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INTRODUCTION: Hereditary transthyretin-mediated amyloidosis (ATTRv, v for variant) is a progressive disease caused by mutations in the TTR gene, leading to sensory-motor, axonal and length-dependent neuropathy. However, some patients may show variable electrophysiological pattern. The aim of this study was to evaluate the electrophysiological features of TTR amyloid neuropathy at the time of the first nerve conduction study (NCS) to assess whether there were distinguishing features useful for early diagnosis. METHODS: We retrospectively revised the first electrophysiological findings of ATTRv patients, and we categorized the neuropathy based on nerve conduction slowing, type of involved fibres and distribution pattern of PNS involvement. Cluster analysis was performed to evaluate the prevalence of neuropathy features between the early and late stage of disease, based on disease duration and disability burden assessed by NIS. RESULTS: We recruited 33 patients (27 males) with mean age 63.9 ± 10.8 years, mean disease duration 2.8 ± 2.4 years and mean NIS 47.6 ± 41.8. Overall, the frequency analysis showed that the most common features of ATTRv neuropathy included the categories of axonal, sensory-motor and neuronopathic-like pattern. This electrophysiological pattern of PNS involvement was constant in patients in late stage of disease, whereas ATTRv patients in early stage of disease displayed variable electrophysiological pattern of PNS involvement. DISCUSSION: Our findings demonstrated that ATTRv neuropathy may present at first NCS in a variable way, and it changes over the course of disease. Such heterogeneity makes the suspicion of ATTRv even more challenging at the time of first electrophysiological examination.
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Neuropatias Amiloides Familiares , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Afeto , Neuropatias Amiloides Familiares/complicações , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/genética , Condução Nervosa , Pré-Albumina/genética , Estudos Retrospectivos , FemininoRESUMO
INTRODUCTION: Since the initial identification of Miller Fisher syndrome (MFS) and Bickerstaff brainstem encephalitis (BBE),significant milestones have been achieved in understanding these diseases.Discoveries of common serum antibodies (IgG anti-GQ1b), antecedent infections, neurophysiological data, andneuroimaging suggested a shared autoimmune pathogenetic mechanism rather than distinct pathogenesis, leadingto the hypothesis that both diseases are part of a unified syndrome, termed "Fisher-Bickerstaff syndrome". The subsequent identification of atypical anti-GQ1b-positive forms expanded the classification to a broader condition known as "Anti-GQ1b-Antibody syndrome". METHODS: An exhaustive literature review was conducted, analyzing a substantial body of research spanning from the initialdescriptions of the syndrome's components to recent developments in diagnostic classification and researchperspectives. RESULTS: Anti-GQ1b syndrome encompasses a continuous spectrum of conditions defined by a common serological profilewith varying degrees of peripheral (PNS) and central nervous system (CNS) involvement. MFS and BBE represent theopposite ends of this spectrum, with MFS primarily affecting the PNS and BBE predominantly involving the CNS.Recently identified atypical forms, such as acute ophthalmoparesis, acute ataxic neuropathy withoutophthalmoparesis, Guillain-Barré syndrome (GBS) with ophthalmoparesis, MFS-GBS and BBE-GBS overlap syndromes,have broadened this spectrum. CONCLUSION: This work aims to provide an extensive, detailed, and updated overview of all aspects of the anti-GQ1b syndromewith the intention of serving as a stepping stone for further shaping thereof. Special attention was given to therecently identified atypical forms, underscoring their significance in redefining the boundaries of the syndrome.
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BACKGROUND: SPG18 is caused by mutations in the endoplasmic reticulum lipid raft associated 2 (ERLIN2) gene. Autosomal recessive (AR) mutations are usually associated with complicated hereditary spastic paraplegia (HSP), while autosomal dominant (AD) mutations use to cause pure SPG18. AIM: To define the variegate clinical spectrum of the SPG18 and to evaluate a dominant negative effect of erlin2 (encoded by ERLIN2) on oligomerization as causing differences between AR and AD phenotypes. METHODS: In a four-generation pedigree with an AD pattern, a spastic paraplegia multigene panel test was performed. Oligomerization of erlin2 was analyzed with velocity gradient assay in fibroblasts of the proband and healthy subjects. RESULTS: Despite the common p.V168M mutation identified in ERLIN2, a phenoconversion to amyotrophic lateral sclerosis (ALS) was observed in the second generation, pure HSP in the third generation, and a complicated form with psychomotor delay and epilepsy in the fourth generation. Erlin2 oligomerization was found to be normal. DISCUSSION: We report the first AD SPG18 family with a complicated phenotype, and we ruled out a dominant negative effect of V168M on erlin2 oligomerization. Therefore, our data do not support the hypothesis of a relationship between the mode of inheritance and the phenotype, but confirm the multifaceted nature of SPG18 on both genetic and clinical point of view. Clinicians should be aware of the importance of conducting an in-depth clinical evaluation to unmask all the possible manifestations associated to an only apparently pure SPG18 phenotype. We confirm the genotype-phenotype correlation between V168M and ALS emphasizing the value of close follow-up.
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Proteínas de Membrana , Mutação , Linhagem , Paraplegia Espástica Hereditária , Humanos , Paraplegia Espástica Hereditária/genética , Feminino , Masculino , Adulto , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Fenótipo , Adulto Jovem , Adolescente , Genes Dominantes , Criança , IdosoRESUMO
Autoimmune nodopathies are inflammatory diseases of the peripheral nervous system with clinical and neurophysiological peculiar characteristics. In this nosological category, we find patients with autoantibodies against Neurofascin 140/186 and 155, Contactin1, and Caspr1 directed precisely towards nodal and paranodal structures. These antibodies are extremely rare and cause severe clinical symptoms. We describe the clinical case of a patient with autoimmune nodopathy caused by the coexistence of anti-neurofascin (NF) 186/140 and 155, characterized by progressive weakness in all limbs leading to tetraplegia, involving cranial nerves, and respiratory insufficiency. Response to first-line treatments was good followed by rapid dramatic clinical relapse. There are few reported cases of anti-pan NF neuropathy in the literature, and they present a clinical phenotype similar to our patient. In these cases, early recognition of clinical red flags of nodopathies and serial neurophysiological studies can facilitate the diagnosis. However, the severe clinical relapse suggests a possible early use of immunosuppressive therapies for this rare category of patients.
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Moléculas de Adesão Celular , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica , Humanos , Moléculas de Adesão Celular/genética , Fatores de Crescimento Neural/genética , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/complicações , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/diagnóstico , Autoanticorpos , RecidivaRESUMO
BACKGROUND: Inotersen is an antisense oligonucleotide used to treat hereditary transthyretin amyloidosis (ATTRv). The most common drug-related adverse effects (AEs) include thrombocytopenia and glomerulonephritis. Hepatic damage is rare, but liver enzyme monitoring is mandatory. CASE REPORT: A 70-year-old man with ATTRv (Val30Met) treated with inotersen developed a severe increase of transaminases, with normal bilirubin and cholinesterase levels, that forced us to stop therapy. At the same time, other causes of acquired hepatitis were excluded, and the hypothesis of an inotersen-related hepatic toxicity was supported by the normalization of liver enzymes after 40 days from the drug interruption. DISCUSSION: Our case showed that 1-year inotersen treatment can stabilize neurological impairment and even improve quality of life and suggests to carefully monitor liver enzymes in order to avoid an inotersen-related hepatic dysfunction.
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Neuropatias Amiloides Familiares , Qualidade de Vida , Masculino , Humanos , Idoso , Oligonucleotídeos/efeitos adversos , Oligonucleotídeos Antissenso , Neuropatias Amiloides Familiares/tratamento farmacológico , Fígado , Pré-AlbuminaRESUMO
INTRODUCTION: Myasthenia gravis is a long-lasting autoimmune neuromuscular disease caused by antibodies attacking the neuromuscular junction, which can result in muscle weakness, fatigue, and respiratory failure in severe cases. Myasthenic crisis is a life-threatening event that requires hospitalization and treatments with intravenous immunoglobulin or plasma exchange. We reported the case of an AChR-Ab-positive myasthenia gravis patient with refractory myasthenic crisis, in which starting eculizumab as rescue therapy led to a complete resolution of the acute neuromuscular condition. CASE PRESENTATION: A 74-year-old man diagnosed with myasthenia gravis. ACh-receptor antibodies positivity comes to our observation for a recrudescence of symptoms, unresponsive to conventional rescue therapies. Due to the clinical worsening over the following weeks, the patient was admitted to intensive care unit, where he underwent therapy with eculizumab. About 5 days after the treatment, there was a significant and complete recovery of clinical condition with weaning-off from invasive ventilation and discharge to outpatient regimen, with reduction of steroid intake and biweekly maintenance with eculizumab. DISCUSSION: Eculizumab, a humanized monoclonal antibody that inhibits complement activation, is now approved as treatment for refractory generalized myasthenia gravis with anti-AChR antibodies. The use of eculizumab in myasthenic crisis is still investigational, but this case report suggests that it may be a promising treatment option for patients with severe clinical condition. Ongoing clinical trials will be needed to further evaluate the safety and efficacy of eculizumab in myasthenic crisis.
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Anticorpos Monoclonais Humanizados , Inativadores do Complemento , Miastenia Gravis , Receptores Colinérgicos , Humanos , Masculino , Idoso , Miastenia Gravis/imunologia , Miastenia Gravis/terapia , Anticorpos Monoclonais Humanizados/uso terapêutico , Inativadores do Complemento/uso terapêutico , Receptores Colinérgicos/imunologia , Autoanticorpos/sangueRESUMO
Hereditary TTR amyloidosis (ATTRv) is a progressive e disabling disease, leading to a gradual loss of ambulation and death. In the last decade, new treatments have drastically revolutionized natural history of disease, and they are more efficacious if precociously administered. However, diagnostic delay still represents an important challenge to resolve. We reported a case of two asymptomatic brothers that received a very precocious diagnosis of ATTRv thanks to the diagnosis of carpal tunnel syndrome. We proposed screening of the well-defined carpal tunnel syndrome to detect patients with ATTRv in a pre-symptomatic stage.
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Neuropatias Amiloides Familiares , Amiloidose , Síndrome do Túnel Carpal , Neuropatias Amiloides Familiares/complicações , Neuropatias Amiloides Familiares/diagnóstico , Síndrome do Túnel Carpal/diagnóstico , Diagnóstico Tardio , Humanos , Masculino , Pré-AlbuminaRESUMO
INTRODUCTION: In Charcot-Marie-Tooth type 1A (CMT1A) patients, daily life is mainly influenced by mobility and ambulation dysfunctions. The aim of our work was to evaluate the perception of disturbances that mostly impact on daily life in CMT1A patients and its difference on the basis of age, gender, disability, and quality of life. METHODS: Forty-one CMT1A patients underwent neurological assessment focused on establishing clinical disability through the Charcot-Marie-Tooth Neuropathy Score (CMTNS) and quality of life through the Short Form-36 (SF-36) questionnaire. We identified from CMT disturbances 5 categories [weakness in lower limbs (WLL), weakness in upper limbs (WUL), skeletal deformities (SD), sensory symptoms (SS), balance (B)] and patients classified the categories from the highest to the lowest impact on daily life (1: highest; 5: lowest). Ranking of the 5 categories, in the overall sample and in the different subgroups (dividing by gender, median of age and disease duration, CMTNS, domains of SF-36), was obtained and differences among subgroups were assessed using a bootstrap approach. RESULTS: Rank analysis showed that WLL was the most important disturbance on daily life whereas WUL had the lowest impact. In the older CMT1A group, the most important disturbance on daily life was B that was also the most relevant disturbance in patients with a greater disability. SD influenced daily life in younger patients. SS had less impact on daily life, with the exception of patients with a milder disability. DISCUSSION: Our findings demonstrated that the perception of disturbances that mostly impact on CMT1A patients' daily life changes over the lifetime and with degree of disability.
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Doença de Charcot-Marie-Tooth , Pessoas com Deficiência , Humanos , Exame Neurológico , Qualidade de Vida , CaminhadaRESUMO
BACKGROUND: Migraine affects more than a billion people all over the world and requires critical employment of healthcare resources. Telemedicine could be a reasonable tool to manage people suffering from headaches, and it received a big push from the COVID-19 pandemic. OBJECTIVE: This review aims to propose a practical approach for the virtual management of these patients. METHODS: To do this, we conducted a literature search, including 32 articles relevant to the topic treated in this review. RESULTS: The most challenging step in telemedicine applied to practical neurology remains the clinical assessment, but through a careful headache history and a recently proposed entirely virtual neurological assessment, this hitch can be easily overcome. Electronic diary compilations and virtual administration of disability-measuring scales, conversely, are the key features of effective long-term follow-up although we do not have apps that met the criteria of scientific reliability. Furthermore, tele-rehabilitation seems to be effective and has demonstrated to be a solution to alternatively treat chronic patients at home, and can be considered part of the remote management of headache patients. Moreover, virtual management of headaches finds an application in specific communities of patients, as pediatric patients and for rural communities of low- and middle-income countries suffer from health disparities, with inadequate resources and knowledge gaps. CONCLUSION: Telemedicine could be promising for patients with no regular or convenient access to headache specialists and seems to be a priority in managing migraine patients to avoid non-urgent hospitalizations.
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COVID-19 , Transtornos de Enxaqueca , Telemedicina , Criança , Cefaleia , Humanos , Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/terapia , Pandemias , Reprodutibilidade dos TestesRESUMO
(1) The co-occurrence of AQP4 and myelin oligodendrocyte glycoprotein (MOG) antibodies in patients with demyelinating disorders is extremely rare. In addition, a concomitant involvement of the peripheral nervous system (PNS) has been described either in association with AQP4 antibodies-positive neuromyelitis optica spectrum disorder (NMOSD), or MOG-associated disease. We report on a case of NMOSD with co-occurrence of AQP4 and MOG antibodies and concomitant central and peripheral nervous system involvement. We also reviewed available cases of AQP4-MOG double-positive patients. (2) Brain and spine MRI, cerebrospinal fluid studies, and electrophysiological test were performed. Serum AQP4 and MOG positivity was assessed with live cell-based assay. (3) A 62-year-old woman presented with recurrent optic neuritis, myelitis, and radiculitis, tested positive for AQP4 and MOG antibodies, and was treated successfully with rituximab. (4) Although few cases of AQP4-MOG double-positive patients were already described mostly affecting females with a concomitant spinal cord and optical nerve involvement, we describe the first case of double-positive NMOSD with the peculiar involvement of both central and peripheral nervous system.
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Neuromielite Óptica , Feminino , Humanos , Neuromielite Óptica/diagnóstico por imagem , Glicoproteína Mielina-Oligodendrócito , Aquaporina 4 , Autoanticorpos , Imunoglobulina G , Sistema Nervoso PeriféricoRESUMO
Charcot-Marie-Tooth (CMT) diseases are a clinically and genetically heterogeneous group of disorders. Different variants in the neurofilament heavy chain (NEFH) gene have been described to cause the CMT2CC subtype. Here we report the first Italian patient affected by CMT2CC, harboring a novel variant in NEFH. In describing our patient, we also reviewed previously CMT2CC individuals, and suggested to consider NEFH variant if patients have an axonal sensory-motor neuropathy with a prominent proximal muscles involvement with early requirement of walking aids or wheelchair, remembering a motor neuron disorder.
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Doença de Charcot-Marie-Tooth , Doença de Charcot-Marie-Tooth/genética , Mutação da Fase de Leitura/genética , Humanos , Itália , Proteínas de Neurofilamentos , ProteínasRESUMO
Hereditary transthyretin amyloidosis (ATTRv) is a condition with adult onset, caused by mutation of the transthyretin (TTR) gene and characterized by extracellular deposition of amyloid fibrils in tissue, especially in the peripheral nervous system (PNS) and heart. PNS involvement leads to a rapidly progressive and disabling sensory-motor axonal neuropathy. Although awareness among neurologists increased in recent years thanks to new treatment options, ATTRv is frequently misdiagnosed, and thus a correct diagnosis can be delayed by several years. This review aims to draw the history and features of polyneuropathy in ATTRv based on pathological and electrophysiological correlates. We assessed original articles and case reports based on their relevance to ATTRv neuropathy and we included those appropriate for the scheme of this narrative review. Amyloid fibrils initially deposit in ganglia, causing an axonal neuropathy without amyloid deposits in distal segments (eg, sural nerve biopsy). Over time, amyloid fibrils spread along the nerves, leading to some demyelinating features in the context of severe axonal loss. This review highlights how the features of neuropathy change based on type of ATTRv (early vs late onset) and stage of disease.
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Neuropatias Amiloides Familiares , Amiloide , Neuropatias Amiloides Familiares/complicações , Neuropatias Amiloides Familiares/genética , Humanos , Mutação/genética , Polineuropatias , Pré-Albumina/genéticaRESUMO
INTRODUCTION: COVID-19 pandemic radically transformed our daily clinical practice, raising the need not to lose close contact with patients without being able to see them face-to-face. These issues are even more felt and evident in fragile patients, as those affected by neuromuscular disease. An important help came from new digital technologies that allow clinicians to remotely monitor health status and any deterioration of chronically ill patients. METHODS: In this mini-review, an initiative of the "Digital Technologies, Web and Social Media Study Group" of the Italian Society of Neurology, we propose to analyze the approach to neuromuscular patients by looking over raising evidence on the main cornerstones of Telemedicine (TM): clinician-patient interaction, remote clinical assessment, remote monitoring, and digital therapeutics. In particular, we explored the strategies developed by researchers and their impact on the physical and emotional status of the patients, with particular focusing on their adherence to the program of virtual monitoring. RESULTS: TM plays an important role in each of four stages of approach to neuromuscular disease, having demonstrated validity in keep close clinical patient interaction, clinical assessment, remote monitoring, and telerehabilitation. Nevertheless, there is no remote alternative to electrophysiological testing neither validate tools to assess disability. CONCLUSION: The role of TM in neuromuscular care is yet underestimated but is crucial, beyond the pandemic era. Further development of TM is advisable, through making specific apps, remotely controlled by clinicians, and making more engaging clinicians-patients interaction. Last, it is necessary to ensure adequate internet access to everyone.
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COVID-19 , Doenças Neuromusculares , Telemedicina , Humanos , Doenças Neuromusculares/terapia , Pandemias , SARS-CoV-2RESUMO
Respiratory failure is the most worrisome problem of COVID-19. Patients may develop severe pneumonia requiring invasive mechanical ventilation and a significant proportion of them dies. It has been suggested that brainstem might play a role in severe respiratory failure of COVID-19 patients. We described three COVID-19 patients in ICU at Federico II Hospital in Naples that, although had recovered from pneumonia, could not be weaned from invasive mechanical ventilation. Our clinical evaluation was consistent with an involvement of the brainstem and especially of respiratory centre thus possibly explaining the weaning failure in patients that were awake and had recovered from lung involvement. Our data, though limited, indicate that brainstem involvement may play a role in respiratory failure and perhaps in the high death rate of COVID-19 patients. Moreover, the weaning failure from mechanical ventilation due to central respiratory drive depression might underlie the unusual long stay in ICU reported for COVID-19 patients.
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Betacoronavirus , Tronco Encefálico/virologia , Infecções por Coronavirus/virologia , Pneumonia Viral/virologia , Insuficiência Respiratória/virologia , COVID-19 , Infecções por Coronavirus/etiologia , Infecções por Coronavirus/mortalidade , Humanos , Pandemias , Pneumonia Viral/etiologia , Pneumonia Viral/mortalidade , Respiração Artificial , SARS-CoV-2RESUMO
We present the clinical case of a woman suffering from CLIPPERS syndrome (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids). The images obtained from the brain magnetic resonance show the lesions typical of the disease.
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INTRODUCTION: Use of peripheral nerve ultrasound alongside standard electrodiagnostic tests may help to gain insight into the pathophysiology of peripheral nerve involvement in type 2 spinocerebellar ataxia (SCA2). METHODS: Twenty-seven patients with SCA2 underwent ultrasound cross-sectional area (CSA) measurement of median, ulnar, sural and tibial nerves, and motor (median, ulnar, tibial) and sensory (median, ulnar, radial, sural) nerve conduction studies. RESULTS: Twenty patients had pathologically small-nerve CSAs, suggestive of sensory neuronopathy. In these patients, electrophysiology showed non-length-dependent sensory neuropathy (14 of 20), "possible sensory neuropathy" (1 of 20), or normal findings (5 of 20). Four different patients had length-dependent sensory neuropathy on electrophysiology, and 1 had enlarged nerve CSAs. Regression analysis showed an inverse relationship between ataxia scores and upper limb nerve CSA (P < 0.03). DISCUSSION: Our findings suggest that a majority of patients with SCA2 (74%) have a sensory neuronopathy and this correlates with disability. A minority of patients have findings consistent with axonal neuropathy (18%). Muscle Nerve, 2019.
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Nervos Periféricos/fisiopatologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Ataxias Espinocerebelares/fisiopatologia , Extremidade Superior/fisiopatologia , Adulto , Idoso , Ataxia Cerebelar/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/metabolismo , Condução Nervosa/fisiologia , Doenças do Sistema Nervoso Periférico/diagnóstico , Transtornos de Sensação/fisiopatologia , Ultrassonografia/métodosRESUMO
Introduction: Miller Fisher syndrome (MFS) is considered a rare variant of Guillain-Barré syndrome (GBS), a group of acute-onset immune-mediated neuropathies characterized by the classic triad of ataxia, areflexia, and ophthalmoparesis. The present review aimed to provide a detailed and updated profile of all aspects of the syndrome through a collection of published articles on the subject, ranging from the initial description to recent developments related to COVID-19. Methods: We searched PubMed, Scopus, EMBASE, and Web of Science databases and gray literature, including references from the identified studies, review studies, and conference abstracts on this topic. We used all MeSH terms pertaining to "Miller Fisher syndrome," "Miller Fisher," "Fisher syndrome," and "anti-GQ1b antibody." Results: An extensive bibliography was researched and summarized in the review from an initial profile of MFS since its description to the recent accounts of diagnosis in COVID-19 patients. MFS is an immune-mediated disease with onset most frequently following infection. Anti-ganglioside GQ1b antibodies, detected in ~85% of patients, play a role in the pathogenesis of the syndrome. There are usually no abnormalities in MFS through routine neuroimaging. In rare cases, neuroimaging shows nerve root enhancement and signs of the involvement of the central nervous system. The most consistent electrophysiological findings in MFS are reduced sensory nerve action potentials and absent H reflexes. Although MFS is generally self-limited and has excellent prognosis, rare recurrent forms have been documented. Conclusion: This article gives an updated narrative review of MFS with special emphasis on clinical characteristics, neurophysiology, treatment, and prognosis of MFS patients.
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Chronic dysimmune neuropathies encompass a group of neuropathies that share immune-mediated pathomechanism. Chronic dysimmune antibody-related neuropathies include anti-MAG neuropathy, multifocal motor neuropathy, and neuropathies related to immune attack against paranodal antigens. Such neuropathies exhibit distinguishing pathomechanism, clinical and response to therapy features with respect to chronic inflammatory demyelinating polyradiculoneuropathy and its variants, which represent the most frequent form of chronic dysimmune neuropathy. This narrative review provides an overview of pathomechanism; clinical, electrophysiological, and biochemical features; and treatment response of the antibody-mediated neuropathies, aiming to establish when and why to look for antibodies in chronic dysimmune neuropathies.