Erythromelalgia. Part II: Differential diagnoses and management.

The management of erythromelalgia is challenging and requires multidisciplinary effort. Patient education is crucial as unsafe self-administered cooling techniques can lead to significant morbidity, including acral necrosis, infection, and amputation. The goal of management is pain control, reduction of flare frequency, and prevention of complications. This text is focused on the management of erythromelalgia and several other incompletely understood and under-recognized neurovascular disorders such as red scrotum syndrome, red ear syndrome, facial flushing, and complex regional pain syndrome.

Erythromelalgia. Part I: Pathogenesis, clinical features, evaluation, and complications.

Erythromelalgia is a rare pain disorder that is underrecognized and difficult-to-treat. It is characterized by episodes of extremity erythema and pain that can be disabling; it may be genetic, related to an underlying systemic disease, or idiopathic. Considering the prominent cutaneous features characteristic of the condition, dermatologists can play an important role in early recognition and limitation of morbidity. The first article in this 2-part continuing medical education series reviews the epidemiology, pathogenesis, clinical manifestations, evaluation, and complications.

Transverse myelitis in myelin oligodendrocyte glycoprotein antibody-associated disease.

Transverse myelitis (TM) is the second most common presentation of myelin oligodendrocyte antibody-associated disease (MOGAD), occurring in approximately 26% of affected patients. The diagnosis may be complicated by the lack of diagnostic specificity of low titers of MOG antibody in serum, fluctuation in seropositivity overtime, including initially normal MRI in up to 10% of patients, and in many instances complete resolution of radiological abnormalities when MRI is done in a significantly delayed fashion. The use of preventive disease modifying treatments is limited by the uncertainty whether the disease process will remain monophasic or become relapsing, as well as by the lack FDA approved treatments. In this review, we discuss clinical, radiological and cerebrospinal fluid (CSF) characteristics, including the significance of MOG titers and changes in the seropositivity status for the diagnosis of MOGAD-associated TM, its radiological features and management options, highlighting the data on the risk of relapses associated with TM at presentation and the need for further randomized clinical trials to empower effective treatment algorithms.

Familial CNS-Isolated Hemophagocytic Lymphohistiocytosis Due to a Novel PRF1 Mutation Triggered by SARS-CoV2.

Background: Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal hyperinflammatory condition that presents with fever, hepatosplenomegaly, and characteristic laboratory findings. Mutations in the perforin gene PRF1 have been implicated in cases of familial HLH (fHLH) and can cause isolated CNS-HLH in the absence of systemic HLH. Results: A five year-old boy presented with three weeks of headache, blurry vision, and emesis. He was diagnosed with acute disseminated encephalomyelitis (ADEM), thought to be triggered by SARS-CoV-2 given positive nasopharyngeal testing. He completed a five day course of high dose IV methylprednisolone and plasma exchange. In the subsequent months, he was admitted twice due to worsening clinical and radiological activity and after several courses of IV pulse steroids, plasmapheresis, and IV immunoglobulin (IVIG), his condition stabilized with rituximab and monthly IVIG. A few months later, his younger brother presented with a similar syndrome. It was discovered that his parents were second cousins, leading to concern for a genetic disorder. Genetic testing revealed a homozygous mutation for PRF1 in both siblings (variant c.4422G>A). Conclusions: This is the first presentation of CNS-isolated familial HLH triggered by SARS-CoV-2 in the pediatric population. Furthermore, this is the first report of this specific PRF1 mutation, the variant c.4422G>A, as pathogenic. It highlights the relevance of genetic testing in pediatric neuroinflammatory disorders that do not respond adequately to conventional treatments. It is possible that as our knowledge in neurogenetics develops, certain genes will be identified as predisposing factors to syndromes such as ADEM.

Persistent severe lymphopenia 5 years after dimethyl fumarate discontinuation.

One known adverse event associated with dimethyl fumarate (DMF) is grade III lymphopenia which usually resolves within 2-3 months upon DMF discontinuation. Here, we report a case of a 50-year-old woman with MS who developed grade III lymphopenia within 6 months of DMF initiation, and despite treatment cessation within the next 6 months, she has continued to have severe persistent lymphopenia for over 5 years. Our observation suggests prolonged and possibly irreversible lymphopenia as a possible adverse event of DMF, and it emphasizes the need for monitoring lymphocyte numbers, and to cease dosing promptly after onset of grade III lymphopenia.

Adverse event profile differences between rituximab and ocrelizumab: Findings from the FDA Adverse Event Reporting Database.

BACKGROUND: Rituximab and ocrelizumab are anti-CD20 monoclonal antibodies that have shown a marked reduction in multiple sclerosis (MS) inflammatory activity. However, their real-world safety profile has not been adequately compared. OBJECTIVE: To investigate the adverse event (AE) profile of rituximab and ocrelizumab reported to the Food and Drug Administration Adverse Event Reporting System (FAERS) database. METHODS: The FAERS database was filtered by indication (MS) and drug (rituximab or ocrelizumab). Disproportionality analyses including but not limited to reporting odds ratio (ROR) were conducted to identify drug-AE associations. A signal was detected if the lower limit of the 95% confidence interval of ROR (ROR025) exceeded 1. RESULTS: There were 623 and 7948 reports for rituximab and ocrelizumab, respectively. The most frequent AEs with rituximab and ocrelizumab were infusion-related reaction (4.82%) and urinary tract infection (10.52%), respectively. The strongest drug-AE association for rituximab and ocrelizumab were ear pruritus (ROR025: 47.53) and oral herpes (ROR025: 38.99), respectively. Ocrelizumab was associated with an almost two times higher frequency of infections than rituximab (21.93% vs 11.05%, respectively). CONCLUSION: This study revealed differences in reporting AEs between rituximab and ocrelizumab. Infections were reported more frequently with ocrelizumab. Although speculative, a potentially different or more extensive B-cell depletion by ocrelizumab might explain these findings. Additional pharmacovigilance studies need to be performed to better characterize differences in the AE profile in B-cell-depleting therapies.

Protective effects of 4-aminopyridine in experimental optic neuritis and multiple sclerosis.

Chronic disability in multiple sclerosis is linked to neuroaxonal degeneration. 4-aminopyridine (4-AP) is used and licensed as a symptomatic treatment to ameliorate ambulatory disability in multiple sclerosis. The presumed mode of action is via blockade of axonal voltage gated potassium channels, thereby enhancing conduction in demyelinated axons. In this study, we provide evidence that in addition to those symptomatic effects, 4-AP can prevent neuroaxonal loss in the CNS. Using in vivo optical coherence tomography imaging, visual function testing and histologic assessment, we observed a reduction in retinal neurodegeneration with 4-AP in models of experimental optic neuritis and optic nerve crush. These effects were not related to an anti-inflammatory mode of action or a direct impact on retinal ganglion cells. Rather, histology and in vitro experiments indicated 4-AP stabilization of myelin and oligodendrocyte precursor cells associated with increased nuclear translocation of the nuclear factor of activated T cells. In experimental optic neuritis, 4-AP potentiated the effects of immunomodulatory treatment with fingolimod. As extended release 4-AP is already licensed for symptomatic multiple sclerosis treatment, we performed a retrospective, multicentre optical coherence tomography study to longitudinally compare retinal neurodegeneration between 52 patients on continuous 4-AP therapy and 51 matched controls. In line with the experimental data, during concurrent 4-AP therapy, degeneration of the macular retinal nerve fibre layer was reduced over 2 years. These results indicate disease-modifying effects of 4-AP beyond symptomatic therapy and provide support for the design of a prospective clinical study using visual function and retinal structure as outcome parameters.

Retinal measurements predict 10-year disability in multiple sclerosis.

Objective: Optical coherence tomography (OCT)-derived measures of the retina correlate with disability and cortical gray matter atrophy in multiple sclerosis (MS); however, whether such measures predict long-term disability is unknown. We evaluated whether a single OCT and visual function assessment predict the disability status 10 years later. Methods: Between 2006 and 2008, 172 people with MS underwent Stratus time domain-OCT imaging [160 with measurement of total macular volume (TMV)] and high and low-contrast letter acuity (LCLA) testing (n = 150; 87%). All participants had Expanded Disability Status Scale (EDSS) assessments at baseline and at 10-year follow-up. We applied generalized linear regression models to assess associations between baseline TMV, peripapillary retinal nerve fiber layer (pRNFL) thickness, and LCLA with 10-year EDSS scores (linear) and with clinically significant EDSS worsening (binary), adjusting for age, sex, optic neuritis history, and baseline disability status. Results: In multivariable models, lower baseline TMV was associated with higher 10-year EDSS scores (mean increase in EDSS of 0.75 per 1 mm3 loss in TMV (mean difference = 0.75; 95% CI: 0.11-1.39; P = 0.02). In analyses using tertiles, individuals in the lowest tertile of baseline TMV had an average 0.86 higher EDSS scores at 10 years (mean difference = 0.86; 95% CI: 0.23-1.48) and had over 3.5-fold increased odds of clinically significant EDSS worsening relative to those in the highest tertile of baseline TMV (OR: 3.58; 95% CI: 1.30-9.82; P trend = 0.008). pRNFL and LCLA predicted the 10-year EDSS scores only in univariate models. Interpretation: Lower baseline TMV measured by OCT significantly predicts higher disability at 10 years, even after accounting for baseline disability status.

Microvascular blood flow velocities measured with a retinal function imager: inter-eye correlations in healthy controls and an exploration in multiple sclerosis.

BACKGROUND: The retinal microcirculation has been studied in various diseases including multiple sclerosis (MS). However, inter-eye correlations and potential differences of the retinal blood flow velocity (BFV) remain largely unstudied but may be important in guiding eye selection as well as the design and interpretation of studies assessing or utilizing retinal BFV. The primary aim of this study was to determine inter-eye correlations in BFVs in healthy controls (HCs). Since prior studies raise the possibility of reduced BFV in MS eyes, a secondary aim was to compare retinal BFVs between MS eyes, grouped based on optic neuritis (ON) history and HC eyes. METHODS: Macular arteriole and venule BFVs were determined using a retinal function imager (RFI) in both eyes of 20 HCs. One eye from a total of 38 MS patients comprising 13 eyes with ON (MSON) and 25 eyes without ON (MSNON) history were similarly imaged with RFI. RESULTS: OD (right) and OS (left) BFVs were not significantly different in arterioles (OD: 3.95 ± 0.59 mm/s; OS: 4.08 ± 0.60 mm/s, P = 0.10) or venules (OD: 3.11 ± 0.46 mm/s; OS: 3.23 ± 0.52 mm/s, P = 0.06) in HCs. Very strong inter-eye correlations were also found between arteriolar (r = 0.84, P < 0.001) and venular (r = 0.87, P < 0.001) BFVs in HCs. Arteriolar (3.48 ± 0.88 mm/s) and venular (2.75 ± 0.53 mm/s) BFVs in MSNON eyes were significantly lower than in HC eyes (P = 0.009 and P = 0.005, respectively). Similarly, arteriolar (3.59 ± 0.69 mm/s) and venular (2.80 ± 0.45 mm/s) BFVs in MSON eyes were also significantly lower than in HC eyes (P = 0.046 and P = 0.048, respectively). Arteriolar and venular BFVs in MSON and MSNON eyes did not differ from each other (P = 0.42 and P = 0.48, respectively). CONCLUSIONS: Inter-eye arteriolar and venular BFVs do not differ significantly in HCs and are strongly correlated. Our findings support prior observations that arteriolar and venular BFVs may be reduced in MS eyes. Moreover, this seems to be the case in both MS eyes with and without a history of ON, raising the possibility of global blood flow alterations in MS. Future larger studies are needed to assess differences in BFVs between MSON and MSNON eyes.

Brain and retinal atrophy in African-Americans versus Caucasian-Americans with multiple sclerosis: a longitudinal study.

On average, African Americans with multiple sclerosis demonstrate higher inflammatory disease activity, faster disability accumulation, greater visual dysfunction, more pronounced brain tissue damage and higher lesion volume loads compared to Caucasian Americans with multiple sclerosis. Neurodegeneration is an important component of multiple sclerosis, which in part accounts for the clinical heterogeneity of the disease. Brain atrophy appears to be widespread, although it is becoming increasingly recognized that regional substructure atrophy may be of greater clinical relevance. Patient race (within the limitations of self-identified ancestry) is regarded as an important contributing factor. However, there is a paucity of studies examining differences in neurodegeneration and brain substructure volumes over time in African Americans relative to Caucasian American patients. Optical coherence tomography is a non-invasive and reliable tool for measuring structural retinal changes. Recent studies support its utility for tracking neurodegeneration and disease progression in vivo in multiple sclerosis. Relative to Caucasian Americans, African American patients have been found to have greater retinal structural injury in the inner retinal layers. Increased thickness of the inner nuclear layer and the presence of microcystoid macular pathology at baseline predict clinical and radiological inflammatory activity, although whether race plays a role in these changes has not been investigated. Similarly, assessment of outer retinal changes according to race in multiple sclerosis remains incompletely characterized. Twenty-two African Americans and 60 matched Caucasian Americans with multiple sclerosis were evaluated with brain MRI, and 116 African Americans and 116 matched Caucasian Americans with multiple sclerosis were monitored with optical coherence tomography over a mean duration of 4.5 years. Mixed-effects linear regression models were used in statistical analyses. Grey matter (-0.9%/year versus -0.5%: P =0.02), white matter (-0.7%/year versus -0.3%: P =0.04) and nuclear thalamic (-1.5%/year versus -0.7%/year: P =0.02) atrophy rates were approximately twice as fast in African Americans. African Americans also exhibited higher proportions of microcystoid macular pathology (12.1% versus 0.9%, P =0.001). Retinal nerve fibre layer (-1.1% versus -0.8%: P =0.02) and ganglion cell+ inner plexiform layer (-0.7%/year versus -0.4%/year: P =0.01) atrophy rates were faster in African versus Caucasian Americans. African Americans on average exhibited more rapid neurodegeneration than Caucasian Americans and had significantly faster brain and retinal tissue loss. These results corroborate the more rapid clinical progression reported to occur, in general, in African Americans with multiple sclerosis and support the need for future studies involving African Americans in order to identify individual differences in treatment responses in multiple sclerosis.

Emerging Applications of Optical Coherence Tomography Angiography (OCTA) in neurological research.

PURPOSE: To review the clinical and research value of optical coherence tomography angiography (OCTA) in the field of neurology. METHODS: Current literature involving OCTA were reviewed through PubMed using the search terms "optical coherence tomography angiography", with "multiple sclerosis", "Alzheimer's disease", "optic neuropathy", or other closely-related terms. RESULTS: OCTA has been applied in research to advance our understanding of the pathobiology of neurological disorders. OCTA-derived blood flow and vessel density measures are altered in multiple sclerosis (MS), Alzheimer's disease (AD), and various optic neuropathies (ON) in varying regions of the posterior segment vasculature of the eye. These emerging research findings support the occurrence of retinal vascular alterations across a host of neurological disorders and raise the possibility that vasculopathy can be clinically relevant since it contributes to the pathobiology of several neurological disorders. CONCLUSION: OCTA may be beneficial for neurological research. Additional investigations using OCTA in neurological disorders will help to further validate its clinical and research utilities in terms of characterizing the role of vasculopathy in neurological disorders.