RESUMEN
Anti-IgLON5 disease is a rare and likely underdiagnosed subtype of autoimmune encephalitis. The disease displays a heterogeneous phenotype that includes sleep, movement and bulbar-associated dysfunction. The presence of IgLON5-antibodies in CSF/serum, together with a strong association with HLA-DRB1*10:01â¼DQB1*05:01, supports an autoimmune basis. In this study, a multicentric human leukocyte antigen (HLA) study of 87 anti-IgLON5 patients revealed a stronger association with HLA-DQ than HLA-DR. Specifically, we identified a predisposing rank-wise association with HLA-DQA1*01:05â¼DQB1*05:01, HLA-DQA1*01:01â¼DQB1*05:01 and HLA-DQA1*01:04â¼DQB1*05:03 in 85% of patients. HLA sequences and binding cores for these three DQ heterodimers were similar, unlike those of linked DRB1 alleles, supporting a causal link to HLA-DQ. This association was further reflected in an increasingly later age of onset across each genotype group, with a delay of up to 11â years, while HLA-DQ-dosage dependent effects were also suggested by reduced risk in the presence of non-predisposing DQ1 alleles. The functional relevance of the observed HLA-DQ molecules was studied with competition binding assays. These proof-of-concept experiments revealed preferential binding of IgLON5 in a post-translationally modified, but not native, state to all three risk-associated HLA-DQ receptors. Further, a deamidated peptide from the Ig2-domain of IgLON5 activated T cells in two patients, compared with one control carrying HLA-DQA1*01:05â¼DQB1*05:01. Taken together, these data support a HLA-DQ-mediated T-cell response to IgLON5 as a potentially key step in the initiation of autoimmunity in this disease.
Asunto(s)
Cadenas beta de HLA-DQ , Cadenas HLA-DRB1 , Humanos , Cadenas HLA-DRB1/genética , Masculino , Cadenas beta de HLA-DQ/genética , Femenino , Persona de Mediana Edad , Adulto , Moléculas de Adhesión Celular Neuronal/genética , Moléculas de Adhesión Celular Neuronal/inmunología , Anciano , Autoanticuerpos/inmunología , Predisposición Genética a la Enfermedad , Adulto Joven , Adolescente , GenotipoRESUMEN
A 76-year-old female with no apparent immunosuppressive conditions and no history of exposure to freshwater and international travel presented with headache and nausea 3 weeks before the presentation. On admission, her consciousness was E4V4V6. Cerebrospinal fluid analysis showed pleocytosis with mononuclear cell predominance, elevated protein, and decreased glucose. Despite antibiotic and antiviral therapy, her consciousness and neck stiffness gradually worsened, right eye-movement restriction appeared, and the right direct light reflex became absent. Brain magnetic resonance imaging revealed hydrocephalus in the inferior horn of the left lateral ventricle and meningeal enhancement around the brainstem and cerebellum. Tuberculous meningitis was suspected, and pyrazinamide, ethambutol, rifampicin, isoniazid, and dexamethasone were started. In addition, endoscopic biopsy was performed from the white matter around the inferior horn of the left lateral ventricle to exclude brain tumor. A brain biopsy specimen revealed eosinophilic round cytoplasm with vacuoles around blood vessels, and we diagnosed with amoebic encephalitis. We started azithromycin, flucytosine, rifampicin, and fluconazole, but her symptoms did not improve. She died 42 days after admission. In autopsy, the brain had not retained its structure due to autolysis. Hematoxylin and eosin staining of her brain biopsy specimen showed numerous amoebic cysts in the perivascular brain tissue. Analysis of the 16S ribosomal RNA region of amoebas from brain biopsy and autopsy specimens revealed a sequence consistent with Balamuthia mandrillaris. Amoebic meningoencephalitis can present with features characteristic of tuberculous meningitis, such as cranial nerve palsies, hydrocephalus, and basal meningeal enhancement. Difficulties in diagnosing amoebic meningoencephalitis are attributed to the following factors: (1) excluding tuberculous meningitis by microbial testing is difficult, (2) amoebic meningoencephalitis has low incidence and can occur without obvious exposure history, (3) invasive brain biopsy is essential in diagnosing amoebic meningoencephalitis. We should recognize the possibility of amoebic meningoencephalitis when evidence of tuberculosis meningitis cannot be demonstrated.
Asunto(s)
Amebiasis , Amoeba , Balamuthia mandrillaris , Infecciones Protozoarias del Sistema Nervioso Central , Hidrocefalia , Encefalitis Infecciosa , Tuberculosis Meníngea , Humanos , Femenino , Anciano , Tuberculosis Meníngea/diagnóstico , Tuberculosis Meníngea/patología , Infecciones Protozoarias del Sistema Nervioso Central/diagnóstico , Rifampin , Amebiasis/diagnóstico , Amebiasis/patología , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Encefalitis Infecciosa/diagnóstico , Encefalitis Infecciosa/patología , Hidrocefalia/patologíaRESUMEN
Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) is a late-onset, slow-progressing multisystem neurodegenerative disorder. Biallelic AAGGG repeat expansion in RFC1 has been identified as causative of this disease, and repeat conformation heterogeneity (ACAGG repeat) was also recently implied. To molecularly characterize this disease in Japanese patients with adult-onset ataxia, we accumulated and screened 212 candidate families by an integrated approach consisting of flanking PCR, repeat-primed PCR, Southern blotting and long-read sequencing using Sequel II, GridION or PromethION. We identified 16 patients from 11 families, of whom seven had ACAGG expansions [(ACAGG)exp/(ACAGG)exp] (ACAGG homozygotes), two had ACAGG and AAGGG expansions [(ACAGG)exp/(AAGGG)exp] (ACAGG/AAGGG compound heterozygotes) and seven had AAGGG expansions [(AAGGG)exp/(AAGGG)exp] (AAGGG homozygotes). The overall detection rate was 5.2% (11/212 families including one family having two expansion genotypes). Long-read sequencers revealed the entire sequence of both AAGGG and ACAGG repeat expansions at the nucleotide level of resolution. Clinical assessment and neuropathology results suggested that patients with ACAGG expansions have similar clinical features to previously reported patients with homozygous AAGGG expansions, although motor neuron involvement was more notable in patients with ACAGG expansions (even if one allele was involved). Furthermore, a later age of onset and slower clinical progression were implied in patients with ACAGG/AAGGG compound heterozygous expansions compared with either ACAGG or AAGGG homozygotes in our very limited cohort. Our study clearly shows the occurrence of repeat conformation heterogeneity, with possible different impacts on the affected nervous systems. The difference in disease onset and progression between compound heterozygotes and homozygotes might also be suspected but with very limited certainty due to the small sample number of cases in our study. Studies of additional patients are needed to confirm this.
Asunto(s)
Vestibulopatía Bilateral , Ataxia Cerebelosa , Enfermedades del Sistema Nervioso Periférico , Enfermedades Vestibulares , Neuronitis Vestibular , Adulto , Ataxia , Vestibulopatía Bilateral/diagnóstico , Vestibulopatía Bilateral/genética , Ataxia Cerebelosa/diagnóstico , Ataxia Cerebelosa/genética , Humanos , Reflejo Anormal , Proteína de Replicación C/genética , Síndrome , Enfermedades Vestibulares/genéticaRESUMEN
Progressive supranuclear palsy (PSP) with predominant frontal presentation (PSP-F) is a clinical phenotype of PSP that is characterized by frontal cognitive impairment and behavioral changes. Here, we report on a patient with pathologically diagnosed PSP-F in whom we were able to observe temporal changes of the clinical manifestations. A 77-year-old right-handed man developed progressive nonfluent aphasia (PNFA) at the age of 69 years, festinating gait, and clumsiness of his left arm at age 75, disinhibition at age 76, and unprovoked falls at age 77. Neurological examination at age 77 revealed limb-kinetic apraxia of the left upper and lower limbs, rigidity, cortical sensory loss, and vertical supranuclear gaze palsy. According to the Movement Disorder Society clinical diagnostic criteria for PSP, his clinical manifestations shifted from suggestive PSP with predominant speech/language disorder to probable PSP-F over nine years. Cerebral atrophy on brain magnetic resonance imaging and decreased accumulation of 99m Tc-ECD on cerebral blood flow single-photon emission computed tomography were noted with right side predominance. Pathologically, 4-repeat tau-immunoreactive globose-type neurofibrillary tangles, coiled bodies, tufted astrocytes, and neuropil threads were observed predominantly in the frontal cortex. Tau pathology of the substantia nigra, locus coeruleus and subthalamic nucleus was mild. These findings suggested that localized tau pathology involving the pars opercularis extended to the precentral gyrus, prefrontal cortex, and brainstem. This case report demonstrates that PSP-F can present as a PNFA due to crossed aphasia.
Asunto(s)
Afasia , Afasia Progresiva Primaria no Fluente , Parálisis Supranuclear Progresiva , Afasia/patología , Humanos , Imagen por Resonancia Magnética , Ovillos Neurofibrilares/patología , Afasia Progresiva Primaria no Fluente/complicaciones , Afasia Progresiva Primaria no Fluente/patología , Parálisis Supranuclear Progresiva/complicaciones , Parálisis Supranuclear Progresiva/patologíaRESUMEN
Paraneoplastic disorders of the peripheral nervous system are immune-mediated neurological syndromes associated with tumors. Several clinical phenotypes have been associated with these disorders. Sensory neuronopathy is the most well-known clinical phenotype, and is caused by neuronal cell injury to the dorsal root ganglia. Symptoms of the peripheral nervous system usually lead to the discovery of tumors. Antineuronal antibodies are occasionally identified in the serum and/or cerebrospinal fluid of these patients. The prevalence of small-cell lung cancer is notable in these patients. Early tumor resection, coupled with the initiation of immunotherapy, may prove effective in improving and stabilizing clinical symptoms.
Asunto(s)
Síndromes Paraneoplásicos del Sistema Nervioso , Humanos , Síndromes Paraneoplásicos del Sistema Nervioso/terapia , Síndromes Paraneoplásicos del Sistema Nervioso/diagnóstico , Síndromes Paraneoplásicos del Sistema Nervioso/inmunología , Enfermedades del Sistema Nervioso Periférico/inmunología , Enfermedades del Sistema Nervioso Periférico/terapia , Enfermedades del Sistema Nervioso Periférico/etiología , Inmunoterapia , Autoanticuerpos/inmunologíaRESUMEN
A 74-year-old man developed orthostatic syncope, a feeling of food stuck in his chest, and postprandial vomiting 3 years before presentation. Examination revealed severe orthostatic hypotension and cerebellar ataxia, and he was diagnosed with multiple system atrophy (MSA) with predominant cerebellar ataxia. Videofluoroscopic examination of swallowing showed lower oesophageal stricture and barium stagnation within the oesophagus. Oesophagogastroduodenoscopy revealed hypercontraction of the lower oesophagus, and high-resolution oesophageal manometry showed premature contractions of the lower oesophagus and decreased oesophageal peristalsis. The median integrated relaxation pressure in the lower oesophageal sphincter was normal, and achalasia was therefore excluded. Based on the Chicago classification version 4.0, his oesophageal dysmotility was classified as distal oesophageal spasm (DES). The stuck feeling in his chest and vomiting improved following endoscopic balloon dilation. This case suggests that DES can cause oesophageal food stagnation and postprandial vomiting in patients with MSA.
RESUMEN
We report two patients with autoimmune cerebellar ataxia who fulfilled the diagnostic criteria of multiple system atrophy (MSA) and responded to immunotherapies. Patient 1 was a 72-year-old man who was diagnosed with clinically probable MSA according to Movement Disorder Society criteria. Patient 2 was a 68-year-old man who was diagnosed with clinically established MSA according to Movement Disorder Society criteria. Both patients showed cerebellar ataxia, autonomic dysfunction, and pyramidal tract signs; however, they also had atypical clinical features. Patient 1 exhibited self-|limiting mild improvement of clinical symptoms and had inflammatory findings in his cerebrospinal fluid. Patient 2 showed a rapidly progressive clinical course. We therefore examined anti-neuronal antibodies using tissue-based immunohistochemical assays with frozen rat cerebellum sections. We detected autoantibodies that mainly reacted with the cytoplasm of Purkinje cells. The two patients then underwent immunotherapies, which led to substantial improvements in their clinical symptoms. Our findings indicate that some patients with autoimmune cerebella ataxia have clinical features that resemble MSA, and respond well to immunotherapies.
RESUMEN
INTRODUCTION: Anti-immunoglobulin-like cell adhesion molecule 5 (IgLON5) disease is a rare autoimmune encephalitis that can mimic progressive supranuclear palsy or corticobasal syndrome. Moreover, anti-IgLON5 disease can present with symptoms characteristic of multiple system atrophy (MSA), such as cerebellar ataxia and autonomic dysfunction. However, the clinical features of anti-IgLON5 disease resembling MSA have not been well established. METHODS: We enrolled 35 patients with suspected MSA for whom anti-IgLON5 antibody tests were requested. We evaluated immunoglobulin G (IgG) against IgLON5 using cell-based assays. We also summarized the clinical characteristics of patients who were positive for anti-IgLON5 antibodies. RESULTS: We identified serum and cerebrospinal fluid anti-IgLON5 antibodies in three patients. These patients had many clinical features characteristic of MSA, including parkinsonism, cerebellar ataxia, severe orthostatic hypotension, acute respiratory failure, sleep parasomnia, vocal cord paralysis, and pyramidal tract signs. Clinical features atypical for MSA were myorhythmia, horizontal eye movement restriction, fasciculations, and painful muscle cramps. CONCLUSION: Anti-IgLON5 disease may be an important differential diagnosis of MSA. A comprehensive physical examination, including assessments of eye movement, lower motor neuron signs, and atypical involuntary movements, is important to avoid misdiagnosis.
Asunto(s)
Autoanticuerpos , Moléculas de Adhesión Celular Neuronal , Atrofia de Múltiples Sistemas , Humanos , Atrofia de Múltiples Sistemas/diagnóstico , Atrofia de Múltiples Sistemas/sangre , Masculino , Femenino , Diagnóstico Diferencial , Anciano , Persona de Mediana Edad , Autoanticuerpos/sangre , Autoanticuerpos/líquido cefalorraquídeo , Moléculas de Adhesión Celular Neuronal/inmunologíaRESUMEN
Anti-IgLON5 disease shows various neurological manifestations, of which dysautonomia is one of the major symptoms and is rarely improved by immunotherapy. We herein report a patient with anti-IgLON5 disease who showed several autonomic failures, including vocal cord palsy for four months. The patient presented with cognitive impairments, bulbar symptoms accompanied by myorhythmia in the pharynx and tongue, cerebellar ataxia with tremor, motor neuron symptoms in the limbs, gastrointestinal dysfunction, orthostatic hypotension, non-rapid eye movement sleep disorder on polysomnography, and severe vocal cord palsy. Combined immunotherapy improved his symptoms, including vocal cord palsy, suggesting that combined immunotherapy might improve dysautonomia in anti-IgLON5 disease.
Asunto(s)
Inmunoterapia , Disautonomías Primarias , Parálisis de los Pliegues Vocales , Humanos , Masculino , Disautonomías Primarias/etiología , Parálisis de los Pliegues Vocales/terapia , Parálisis de los Pliegues Vocales/etiología , Inmunoterapia/métodos , Moléculas de Adhesión Celular Neuronal/inmunología , Resultado del Tratamiento , Persona de Mediana Edad , Autoanticuerpos/sangre , Autoanticuerpos/inmunologíaRESUMEN
Autoimmune parkinsonism and related disorders are immune-mediated central nervous system disorders that present with extrapyramidal signs such as involuntary movements, hypokinesia, and rigidity. Patients commonly have neurological signs other than the extrapyramidal signs. Some patients show a slowly progressive clinical course with neurological symptoms resembling those of neurodegenerative disorders. Occasionally, specific autoantibodies targeting the basal ganglia or related sites are detected in their serum or cerebrospinal fluid. These autoantibodies are important diagnostic markers for these disorders.
Asunto(s)
Enfermedades de los Ganglios Basales , Discinesias , Trastornos Parkinsonianos , Humanos , Trastornos Parkinsonianos/diagnóstico , Ganglios Basales , Enfermedades de los Ganglios Basales/diagnóstico , AutoanticuerposRESUMEN
Among the abnormal kyudo movements ("yips"), "motare" is the inability to release the arrow at the intended timing if aiming the target. We hypothesized that "motare" is a task-specific focal dystonia (TSFD). We interviewed three participants with "motare," three participants with "hayake", and three controls without "motare" nor "hayake". Moreover, we conducted a surface electromyography (sEMG) examination and found that "motare" was characterized by stereotypy, sensory tricks, and morning benefit; however, these findings were not observed in "hayake". Abnormal co-contraction of the upper extremity antagonist muscles was observed in one of the three "motare" participants. Overall, these findings suggest that "motare" have the characteristics of TSFD not previously reported.
Asunto(s)
Discinesias , Distonía , Trastornos Distónicos , Humanos , Trastornos Distónicos/diagnóstico , ElectromiografíaRESUMEN
In Kyudo (Japanese archery), there are four disorders that hinder an archer's performance: Hayake (releasing the bow too early), Motare (unable to release the bow when intended), Biku (jerking when aiming), and Yusuri (shaking when drawing the bow, or aiming). These disorders are similar to Yips, a psycho-neuromuscular movement disorder, recognized in various sports, but few studies have examined yips in Kyudo. This study examined the frequency, classification, and risk factors of yips in Kyudo among medical students. The results showed that 41 of 65 students (63.1%) experienced at least one disorder. The frequency of Hayake was the highest (35 patients; 85.3%). An experience of playing was associated with the increased risk of yips in Kyudo. Motare was the only disorder that appeared on its own, and without complications from other disorders. Based on its characteristics, it was suspected that task-specific focal dystonia involved in Motare.
Asunto(s)
Trastornos Distónicos , Trastornos del Movimiento , Deportes , Humanos , Japón/epidemiología , PrevalenciaRESUMEN
A 57-year-old woman with amyotrophic lateral sclerosis (ALS) receiving mechanical ventilation developed intractable right temporal headache. She was diagnosed with brain abscess secondary to chronic suppurative otitis media. In this case, the otitis media was caused by nasopharyngeal reflux associated with eustachian tube muscle weakness and a supine position. In addition, ALS patients under mechanical ventilation have a limited ability to convey their pain. Their complaints are often overlooked because many physicians do not know that pain is common in ALS. Physicians should recognize brain abscess as a severe complication of ALS and listen to the complaints of these patients.
Asunto(s)
Esclerosis Amiotrófica Lateral/complicaciones , Antibacterianos/uso terapéutico , Absceso Encefálico/complicaciones , Absceso Encefálico/tratamiento farmacológico , Absceso Encefálico/etiología , Meropenem/uso terapéutico , Dolor/etiología , Esclerosis Amiotrófica Lateral/fisiopatología , Absceso Encefálico/fisiopatología , Femenino , Humanos , Persona de Mediana Edad , Respiración Artificial , Resultado del TratamientoRESUMEN
We report the case of a 71-year-old man with impaired left finger extension. The presence of nodular fibrosing lesions in his palm suggested Dupuytren contracture as the diagnosis. However, detailed neurological examination revealed muscle weakness associated with C7-Th1 lesions, and needle electromyography revealed denervation within the same distribution. Therefore, the patient was diagnosed with distal-type cervical spondylolisthesis muscular atrophy complicated with Dupuytren contracture. Due to shared symptoms with impaired finger extension, the other two conditions can be overlooked in patients affected by both diseases. Detailed clinical investigation of nodular fibrosing lesions, muscle weakness at the C7-Th1 level, and needle electromyography findings facilitate differential diagnosis of Dupuytren contracture and distal-type cervical spondylolisthesis. (Received June 24, 2019; Accepted September 17, 2019; Published November 1, 2019).