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1.
Lancet Rheumatol ; 2022 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-35527808

RESUMO

Background: Concerns have been raised regarding the risks of SARS-CoV-2 breakthrough infections in vaccinated patients with immune-mediated inflammatory diseases treated with immunosuppressants, but clinical data on breakthrough infections are still scarce. The primary objective of this study was to compare the incidence and severity of SARS-CoV-2 breakthrough infections between patients with immune-mediated inflammatory diseases using immunosuppressants, and controls (patients with immune-mediated inflammatory diseases not taking immunosuppressants and healthy controls) who had received full COVID-19 vaccinations. The secondary objective was to explore determinants of breakthrough infections of the delta (B.1.617.2) variant of SARS-CoV-2, including humoral immune responses after vaccination. Methods: In this substudy, we pooled data collected in two large ongoing prospective multicentre cohort studies conducted in the Netherlands (Target to-B! [T2B!] study and Amsterdam Rheumatology Center COVID [ARC-COVID] study). Both studies recruited adult patients (age ≥18 years) with immune-mediated inflammatory diseases and healthy controls. We sourced clinical data from standardised electronic case record forms, digital questionnaires, and medical files. We only included individuals who were vaccinated against SARS-CoV-2. For T2B!, participants were recruited between Feb 2 and Aug 1, 2021, and for ARC-COVID, participants were recruited between April 26, 2020, and March 1, 2021. In this study we assessed data on breakthrough infections collected between July 1 and Dec 15, 2021, a period in which the delta SARS-CoV-2 variant was the dominant variant in the Netherlands. We defined a SARS-CoV-2 breakthrough infection as a PCR-confirmed or antigen test-confirmed SARS-CoV-2 infection that occurred at least 14 days after vaccination. All breakthrough infections during this period were assumed to be due to the delta variant due to its dominance during the study period. We analysed post-vaccination serum samples for anti-receptor binding domain (RBD) antibodies to assess the humoral vaccination response (T2B! study only) and anti-nucleocapsid antibodies to identify asymptomatic breakthrough infections (ARC-COVID study only). We used multivariable logistic regression analyses to explore potential clinical and humoral determinants associated with the odds of breakthrough infections. The T2B! study is registered with the Dutch Trial Register, Trial ID NL8900, and the ARC-COVID study is registered with Dutch Trial Register, trial ID NL8513. Findings: We included 3207 patients with immune-mediated inflammatory diseases who receive immunosuppressants, and 1807 controls (985 patients with immune-mediated inflammatory disease not on immunosuppressants and 822 healthy controls). Among patients receiving immunosuppressants, mean age was 53 years (SD 14), 2042 (64%) of 3207 were female and 1165 (36%) were male; among patients not receiving immunosuppressants, mean age was 54 years (SD 14), 598 (61%) of 985 were female and 387 (39%) were male; and among healthy controls, mean age was 57 years (SD 13), 549 (67%) of 822 were female and 273 (33%) were male. The cumulative incidence of PCR-test or antigen-test confirmed SARS-CoV-2 breakthrough infections was similar in patients on immunosuppressants (148 of 3207; 4·6% [95% CI 3·9-5·4]), patients not on immunosuppressants (52 of 985; 5·3% [95% CI 4·0-6·9]), and healthy controls (33 of 822; 4·0% [95% CI 2·8-5·6]). There was no difference in the odds of breakthrough infection for patients with immune-mediate inflammatory disease on immunosuppressants versus combined controls (ie, patients not on immunosuppressants and healthy controls; adjusted odds ratio 0·88 [95% CI 0·66-1·18]). Seroconversion after vaccination (odds ratio 0·58 [95% CI 0·34-0·98]; T2B! cohort only) and SARS-CoV-2 infection before vaccination (0·34 [0·18-0·56]) were associated with a lower odds of breakthrough infections. Interpretation: The incidence and severity of SARS-CoV-2 breakthrough infections in patients with immune-mediated inflammatory diseases on immunosuppressants was similar to that in controls. However, caution might still be warranted for those on anti-CD20 therapy and those with traditional risk factors. Funding: ZonMw (the Netherlands Organization for Health Research and Development) and Reade foundation.

2.
BMC Med ; 20(1): 100, 2022 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-35236350

RESUMO

BACKGROUND: Studies have suggested incremental short-term adverse events (AE) after repeated vaccination. In this report, we assessed occurrence and risk factors for short-term AEs following repeated SARS-CoV-2 vaccination in patients with various immune-mediated inflammatory diseases (IMIDs). METHODS: Self-reported daily questionnaires on AEs during the first 7 days after vaccination were obtained of 2259 individuals (2081 patients and 178 controls) participating in an ongoing prospective multicenter cohort study on SARS-CoV-2 vaccination in patients with various IMIDs in the Netherlands (T2B-COVID). Relative risks were calculated for potential risk factors associated with clinically relevant AE (rAE), defined as AE lasting longer than 2 days or impacting daily life. RESULTS: In total, 5454 vaccinations were recorded (1737 first, 1992 second and 1478 third vaccinations). Multiple sclerosis, Crohn's disease and rheumatoid arthritis were the largest disease groups. rAEs were reported by 57.3% (95% CI 54.8-59.8) of patients after the first vaccination, 61.5% (95% CI 59.2-63.7) after the second vaccination and 58% (95% CI 55.3-60.6) after the third vaccination. At day 7 after the first, second and third vaccination, respectively, 7.6% (95% CI 6.3-9.1), 7.4% (95% CI 6.2-8.7) and 6.8% (95% CI 5.4-8.3) of patients still reported AEs impacting daily life. Hospital admissions and allergic reactions were uncommon (<0.7%). Female sex (aRR 1.43, 95% CI 1.32-1.56), age below 50 (aRR 1.14, 95% CI 1.06-1.23), a preceding SARS-CoV-2 infection (aRR 1.14, 95% CI 1.01-1.29) and having an IMID (aRR 1.16, 95% CI 1.01-1.34) were associated with increased risk of rAEs following a vaccination. Compared to the second vaccination, the first vaccination was associated with a lower risk of rAEs (aRR 0.92, 95% CI 0.84-0.99) while a third vaccination was not associated with increased risk on rAEs (aRR 0.93, 95% CI 0.84-1.02). BNT162b2 vaccines were associated with lower risk on rAEs compared to CX-024414 (aRR 0.86, 95% CI 0.80-0.93). CONCLUSIONS: A third SARS-CoV-2 vaccination was not associated with increased risk of rAEs in IMID patients compared to the second vaccination. Patients with an IMID have a modestly increased risk of rAEs after vaccination when compared to controls. Most AEs are resolved within 7 days; hospital admissions and allergic reactions were uncommon. TRIAL REGISTRATION: NL74974.018.20 , Trial ID: NL8900. Registered on 9 September 2020.


Assuntos
Vacinas contra COVID-19 , COVID-19 , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Estudos de Coortes , Feminino , Humanos , Estudos Prospectivos , Fatores de Risco , SARS-CoV-2 , Vacinação/efeitos adversos
3.
Lancet Rheumatol ; 4(5): e338-e350, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35317410

RESUMO

Background: Disease-specific studies have reported impaired humoral responses after SARS-CoV-2 vaccination in patients with immune-mediated inflammatory disorders treated with specific immunosuppressants. Disease-overarching studies, and data on recall responses and third vaccinations are scarce. Our primary objective was to investigate the effects of immunosuppressive monotherapies on the humoral immune response after SARS-CoV-2 vaccination in patients with prevalent immune-mediated inflammatory disorders. Methods: We did a cohort study in participants treated in outpatient clinics in seven university hospitals and one rheumatology treatment centre in the Netherlands as well as participants included in two national cohort studies on COVID-19-related disease severity. We included patients aged older than 18 years, diagnosed with any of the prespecified immune-mediated inflammatory disorders, who were able to understand and complete questionnaires in Dutch. Participants with immune-mediated inflammatory disorders who were not on systemic immunosuppressants and healthy participants were included as controls. Anti-receptor binding domain IgG responses and neutralisation capacity were monitored following standard vaccination regimens and a three-vaccination regimen in subgroups. Hybrid immune responses-ie, vaccination after previous SARS-CoV-2 infection-were studied as a proxy for recall responses. Findings: Between Feb 2 and Aug 1, 2021, we included 3222 participants in our cohort. Sera from 2339 participants, 1869 without and 470 participants with previous SARS-CoV-2 infection were analysed (mean age 49·9 years [SD 13·7]; 1470 [62·8%] females and 869 [37·2%] males). Humoral responses did not differ between disorders. Anti-CD20 therapy, sphingosine 1-phosphate receptor (S1P) modulators, and mycophenolate mofetil combined with corticosteroids were associated with lower relative risks for reaching seroconversion following standard vaccination (0·32 [95% CI 0·19-0·49] for anti-CD20 therapy, 0·35 [0·21-0·55] for S1P modulators, and 0·61 [0·40-0·90] for mycophenolate mofetil combined with corticosteroids). A third vaccination increased seroconversion for mycophenolate mofetil combination treatments (from 52·6% after the second vaccination to 89·5% after the third) but not significantly for anti-CD20 therapies (from 36·8% to 45·6%) and S1P modulators (from 35·5% to 48·4%). Most other immunosuppressant groups showed moderately reduced antibody titres after standard vaccination that did not increase after a third vaccination, although seroconversion rates and neutralisation capacity were unaffected. In participants with previous SARS-CoV-2 infection, SARS-CoV-2 antibodies were boosted after vaccination, regardless of immunosuppressive treatment. Interpretation: Humoral responses following vaccination are impaired by specific immunosuppressants. After standard vaccination regimens, patients with immune-mediated inflammatory disorders taking most immunosuppressants show similar seroconversion to controls, although antibody titres might be moderately reduced. As neutralisation capacity and recall responses are also preserved in these patients, this is not likely to translate to loss of (short-term) protection. In patients on immunosuppressants showing poor humoral responses after standard vaccination regimens, a third vaccination resulted in additional seroconversion in patients taking mycophenolate mofetil combination treatments, whereas the effect of a third vaccination in patients on anti-CD20 therapy and S1P modulators was limited. Funding: ZonMw (The Netherlands Organization for Health Research and Development).

4.
Brain ; 2022 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-35139161

RESUMO

Intravenous immunoglobulins (IVIg) are an efficacious treatment for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Biomarkers for disease activity are lacking, making the need for ongoing treatment difficult to assess, leading to potential overtreatment, and high health care costs. Our objective was to determine whether IVIg withdrawal is non-inferior to continuing IVIg treatment and to determine how often patients are overtreated. We performed a randomized, double-blind, IVIg-controlled non-inferiority trial in seven centers in the Netherlands. Adults with clinically stable CIDP using IVIg maintenance treatment for at least 6 months were included. Patients received either IVIg withdrawal (placebo) as investigational treatment or continuation of IVIg treatment (control). The primary outcome was the mean change in logit scores from baseline to 24-weeks follow-up on the patient-reported Inflammatory Rasch-Overall Disability Scale (iRODS). The non-inferiority margin was predefined as between-group difference in mean change scores of -0.65. Patients who deteriorated could reach a relapse endpoint according to predefined criteria. Patients with a relapse endpoint after IVIg withdrawal entered a restabilization phase. All patients from the withdrawal group who remained stable, were included in an open-label extension phase of 52 weeks. We included 60 patients of whom 29 were randomised to IVIg withdrawal and 31 to continuation of treatment. The mean age was 58 years (SD 14.7) and 67% was male. The between-group difference in mean change iRODS scores was -0.47 (95%CI -1.24 to 0.31), indicating that non-inferiority of IVIg withdrawal could not be established. In the IVIg withdrawal group, 41% remained stable for 24 weeks, compared to 58% in the IVIg continuation group (-17%; 95%CI -39 to 8). Of the IVIg withdrawal group, 28% remained stable at end of the extension phase. Of the patients in the restabilization phase, 94% restabilized within 12 weeks. In conclusion, it remains inconclusive whether IVIg withdrawal is non-inferior compared to continuing treatment, partly due to larger than expected confidence intervals leading to an underpowered study. Despite these limitations, a considerable proportion of patients could stop treatment and almost all patients who relapsed were restabilized quickly. Unexpectedly, a high proportion of IVIg treated patients experienced a relapse endpoint, emphasizing the need for more objective measures for disease activity in future trials, as the patient reported outcome measures might not have been able to identify true relapses reliably. Overall, this study suggests that withdrawal attempts are safe and should be performed regularly in clinically stable patients.

5.
J Ultrasound ; 2022 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-35182316

RESUMO

PURPOSE: Nerve size is a commonly used sonographic parameter when assessing suspected entrapment of the ulnar nerve. We aimed to create a robust set of normal values, based on a critical review of published normal values. METHODS: We performed a systematic evaluation of studies on normal ulnar nerve sizes, identified in PubMed, Embase, and Cochrane databases. Using meta-analyses, we determined pooled mean cross-sectional area (CSA) values for different anatomical locations of the ulnar nerve throughout the arm. Subgroup analyses were performed for gender, probe frequency, in- or exclusion of diabetic patients, position of the elbow and Asian versus other populations. RESULTS: We identified 90 studies of which 77 studies were included for further analyses after quality review, resulting in data from 5772 arms of 3472 participants. Subgroup analyses show lower CSA values at at the wrist crease and proximal to the wrist crease when using low frequency probes (< 15 MHz) and at the wrist crease, proximal to the wrist crease, proximal forearm and the distal upper arm in Asians. CSA values were lower when in flexed position compared to extended position for the cubital tunnel inlet only. No difference was found for gender. CONCLUSIONS: Our systematic review provides a comprehensive set of normal values at sites along the entire length of the ulnar nerve. This provides a foundation for clinical practise and upon which future studies could be more systematically compared.

7.
Muscle Nerve ; 65(3): 317-325, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34854491

RESUMO

INTRODUCTION/AIMS: Progressive axonal loss in multifocal motor neuropathy (MMN) is often assessed with nerve conduction studies (NCS), by recording maximum compound muscle action potentials (CMAPs). However, reinnervation maintains the CMAP amplitude until a significant portion of the motor unit (MU) pool is lost. Therefore, we performed more informative CMAP scans to study MU characteristics in a large cohort of patients with MMN. METHODS: We derived the maximum CMAP amplitude (CMAPmax ), an MU number estimate (MUNE), and the largest MU amplitude stimulus current required to elicit 5%, 50%, and 95% of CMAPmax (S5, S50, S95) and relative ranges ([S95 - S5] × 100 / S50) from the scans. These metrics were compared with clinical, laboratory, and NCS results. RESULTS: Forty MMN patients and 24 healthy controls were included in the study. CMAPmax and MUNE were reduced in MMN patients (both P < .001). Largest MU amplitude as a percentage of CMAPmax was increased in MMN patients (P < .001). Disease duration and treatment duration were not associated with MUNE. Relative range was larger in patients with anti-GM1 antibodies than in those without anti-GM1 antibodies (P = .016) and controls (P < .001). The largest MU amplitudes were larger in patients without anti-GM1 antibodies than in patients with anti-GM1 antibodies (P = .037) and controls (P = .044). DISCUSSION: We found that MU loss is common in MMN and accompanied by enlarged MUs. Presence of anti-GM1 antibodies was associated with increased relative range of MU thresholds and reduction in largest MU amplitude. Our findings indicate that CMAP scans complement routine NCS, and may have potential for practical monitoring of treatment efficacy and disease progression.


Assuntos
Polineuropatias , Potenciais de Ação/fisiologia , Estudos de Coortes , Progressão da Doença , Humanos , Condução Nervosa/fisiologia , Polineuropatias/diagnóstico por imagem
9.
Eur J Neurol ; 28(11): 3556-3583, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34327760

RESUMO

OBJECTIVE: To revise the 2010 consensus guideline on chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). METHODS: Seventeen disease experts, a patient representative, and two Cochrane methodologists constructed 12 Population/Intervention/Comparison/Outcome (PICO) questions regarding diagnosis and treatment to guide the literature search. Data were extracted and summarized in GRADE summary of findings (for treatment PICOs) or evidence tables (for diagnostic PICOs). RESULTS: Statements were prepared according to the GRADE Evidence-to-Decision frameworks. Typical CIDP and CIDP variants were distinguished. The previous term "atypical CIDP" was replaced by "CIDP variants" because these are well characterized entities (multifocal, focal, distal, motor, or sensory CIDP). The levels of diagnostic certainty were reduced from three (definite, probable, possible CIDP) to only two (CIDP and possible CIDP), because the diagnostic accuracy of criteria for probable and definite CIDP did not significantly differ. Good Practice Points were formulated for supportive criteria and investigations to be considered to diagnose CIDP. The principal treatment recommendations were: (a) intravenous immunoglobulin (IVIg) or corticosteroids are strongly recommended as initial treatment in typical CIDP and CIDP variants; (b) plasma exchange is strongly recommended if IVIg and corticosteroids are ineffective; (c) IVIg should be considered as first-line treatment in motor CIDP (Good Practice Point); (d) for maintenance treatment, IVIg, subcutaneous immunoglobulin or corticosteroids are recommended; (e) if the maintenance dose of any of these is high, consider either combination treatments or adding an immunosuppressant or immunomodulatory drug (Good Practice Point); and (f) if pain is present, consider drugs against neuropathic pain and multidisciplinary management (Good Practice Point).


Assuntos
Neurologia , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Nervos Periféricos , Troca Plasmática , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/diagnóstico , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/terapia
10.
J Peripher Nerv Syst ; 26(3): 242-268, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34085743

RESUMO

To revise the 2010 consensus guideline on chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Seventeen disease experts, a patient representative, and two Cochrane methodologists constructed 12 Population/Intervention/Comparison/Outcome (PICO) questions regarding diagnosis and treatment to guide the literature search. Data were extracted and summarized in GRADE summary of findings (for treatment PICOs) or evidence tables (for diagnostic PICOs). Statements were prepared according to the GRADE Evidence-to-Decision frameworks. Typical CIDP and CIDP variants were distinguished. The previous term "atypical CIDP" was replaced by "CIDP variants" because these are well characterized entities (multifocal, focal, distal, motor, or sensory CIDP). The levels of diagnostic certainty were reduced from three (definite, probable, possible CIDP) to only two (CIDP and possible CIDP), because the diagnostic accuracy of criteria for probable and definite CIDP did not significantly differ. Good Practice Points were formulated for supportive criteria and investigations to be considered to diagnose CIDP. The principal treatment recommendations were: (a) intravenous immunoglobulin (IVIg) or corticosteroids are strongly recommended as initial treatment in typical CIDP and CIDP variants; (b) plasma exchange is strongly recommended if IVIg and corticosteroids are ineffective; (c) IVIg should be considered as first-line treatment in motor CIDP (Good Practice Point); (d) for maintenance treatment, IVIg, subcutaneous immunoglobulin or corticosteroids are recommended; (e) if the maintenance dose of any of these is high, consider either combination treatments or adding an immunosuppressant or immunomodulatory drug (Good Practice Point); and (f) if pain is present, consider drugs against neuropathic pain and multidisciplinary management (Good Practice Point).


Assuntos
Polirradiculoneuropatia Desmielinizante Inflamatória Crônica , Corticosteroides , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Neurologia , Nervos Periféricos , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/diagnóstico , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/terapia
12.
J Neurol Neurosurg Psychiatry ; 92(9): 975-982, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34103346

RESUMO

Acute and chronic immune-mediated neuropathies have been widely reported with medical intervention. Although causal relationship may be uncertain in many cases, a variety of drugs, several vaccination types, surgical procedures and bone marrow transplants have been reported as possible cause or trigger of a putative immune-mediated response resulting in acute and chronic neuropathies. We conducted a systematic review of the literature from 1966 to 2020 on reported cases of possible iatrogenic immune-mediated neuropathies. We determined in each case the likelihood of causality based on frequency of the association, focusing primarily on clinical presentation and disease course as well as available ancillary investigations (electrophysiology, blood and cerebrospinal fluid and neuropathology). The response to immunotherapy and issue of re-exposure were also evaluated. We also considered hypothesised mechanisms of onset of immune-mediated neuropathy in the specific iatrogenic context. We believe that a likely causal relationship exists for only few drugs, mainly antitumour necrosis factor alpha agents and immune checkpoint inhibitors, but remains largely unsubstantiated for most other suggested iatrogenic causes. Unfortunately, given the lack of an accurate diagnostic biomarker for most immune-mediated neuropathies, clinical assessment will often override ancillary investigations, resulting in lower levels of certainty that may continue to cast serious doubts on reliability of their diagnosis. Consequently, future reports of suspected cases should collect and exhaustively assess all relevant data. At the current time, besides lack of evidence for causality, the practical implications on management of suspected cases is extremely limited and therapeutic decisions appear likely no different to those made in non-iatrogenic cases.


Assuntos
Doença Iatrogênica/epidemiologia , Doenças do Sistema Imunitário/etiologia , Doenças do Sistema Nervoso Periférico/etiologia , Humanos , Doenças do Sistema Imunitário/diagnóstico , Doenças do Sistema Imunitário/epidemiologia , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/epidemiologia
13.
Eur J Neurol ; 28(8): 2716-2726, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33934438

RESUMO

BACKGROUND: The immunological pathophysiologies of chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN) differ considerably, but neither has been elucidated completely. Quantitative magnetic resonance imaging (MRI) techniques such as diffusion tensor imaging, T2 mapping, and fat fraction analysis may indicate in vivo pathophysiological changes in nerve architecture. Our study aimed to systematically study nerve architecture of the brachial plexus in patients with CIDP, MMN, motor neuron disease (MND) and healthy controls using these quantitative MRI techniques. METHODS: We enrolled patients with CIDP (n = 47), MMN (n = 29), MND (n = 40) and healthy controls (n = 10). All patients underwent MRI of the brachial plexus and we obtained diffusion parameters, T2 relaxation times and fat fraction using an automated processing pipeline. We compared these parameters between groups using a univariate general linear model. RESULTS: Fractional anisotropy was lower in patients with CIDP compared to healthy controls (p < 0.001), patients with MND (p = 0.010) and MMN (p < 0.001). Radial diffusivity was higher in patients with CIDP compared to healthy controls (p = 0.015) and patients with MND (p = 0.001) and MMN (p < 0.001). T2 relaxation time was elevated in patients with CIDP compared to patients with MND (p = 0.023). Fat fraction was lower in patients with CIDP and MMN compared to patients with MND (both p < 0.001). CONCLUSION: Our results show that quantitative MRI parameters differ between CIDP, MMN and MND, which may reflect differences in underlying pathophysiological mechanisms.


Assuntos
Plexo Braquial , Doença dos Neurônios Motores , Polineuropatias , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica , Plexo Braquial/diagnóstico por imagem , Imagem de Tensor de Difusão , Humanos , Imageamento por Ressonância Magnética , Doença dos Neurônios Motores/diagnóstico por imagem , Polineuropatias/diagnóstico por imagem , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/diagnóstico por imagem
14.
Artigo em Inglês | MEDLINE | ID: mdl-33829936

RESUMO

The kinesin family member 5A (KIF5A) motor domain variants are typically associated with hereditary spastic paraplegia (HSP) or Charcot-Marie-Tooth 2 (CMT2), while KIF5A tail variants predispose to amyotrophic lateral sclerosis (ALS) and neonatal intractable myoclonus. Variants within the stalk domain of KIF5A are relatively rare. We describe a family of three patients with a complex HSP phenotype and a likely pathogenic KIF5A stalk variant. More family members were reported to have walking difficulties. When reviewing the literature on KIF5A stalk variants, we found 22 other cases. The phenotypes varied with most cases having (complex) HSP/CMT2 or ALS. Symptom onset varied from childhood to adulthood and common additional symptoms for HSP are involvement of the upper limbs, sensorimotor polyneuropathy, and foot deformities. We conclude that KIF5A variants lead to a broad clinical spectrum of disease. Phenotype distribution according to variants in specific domains occurs often in the motor and tail domain but are not definite. However, variants in the stalk domain are not bound to a specific phenotype.


Assuntos
Esclerose Amiotrófica Lateral , Paraplegia Espástica Hereditária , Adolescente , Criança , Estudos de Associação Genética , Humanos , Mutação/genética , Fenótipo , Paraplegia Espástica Hereditária/genética , Adulto Jovem
15.
Neurol Clin Pract ; 11(2): 147-157, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33842068

RESUMO

PURPOSE OF REVIEW: To improve our clinical understanding of facial onset sensory and motor neuronopathy (FOSMN). RECENT FINDINGS: We identified 29 new cases and 71 literature cases, resulting in a cohort of 100 patients with FOSMN. During follow-up, cognitive and behavioral changes became apparent in 8 patients, suggesting that changes within the spectrum of frontotemporal dementia (FTD) are a part of the natural history of FOSMN. Another new finding was chorea, seen in 6 cases. Despite reports of autoantibodies, there is no consistent evidence to suggest an autoimmune pathogenesis. Four of 6 autopsies had TAR DNA-binding protein (TDP) 43 pathology. Seven cases had genetic mutations associated with neurodegenerative diseases. SUMMARY: FOSMN is a rare disease with a highly characteristic onset and pattern of disease progression involving initial sensory disturbances, followed by bulbar weakness with a cranial to caudal spread of pathology. Although not conclusive, the balance of evidence suggests that FOSMN is most likely to be a TDP-43 proteinopathy within the amyotrophic lateral sclerosis-FTD spectrum.

16.
Pract Neurol ; 21(3): 186-195, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33541914

RESUMO

Nerve ultrasound scanning has become a valuable diagnostic tool in the routine workup of peripheral nerve disorders, effectively complementing conventional electrodiagnostic studies. The most relevant sonographic features are nerve size and structural integrity. Several peripheral neuropathies show characteristic and distinct patterns of nerve enlargement, allowing their early and accurate identification, and reducing test-burden and diagnostic delay for patients. In mononeuropathies such as carpal tunnel syndrome and ulnar neuropathy at the elbow, nerve enlargement develops only at specific sites of entrapment, while in polyneuropathy the nerve enlargement may be multifocal, regional or even diffuse. Nerve ultrasound scanning can reliably identify chronic inflammatory neuropathies, even when extensive electrodiagnostic studies fail, and it should therefore be embedded in routine diagnostic workup of peripheral neuropathies. In this paper we describe a potential diagnostic strategy to achieve this.


Assuntos
Neurite (Inflamação) , Doenças do Sistema Nervoso Periférico , Diagnóstico Tardio , Humanos , Doenças do Sistema Nervoso Periférico/diagnóstico por imagem , Ultrassonografia
17.
Neurobiol Aging ; 101: 79-84, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33582569

RESUMO

OBJECTIVE: To gain further insight in the immunopathology underlying multifocal motor neuropathy (MMN) by exploring the association between MMN and the human leukocyte antigen (HLA) class II DRB1, DQB1, and DQA loci in depth and by correlating associated haplotypes to detailed clinical and anti-ganglioside antibody data. METHODS: We performed high-resolution HLA-class II typing for the DRB1, DQB1, and DQA1 loci in 126 well-characterized MMN patients and assessed disease associations with haplotypes. We used a cohort of 1305 random individuals as a reference for haplotype distribution in the Dutch population. RESULTS: The DRB1*15:01-DQB1*06:02 haplotype (OR 1.6 [95% CI 1.1-2.2], p < 0.05) and the DRB1*12:01-DQB1*03:01 haplotype (OR 2.7 [95% CI 1.2-5.5], p < 0.05) were more frequent in patients with MMN than in controls. These haplotypes were not associated with disease course, response to treatment or anti-ganglioside antibodies. CONCLUSIONS: MMN is associated with the DRB1*15:01-DQB1*06:02 and DRB1*12:01-DQB1*03:01 haplotypes. These HLA molecules or gene variants in their immediate vicinity may promote the specific inflammatory processes underlying MMN.


Assuntos
Estudos de Associação Genética/métodos , Predisposição Genética para Doença/genética , Cadeias alfa de HLA-DQ/genética , Cadeias beta de HLA-DQ/genética , Cadeias beta de HLA-DR/genética , Teste de Histocompatibilidade/métodos , Polineuropatias/genética , Adulto , Estudos de Coortes , Feminino , Gangliosídeos/imunologia , Loci Gênicos , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos
18.
J Neurol ; 268(3): 978-988, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32965512

RESUMO

OBJECTIVE: This study aimed at developing a quantitative approach to assess abnormalities on MRI of the brachial plexus and the cervical roots in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN) and to evaluate interrater reliability and its diagnostic value. METHODS: We performed a cross-sectional study in 50 patients with CIDP, 31 with MMN and 42 disease controls. We systematically measured cervical nerve root sizes on MRI bilaterally (C5, C6, C7) in the coronal [diameter (mm)] and sagittal planes [area (mm2)], next to the ganglion (G0) and 1 cm distal from the ganglion (G1). We determined their diagnostic value using a multivariate binary logistic model and ROC analysis. In addition, we evaluated intra- and interrater reliability. RESULTS: Nerve root size was larger in patients with CIDP and MMN compared to controls at all predetermined anatomical sites. We found that nerve root diameters in the coronal plane had optimal reliability (intrarater ICC 0.55-0.87; interrater ICC 0.65-0.90). AUC was 0.78 (95% CI 0.69-0.87) for measurements at G0 and 0.81 (95% CI 0.72-0.91) for measurements at G1. Importantly, our quantitative assessment of brachial plexus MRI identified an additional 10% of patients that showed response to treatment, but were missed by nerve conduction (NCS) and nerve ultrasound studies. CONCLUSION: Our study showed that a quantitative assessment of brachial plexus MRI is reliable. MRI can serve as an important additional diagnostic tool to identify treatment-responsive patients, complementary to NCS and nerve ultrasound.


Assuntos
Neuropatias do Plexo Braquial , Plexo Braquial , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica , Plexo Braquial/diagnóstico por imagem , Neuropatias do Plexo Braquial/diagnóstico por imagem , Estudos Transversais , Humanos , Imageamento por Ressonância Magnética , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/diagnóstico por imagem , Reprodutibilidade dos Testes
19.
Neurology ; 96(6): e845-e852, 2021 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-33219141

RESUMO

OBJECTIVE: To determine the associations between fatigability and muscle strength, motor function, neuromuscular junction (NMJ) function, and perceived fatigue in spinal muscular atrophy (SMA), we assessed 61 patients with SMA. METHODS: Fatigability was defined as the inability to continue a 20-minute submaximal repetitive task of either walking or proximal or distal arm function and expressed as drop-out on the Endurance Shuttle Test Combined Score (ESTCS). We assessed muscle strength with the Medical Research Council (MRC) sum score, motor function with the Hammersmith Functional Motor Scale Expanded (HFMSE) and Motor Function Measure (MFM), NMJ function with repetitive nerve stimulation of the accessory and ulnar nerve, and perceived fatigue with the PROMIS Fatigue Short Form questionnaire in 61 children and adults with SMA types 2-4. We applied Cox regression analysis to explore the associations between fatigability and these factors. RESULTS: The hazard of drop-out on the ESTCS decreased 0.8%, 2%, and 1.3% for each point increase in the MRC sum score, the HFMSE score, and the MFM percentual score, respectively. However, we observed prominent fatigability with preserved muscle function and vice versa in 13%-16% of patients. We did not find an association between NMJ dysfunction of the accessory (p = 0.37) and ulnar nerve (p = 0.063) and fatigability, which could be due to a large number of missing values. Perceived fatigue in SMA was comparable to reference values and was not associated with fatigability (p = 0.52). CONCLUSION: Fatigability in SMA is associated with, yet not equivalent to, muscle strength and motor function.


Assuntos
Fadiga/fisiopatologia , Atividade Motora/fisiologia , Força Muscular/fisiologia , Atrofia Muscular Espinal/fisiopatologia , Sistema de Registros , Nervo Acessório/fisiopatologia , Adolescente , Adulto , Criança , Estudos Transversais , Estimulação Elétrica , Teste de Esforço , Fadiga/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Atrofia Muscular Espinal/complicações , Modelos de Riscos Proporcionais , Índice de Gravidade de Doença , Nervo Ulnar/fisiopatologia , Adulto Jovem
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