encephalitis who underwent testing for autoantibodies to neuronal surface antigens between January 1, 2007, and August 31, 2016. Eleven patients with C-NORSE were identified. Their clinical features were compared with those of 32 patients with anti-NMDA receptor encephalitis (NMDARE). RESULTS: The clinical outcome of 11 patients (median age, 27 years; 7 [64%] women) with C-NORSE was evaluated after a median follow-up of 11 months (range, 6-111 months). Status epilepticus was frequently preceded by fever (10/11 [91%]). Brain MRIs showed symmetric T2/fluid-attenuated inversion recovery hyperintensities (8/11 [73%]) and brain atrophy (9/11 [82%]). Only 2 of the 10 treated patients responded to the first-line immunotherapy, and 4 of the 5 patients treated with IV cyclophosphamide responded to the therapy. The long-term outcome was poor in 8 patients (73%). Compared with 32 patients with NMDARE (median age, 27 years; 24 [75%] women), those with C-NORSE had more frequent prodromal fever, status epilepticus, ventilatory support, and symmetric brain MRI abnormalities, had less frequent involuntary movements, absent psychobehavioral symptoms, CSF oligoclonal bands, or tumor association, and had a worse outcome. The C-NORSE score was higher in patients with C-NORSE than those with NMDARE. CONCLUSIONS: Patients with C-NORSE have a spectrum of clinical-immunological features different from those with NMDARE. The C-NORSE score may be useful for discrimination between them. Some patients could respond to immunotherapy.

A possible role of low regulatory T cells in anti-acetylcholine receptor antibody positive myasthenia gravis after bone marrow transplantation.

BACKGROUND: Chronic graft-versus-host disease (GVHD) appears several months following allogenic hematopoietic stem cell transplantation (HSCT) and is clinically analogous to autoimmune disorder. Polymyositis is a common neuromuscular disorder in chronic GVHD, but myasthenia gravis (MG) is extremely rare. Hence, its pathophysiology and treatment have not been elucidated. CASE PRESENTATION: A 63-year-old man with a history of chronic GVHD presented with ptosis, dropped head, and dyspnea on exertion, which had worsened over the previous several months. He showed progressive decrement of compound muscle action potential in the deltoid muscle evoked by 3-Hz repetitive nerve stimulation, a positive edrophonium test, and elevated levels of serum anti-acetylcholine receptor antibodies, which suggested a diagnosis of generalized MG. No thymoma was found. Flow cytometric analysis revealed a remarkable depletion of peripheral Tregs (CD4+CD25highFOXP3+ cells, 0.24% of the total lymphocytes). Administration of prednisolone and tacrolimus was insufficient to alleviate his symptoms; however, the use of rituximab successfully improved his condition. CONCLUSIONS: Myasthenic symptoms appeared in the process of tapering prednisolone for the treatment of chronic GVHD, supporting the diagnosis of MG associated with chronic GVHD. The present case proposes a possibility that reduction of Tregs might contribute to the pathogenesis of MG underlying chronic GVHD. Immunotherapy with rituximab is beneficial for treatment of refractory MG and GVHD.

A case of lymphomatosis cerebri mimicking inflammatory diseases.

BACKGROUND: Lymphomatosis cerebri (LC) is a rare subtype of primary central nervous system malignant lymphoma. The typical features of this disease exhibited on magnetic resonance imaging (MRI) without contrast enhancement are similar to those observed with diffuse leukoencephalopathy, mimicking white matter disorders such as encephalitis. Clinical features and examination findings that are suggestive of inflammatory diseases may indeed confound the diagnosis of LC. CASE PRESENTATION: A 66-year-old woman with continuous fever over a two-month period developed left hemiparesis despite presenting in an alert state with normal cognitive function. Sampling tests showed autoantibodies in the serum and inflammatory changes in the cerebrospinal fluid. The results from an MRI demonstrated multiple non-enhanced brain lesions in the splenium of the corpus callosum and deep white matter. Single photon emission computed tomography revealed increases in blood flow in the basal ganglia, thalamus and brainstem. No systemic malignancies were found. The patient was suspected of having a diagnosis of nonvasculitic autoimmune inflammatory meningoencephalitis and treated with intravenous methylprednisolone pulse therapy. Her fever transiently dropped to within the normal range. However, she had a sudden seizure and a second MRI exhibited infiltrative lesions gradually extending throughout the whole brain. We performed a brain biopsy, and LC was histologically diagnosed. The patient received whole-brain radiation therapy, which diminished the fever and seizures. The patient died one year after the initial onset of fever. CONCLUSIONS: The present case yields an important consideration that brain neoplasms, especially LC, cannot be ruled out, even in cases with clinical characteristics and examinations consistent with inflammatory diseases. Careful follow-up and histological study are vital for the correct diagnosis of LC.

[A patient with familial amyotrophic lateral sclerosis associated with a new valosin-containing protein (VCP) gene mutation].

In this communication, we report a patient with familial amyotrophic lateral sclerosis (ALS) associated with a familial dyslipidemia. Genetic analysis revealed a novel heterozygous valosin-containing protein (VCP) mutation (c.466G>T (p.G156C)). The other gene analysis also disclosed a known homozygous LCAT mutation (c.101C>T (p.P10L)). VCP gene mutation shown should be responsible for familial ALS because of following reasons. The patient's father also was also affected by ALS. The VCP gene mutation (p.G156C) in the patient was located in the vicinity of a site frequently associated with pathogenic VCP variants. The same amino acid transformation as that of this patient has been reported to be involved in the pathogenesis of inclusion body myopathy with Paget's disease of the bone and frontotemporal dementia. This is the first case report of rare association of ALS with VCP mutation and dyslipidemia with LCAT mutation.

Cauda equina involvement in post-radiation lower motor neuron syndrome.

Post-radiation lower motor neuron syndrome (PRLMNS) is a rare neurological complication of radiation therapy and its pathogenesis is unclear. We herein report a patient with PRLMNS who developed leg weakness 17 years after craniospinal radiation as a treatment for suprasellar germinoma. The electrophysiological evaluation, via a novel magnetic stimulation method, indicated a prolonged cauda equina conduction time, suggesting focal demyelination of the nerve roots in the cauda equina. The distribution of the denervated muscles detected by magnetic resonance imaging was consistent with patchy motor nerve root lesions. These results support the hypothesis that PRLMNS originates from ischemic radiculopathy in the cauda equina.