Trans-Synaptic Degeneration Following Acute Optic Neuritis in Multiple Sclerosis.

OBJECTIVE: To explore longitudinal changes in brain volumetric measures and retinal layer thicknesses following acute optic neuritis (AON) in people with multiple sclerosis (PwMS), to investigate the process of trans-synaptic degeneration, and determine its clinical relevance. METHODS: PwMS were recruited within 40 days of AON onset (n = 49), and underwent baseline retinal optical coherence tomography and brain magnetic resonance imaging followed by longitudinal tracking for up to 5 years. A comparator cohort of PwMS without a recent episode of AON were similarly tracked (n = 73). Mixed-effects linear regression models were used. RESULTS: Accelerated atrophy of the occipital gray matter (GM), calcarine GM, and thalamus was seen in the AON cohort, as compared with the non-AON cohort (-0.76% vs -0.22% per year [p = 0.01] for occipital GM, -1.83% vs -0.32% per year [p = 0.008] for calcarine GM, -1.17% vs -0.67% per year [p = 0.02] for thalamus), whereas rates of whole-brain, cortical GM, non-occipital cortical GM atrophy, and T2 lesion accumulation did not differ significantly between the cohorts. In the AON cohort, greater AON-induced reduction in ganglion cell+inner plexiform layer thickness over the first year was associated with faster rates of whole-brain (r = 0.32, p = 0.04), white matter (r = 0.32, p = 0.04), and thalamic (r = 0.36, p = 0.02) atrophy over the study period. Significant relationships were identified between faster atrophy of the subcortical GM and thalamus, with worse visual function outcomes after AON. INTERPRETATION: These results provide in-vivo evidence for anterograde trans-synaptic degeneration following AON in PwMS, and suggest that trans-synaptic degeneration may be related to clinically-relevant visual outcomes. ANN NEUROL 2023;93:76-87.

Respiratory symptoms are common in stiff person syndrome spectrum disorders and are associated with number of body regions involved.

BACKGROUND AND PURPOSE: Stiff person syndrome (SPS) spectrum disorders (SPSSD) cause spasms and rigidity throughout different body regions and can be associated with apnea and acute respiratory failure. There are limited data on the prevalence and predictors of respiratory symptoms with spasms (RSwS) in SPSSD. We sought to characterize the spirometry patterns and the frequency and predictors of RSwS in a large SPSSD cohort. METHODS: Participants were recruited from the Johns Hopkins SPS Center between 1997 and 2021, as part of an ongoing, longitudinal observational study. Medical records were reviewed to assess demographics and clinical characteristics. Data were analyzed using descriptive statistics and multivariable logistic regression models. RESULTS: One-hundred ninety-nine participants (mean age = 53.4 ± 13.6 years, median time to diagnosis = 36 [IQR 66] months, 74.9% women, 69.8% White, 62.8% classic SPS phenotype) were included in final analyses; 35.2% of participants reported RSwS, of whom 24.3% underwent spirometry as part of routine clinical care. Obstructive (23.5%) and restrictive (23.5%) patterns were most commonly observed in those with SPSSD. An increasing number of body regions involved predicted the presence of RSwS (odds ratio [OR] = 1.95, 95% confidence interval [CI] = 1.50-2.53); those with ≥5 body regions involved (vs. ≤4) had higher odds (OR = 6.19, 95% CI = 2.81-13.62) of experiencing RSwS in adjusted models. Two patients died from SPSSD-associated respiratory compromise. CONCLUSIONS: RSwS are common in SPSSD and may be predicted by an increasing number of body regions involved by SPSSD. Close clinical monitoring and having a low threshold to obtain spirometry should be considered in people with SPSSD.

Centripetal Nystagmus, Slow Saccades, Cerebellar Ataxia, and Parkinsonism in a Patient With Anti-GAD65-Associated Stiff Person Syndrome Spectrum Disorder.

ABSTRACT: A 68-year-old woman with positional dizziness and progressive imbalance presented for vestibular evaluation. Examination was notable for spontaneous downbeat nystagmus (DBN), horizontal and vertical gaze-evoked nystagmus (GEN) with centripetal and rebound nystagmus, and positional apogeotropic nystagmus. There was also mild-moderate slowing of saccades horizontally and vertically and poor fast phases with an optokinetic stimulus. Further consultation by a movement disorder specialist uncovered asymmetric decrementing bradykinesia and rigidity, masked facies, and a wide-based stance without camptocormia. Screening serum laboratory results for metabolic, rheumatologic, infectious, heavy metal, endocrine, or vitamin abnormalities was normal. Surveillance imaging for neoplasms was unremarkable, and cerebrospinal fluid (CSF) analysis was negative for 14-3-3 and real-time quaking-induced conversion (RT-QuIC). However, her anti-glutamic acid decarboxylase-65 (GAD65) immunoglobulin G (IgG) level was markedly elevated in serum to 426,202 IU/mL (reference range 0-5 IU/mL) and in CSF to 18.1 nmol/L (reference range <0.03 nmol/L). No other autoantibodies were identified on the expanded paraneoplastic panel. The patient was referred to neuroimmunology, where torso rigidity, spasticity, and significant paravertebral muscle spasms were noted. Overall, the clinical presentation, examination findings, and extensive workup were consistent with a diagnosis of anti-GAD65-associated stiff person syndrome-plus (musculoskeletal plus cerebellar and/or brainstem involvement). She was subsequently treated with intravenous immunoglobulin (IVIg) and has been stable since commencing this therapy. In patients with centripetal nystagmus, especially in association with other cerebellar findings, an autoimmune cerebellar workup should be considered.

Risk Factors for Infection and Health Impacts of the Coronavirus Disease 2019 (COVID-19) Pandemic in People With Autoimmune Diseases.

BACKGROUND: People with autoimmune or inflammatory conditions taking immunomodulatory/suppressive medications may have higher risk of novel coronavirus disease 2019 (COVID-19). Chronic disease care has also changed for many patients, with uncertain downstream consequences. METHODS: We included participants with autoimmune or inflammatory conditions followed by specialists at Johns Hopkins. Participants completed periodic surveys querying comorbidities, disease-modifying medications, exposures, COVID-19 testing and outcomes, social behaviors, and disruptions to healthcare. We assessed whether COVID-19 risk is higher among those on immunomodulating or suppressive agents and characterized pandemic-associated changes to care and mental health. RESULTS: In total, 265 (5.6%) developed COVID-19 over 9 months of follow-up (April-December 2020). Patient characteristics (age, race, comorbidity, medications) were associated with differences in social distancing behaviors during the pandemic. Glucocorticoid exposure was associated with higher odds of COVID-19 in models incorporating behavior and other potential confounders (odds ratio [OR]: 1.43; 95% confidence interval [CI]: 1.08, 1.89). Other medication classes were not associated with COVID-19 risk. Diabetes (OR: 1.72; 95% CI: 1.08, 2.73), cardiovascular disease (OR: 1.68; 95% CI: 1.24, 2.28), and kidney disease (OR: 1.76; 95% CI: 1.04, 2.97) were associated with higher odds of COVID-19. Of the 2156 reporting pre-pandemic utilization of infusion, mental health or rehabilitative services, 975 (45.2%) reported disruptions therein, which disproportionately affected individuals experiencing changes to employment or income. CONCLUSIONS: Glucocorticoid exposure may increase risk of COVID-19 in people with autoimmune or inflammatory conditions. Disruption to healthcare and related services was common. Those with pandemic-related reduced income may be most vulnerable to care disruptions.

Unsupervised MR harmonization by learning disentangled representations using information bottleneck theory.

In magnetic resonance (MR) imaging, a lack of standardization in acquisition often causes pulse sequence-based contrast variations in MR images from site to site, which impedes consistent measurements in automatic analyses. In this paper, we propose an unsupervised MR image harmonization approach, CALAMITI (Contrast Anatomy Learning and Analysis for MR Intensity Translation and Integration), which aims to alleviate contrast variations in multi-site MR imaging. Designed using information bottleneck theory, CALAMITI learns a globally disentangled latent space containing both anatomical and contrast information, which permits harmonization. In contrast to supervised harmonization methods, our approach does not need a sample population to be imaged across sites. Unlike traditional unsupervised harmonization approaches which often suffer from geometry shifts, CALAMITI better preserves anatomy by design. The proposed method is also able to adapt to a new testing site with a straightforward fine-tuning process. Experiments on MR images acquired from ten sites show that CALAMITI achieves superior performance compared with other harmonization approaches.

Early factors associated with later conversion to multiple sclerosis in patients presenting with isolated myelitis.

OBJECTIVE: To identify early clinical and paraclinical factors that may help predict later conversion to multiple sclerosis (MS) in patients presenting with isolated myelitis (ie, 'transverse myelitis' without clinical or radiological evidence of inflammation/demyelination elsewhere in the central nervous system). METHODS: In this retrospective cohort study, we included patients with isolated myelitis who were followed clinically and radiologically at our specialised myelopathy clinic. We excluded patients with MS at the onset, aquaporin-4-IgG seropositivity, myelin oligodendrocyte glycoprotein-IgG seropositivity or other identified aetiology. Logistic regression was used to identify factors predictive of conversion to MS (defined by the 2017 McDonald criteria). RESULTS: We included 100 patients, followed for a median of 4.3 years. Conversion to MS occurred in 25 of 77 patients (32%) with short-segment myelitis (longest lesion spanning <3 vertebral segments on MRI) as compared with 0 of 23 patients (0%) with longitudinally extensive myelitis (p=0.002). Among patients with short-segment myelitis, factors identified as highly predictive of conversion to MS using multivariate logistic regression included cerebrospinal fluid (CSF)-restricted oligoclonal bands (OCB) (OR (OR) 9.2, 95% CI 2.1 to 41.0, p=0.004), younger age (OR 1.1 for each year younger, 95% CI 1.0 to 1.1, p=0.04) and longer follow-up (OR 1.3 for each year longer, 95% CI 1.0 to 1.6, p=0.04). Conversion to MS occurred at a median of 2.8 years after myelitis onset. CONCLUSIONS: Short-segment MRI cord lesion(s), CSF-restricted OCB, younger age and longer follow-up are all factors predictive of conversion to MS in patients presenting with isolated myelitis.

MOGAD: How It Differs From and Resembles Other Neuroinflammatory Disorders.

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a distinct CNS inflammatory disease with symptoms and imaging findings that overlap other neuroinflammatory disorders. We highlight the imaging characteristics of MOGAD and contrast them with neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS). Intracranial features that suggest MOGAD include childhood acute disseminated encephalomyelitis pattern with diffuse signal abnormality in the cortical gray matter, subcortical white matter, deep white matter, and deep gray matter on T2-weighted and FLAIR images; few bilateral T2-hyperintense fluffy and poorly demarcated lesions; pontine or thalamic involvement (or both); and cerebellar peduncle lesions in children. Intraorbitally, one sees edematous, enlarged, tortuous optic nerve or nerves; bilateral long-segment T2 hyperintensity of anterior segments of the optic nerve; sparing of the optic chiasm and retrochiasmatic pathways; and perioptic nerve sheath and surrounding orbital fat enhancement. Spinal involvement is seen as longitudinally extensive transverse myelitis with a sagittal T2-hyperintense intramedullary spinal line, the axial "H" spinal cord sign (central cord gray matter T2 hyperintensity), and conus medullaris involvement. Early accurate diagnosis of MOGAD is important because prognosis and treatment differ from those for NMOSD and MS.

Ocular Motor and Vestibular Characteristics of Antiglutamic Acid Decarboxylase-Associated Neurologic Disorders.

BACKGROUND: Antiglutamic acid decarboxylase (GAD)-associated neurologic disorders are rare, with varied presentations, including stiff-person syndrome (SPS) and cerebellar ataxia (CA). Vestibular and ocular motor (VOM) dysfunction can be the main presentation in a subset of patients. METHODS: Retrospective review of the Johns Hopkins Hospital medical records from 1997 to 2018 identified a total of 22 patients with a diagnosis of anti-GAD-associated SPS or CA who had detailed VOM assessments. Eight had prominent VOM dysfunction at the initial symptom onset and were referred to neurology from ophthalmology or otolaryngology ("early dominant"). Fourteen patients had VOM dysfunction that was not their dominant presentation and were referred later in their disease course from neurology to neuro-ophthalmology ("nondominant"). We reviewed clinical history, immunological profiles, and VOM findings, including available video-oculography. RESULTS: In the 8 patients with early dominant VOM dysfunction, the average age of symptom onset was 53 years, and 5 were men. The most common symptom was dizziness, followed by diplopia. Seven had features of CA, and 4 had additional features of SPS. None had a structural lesion on brain MRI accounting for their symptoms. The most common VOM abnormalities were downbeating and gaze-evoked nystagmus and saccadic pursuit. All received immune therapy and most received symptomatic therapy. Most experienced improvement in clinical outcome measures (modified Rankin scale and/or timed 25-foot walk test) or VOM function. By contrast, in the 14 patients in whom VOM dysfunction was nondominant, most had an SPS phenotype and were women. VOM abnormalities, when present, were more subtle, although mostly still consistent with cerebellar and/or brainstem dysfunction. CONCLUSIONS: Individuals with anti-GAD-associated neurologic disorders may present with prominent VOM abnormalities at the initial symptom onset that localize to the cerebellum and/or brainstem. In our cohort, immune and symptomatic therapies improved clinical outcomes and symptomatology.

Characteristics of morphologic macular abnormalities in neuroimmunology practice.

BACKGROUND: Morphologic macular abnormalities (MMAs) are frequently seen on macular optical coherence tomography (OCT) imaging in neuroimmunology practice, yet studies pragmatically assessing prevalence and risk factors of MMAs to date are limited. OBJECTIVE: To describe the characteristics of MMAs in a neuroimmunology-based academic practice. METHODS: Cross-sectional study of 1450 patients (2900 eyes) who underwent spectral-domain macular OCT between June 2010 and June 2012. The association between MMAs and demographic variables was analyzed using mixed-effects logistic regression. Odds ratios (ORs) were calculated per 5-year age increments. RESULTS: MMAs were observed in 338/2872 eyes (11.7%) of 232/1445 participants (16.1%). The most common abnormalities identified, included drusen (6.0%), epiretinal membrane (ERM; 5.5%), and microcystoid macular pathology (MMP; 1.9%). Overall, patients with MMAs were older (OR: 1.79, p = 5 × 10-5) and more likely to be males (OR: 2.45, p = 0.014). In particular, advancing age was associated with higher risk of drusen and ERM (OR: 1.80 and 4.26, p = 2 × 10-5 and 7 × 10-3, respectively). MMP prevalence declined with age (OR: 0.73, p = 0.015) and was associated with African-American ethnicity (OR: 15.0, p = 5 × 10-5). CONCLUSION: Unexpected or incidental MMAs are common in patients assessed with OCT in neuroimmunology practice, emphasizing the importance of comprehensive OCT image review for risk stratification and appropriate ophthalmology referral.

Retrograde trans-synaptic visual pathway degeneration in multiple sclerosis: A case series.

BACKGROUND: Trans-synaptic degeneration (TSD) describes the propagation of neuronal injury through synaptic pathways in the human nervous system and may be linked to the accelerated retinal atrophy seen in multiple sclerosis (MS). RESULTS: We report six cases where homonymous, hemi-macular ganglion cell + inner plexiform (GCIP) thickness reduction was seen in conjunction with posterior visual pathway lesions. Macular microcystoid changes of the inner nuclear layer (INL) were seen in a subset of three subjects. CONCLUSION: Our findings highlight the utility of assessing regional GCIP changes to identify potential retrograde TSD in MS and demonstrate that INL changes may be an accompaniment in such instances.

Optical coherence tomography reflects brain atrophy in multiple sclerosis: A four-year study.

OBJECTIVE: The aim of this work was to determine whether atrophy of specific retinal layers and brain substructures are associated over time, in order to further validate the utility of optical coherence tomography (OCT) as an indicator of neuronal tissue damage in patients with multiple sclerosis (MS). METHODS: Cirrus high-definition OCT (including automated macular segmentation) was performed in 107 MS patients biannually (median follow-up: 46 months). Three-Tesla magnetic resonance imaging brain scans (including brain-substructure volumetrics) were performed annually. Individual-specific rates of change in retinal and brain measures (estimated with linear regression) were correlated, adjusting for age, sex, disease duration, and optic neuritis (ON) history. RESULTS: Rates of ganglion cell + inner plexiform layer (GCIP) and whole-brain (r = 0.45; p < 0.001), gray matter (GM; r = 0.37; p < 0.001), white matter (WM; r = 0.28; p = 0.007), and thalamic (r = 0.38; p < 0.001) atrophy were associated. GCIP and whole-brain (as well as GM and WM) atrophy rates were more strongly associated in progressive MS (r = 0.67; p < 0.001) than relapsing-remitting MS (RRMS; r = 0.33; p = 0.007). However, correlation between rates of GCIP and whole-brain (and additionally GM and WM) atrophy in RRMS increased incrementally with step-wise refinement to exclude ON effects; excluding eyes and then patients (to account for a phenotype effect), the correlation increased to 0.45 and 0.60, respectively, consistent with effect modification. In RRMS, lesion accumulation rate was associated with GCIP (r = -0.30; p = 0.02) and inner nuclear layer (r = -0.25; p = 0.04) atrophy rates. INTERPRETATION: Over time GCIP atrophy appears to mirror whole-brain, and particularly GM, atrophy, especially in progressive MS, thereby reflecting underlying disease progression. Our findings support OCT for clinical monitoring and as an outcome in investigative trials.

Outer retinal changes following acute optic neuritis.

BACKGROUND: Retinal nerve fiber and ganglion cell+inner plexiform (GCIP) layer thinning following multiple sclerosis-related acute optic neuritis (AON) is well described. However, whether AON results in changes in the inner nuclear (INL), outer plexiform (OPL), outer nuclear (ONL) and/or photoreceptor segment (PS) layers remains undetermined. OBJECTIVES: The objective of this paper is to determine if INL+OPL and/or ONL+PS changes occur following AON. METHODS: Thirty-three AON patients underwent serial optical coherence tomography (OCT) and visual function testing (mean follow-up: 25 months). Longitudinal changes in retinal layer thickness were analyzed using mixed-effects linear regression. RESULTS: Four months following AON, the mean decrease in GCIP thickness relative to baseline was 11.4% (p < 0.001). At four months, a concomitant 3.4% increase in average ONL+PS thickness was observed (p < 0.001). The percentage decrease in GCIP thickness and increase in ONL+PS thickness were strongly correlated (r = -0.70; p < 0.001). Between months 4 to 12, ONL+PS thickness declined and, at 12 months, was no longer significantly different from baseline (mean change: 0.5%; p = 0.37). Similar, albeit less robust, changes in the INL+OPL were observed. CONCLUSIONS: Following AON, dynamic changes occur in the deep retinal layers, which are proportional to GCIP thinning. These novel findings help further our understanding of the biological and/or anatomical sequelae resulting from AON.

Differentiating neuromyelitis optica from other causes of longitudinally extensive transverse myelitis on spinal magnetic resonance imaging.

BACKGROUND: Although spinal magnetic resonance imaging (MRI) findings of neuromyelitis optica (NMO) have been described, there is limited data available that help differentiate NMO from other causes of longitudinally extensive transverse myelitis (LETM). OBJECTIVE: To investigate the spinal MRI findings of LETM that help differentiate NMO at the acute stage from multiple sclerosis (MS) and other causes of LETM. METHODS: We enrolled 94 patients with LETM into our study. Bright spotty lesions (BSL), the lesion distribution and location were evaluated on axial T2-weighted images. Brainstem extension, cord expansion, T1 darkness and lesion enhancement were noted. We also reviewed the brain MRI of the patients during LETM. RESULTS: Patients with NMO had a greater amount of BSL and T1 dark lesions (p < 0.001 and 0.003, respectively). The lesions in NMO patients were more likely to involve greater than one-half of the spinal cord's cross-sectional area; to enhance and be centrally-located, or both centrally- and peripherally-located in the cord. Of the 62 available brain MRIs, 14 of the 27 whom were NMO patients had findings that may be specific to NMO. CONCLUSIONS: Certain spinal cord MRI features are more commonly seen in NMO patients and so obtaining brain MRI during LETM may support diagnosis.

Stiff Person Syndrome Masquerading as Acute Coronary Syndrome.

Stiff person syndrome (SPS) is a rare neuroimmunological disorder characterized by severe progressive muscle stiffness in axial and lower extremity musculature with superimposed painful muscle spasms. Although chest pain is a common reason for SPS patients presenting to the emergency room, this disorder is overlooked and not part of the differential diagnosis of chest pain. Herein, we report on a middle age male presenting with classic symptoms of SPS; however, due to the rarity of this disease, he was initially thought to have acute coronary syndrome. Clinicians should consider the diagnosis of SPS in patients with fluctuating muscle spasms in the torso and/or extremities in the setting of repeated hospitalizations without subsequent symptom relief.

A rare case of hyponatremia from a hypothalamic lesion in a patient with multiple sclerosis.

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) can occur from a variety of neurologic and systemic processes; however, it has rarely been seen in multiple sclerosis (MS). We report a case of SIADH in a patient with MS and compare it with previously reported English-only cases. A 32-year-old woman experienced generalized fatigue followed by confusion and was found to have profound hyponatremia. Her work-up demonstrated SIADH secondary to a discrete enhancing hypothalamic lesion. Despite the seldom occurrence of SIADH in MS, hypothalamic lesions are more common than appreciated and should be considered in patients presenting with hyponatremia or endocrinopathy symptoms.

Molecular diagnostic tests to predict the risk of progressive multifocal leukoencephalopathy in natalizumab-treated multiple sclerosis patients.

Natalizumab is a humanized monoclonal antibody against the alpha4 chain of the alpha4beta1 and alpha4beta7 integrin heterodimers used with high effectiveness in the treatment of multiple sclerosis. The use of this drug can unfortunately be associated with the onset of progressive multifocal leukoencephalopathy, a possibly fatal infection of the central nervous system, caused by polyomavirus JC. To understand and quantify the risk of developing PML is important for patients who are about to start therapy with natalizumab and for patients who already are under treatment with this drug. In this review we describe and critique molecular diagnostic tests proposed in the last years to assess the risk of PML.

Longitudinally extensive myelopathy in children.

When children present with acute myelopathy manifested by sensory, motor, or bowel and bladder symptoms, MRI of the neuraxis with contrast agent is the most important imaging study to obtain. Although occasionally normal, MRI often demonstrates signal abnormality within the spinal cord. Classically, longitudinally extensive transverse myelitis (≥3 vertebral bodies in length) has been described with neuromyelitis optica (NMO), but alternative diagnoses should be considered. This pictorial essay reviews the differential diagnoses that may present with longitudinally extensive spinal cord signal abnormalities. Multiple inflammatory, infectious, vascular, metabolic and neurodegenerative etiologies can present with a myelopathy. Thus, radiologists can assist in the diagnosis by familiarizing themselves with the spectrum of diseases in childhood that result in longitudinally extensive signal abnormalities in the absence of trauma.

Progressive multifocal leukoencephalopathy associated with brentuximab vedotin therapy: a report of 5 cases from the Southern Network on Adverse Reactions (SONAR) project.

BACKGROUND: Brentuximab vedotin (BV) is an anti-CD30 monoclonal antibody-drug conjugate that was approved in 2011 for the treatment of patients with anaplastic large cell and Hodgkin lymphomas. The product label indicates that 3 patients who were treated with BV developed progressive multifocal leukoencephalopathy (PML), a frequently fatal JC virus-induced central nervous system infection. Prior immunosuppressive therapy and compromised immune systems were postulated risk factors. In the current study, the authors reported 5 patients who developed BV-associated PML, including 2 immunocompetent patients. METHODS: Case information was obtained from clinicians (4 patients) or a US Food and Drug Administration database (1 patient). RESULTS: All 5 patients had lymphoid malignancies. Two patients with cutaneous T-cell lymphomas had not previously received chemotherapy. PML developed after a median of 3 BV doses (range, 2 doses-6 doses) and within a median of 7 weeks after BV initiation (range, 3 weeks-34 weeks). Presenting findings included aphasia, dysarthria, confusion, hemiparesis, and gait dysfunction; JC virus in the cerebrospinal fluid (2 patients) or central nervous system biopsy (3 patients); and brain magnetic resonance imaging scans with white matter abnormalities (5 patients). Four patients died at a median of 8 weeks (range, 6 weeks-16 weeks) after PML diagnosis. The sole survivor developed immune reconstitution inflammatory syndrome. CONCLUSIONS: PML can develop after a few BV doses and within weeks of BV initiation. Clinicians should be aware of this syndrome, particularly when neurologic changes develop after the initiation of BV treatment. The decision to administer BV to patients with indolent cutaneous lymphomas should be based on consideration of risk-benefit profiles and of alternative options.