Angela Applebee

The contemporary spectrum of multiple sclerosis misdiagnosis: A multicenter study

Objective: To characterize patients misdiagnosed with multiple sclerosis (MS). Methods: Neurologists at 4 academic MS centers submitted data on patients determined to have been misdiagnosed with MS. Results: Of 110 misdiagnosed patients, 51 (46%) were classified as “definite” and 59 (54%) “probable” misdiagnoses according to study definitions. Alternate diagnoses included migraine alone or in combination with other diagnoses 24 (22%), fibromyalgia 16 (15%), nonspecific or nonlocalizing neurologic symptoms with abnormal MRI 13 (12%), conversion or psychogenic disorders 12 (11%), and neuromyelitis optica spectrum disorder 7 (6%). Duration of misdiagnosis was 10 years or longer in 36 (33%) and an earlier opportunity to make a correct diagnosis was identified for 79 patients (72%). Seventy-seven (70%) received disease-modifying therapy and 34 (31%) experienced unnecessary morbidity because of misdiagnosis. Four (4%) participated in a research study of an MS therapy. Leading factors contributing to misdiagnosis were consideration of symptoms atypical for demyelinating disease, lack of corroborative objective evidence of a CNS lesion as satisfying criteria for MS attacks, and overreliance on MRI abnormalities in patients with nonspecific neurologic symptoms. Conclusions: Misdiagnosis of MS leads to unnecessary and potentially harmful risks to patients. Misinterpretation and misapplication of MS clinical and radiographic diagnostic criteria are important contemporary contributors to misdiagnosis.

In vivo quantitative whole‐brain T1 rho MRI of multiple sclerosis

To apply quantitative whole‐brain T1‐rho (T1ρ) and T2 imaging to the detection and quantification of brain changes resulting from multiple sclerosis (MS).

Effects of Dalfampridine Extended-release Tablets on 6-minute Walk Distance in Patients With Multiple Sclerosis: A Post Hoc Analysis of a Double-blind, Placebo-controlled Trial

PURPOSE Dalfampridine extended-release (ER) tablets 10 mg BID have been approved for use in improving walking in people with multiple sclerosis (MS). This subgroup analysis evaluated the effects of dalfampridine ER 5 and 10 mg BID on distance walked, as assessed using the 6-minute walk (6MW) test. METHODS This analysis of data from a randomized, placebo-controlled, double-blind study (N = 430) included only the 153 patients with 6MW data available. Participants (aged 18-70 years) were randomly assigned in a 1:1:1 ratio to receive dalfampridine ER 5 or 10 mg or placebo, BID for 4 weeks. The 6MW was used for assessing walking distance at baseline and 2 weeks after the start of treatment at the 26 study sites that were able to perform this test. Participants were administered the 12-item MS Walking Scale (MSWS-12), a patient-reported measure of the impact of MS on walking. Post hoc outcomes included the percentages of patients who achieved an increase from baseline in 6MW distance of ≥20% and who achieved a minimal clinically important difference (MCID) from baseline in 6MW distance, defined as ≥+55 m. Changes from baseline in walking speed (MSWS-12) were compared, stratified by subgroup that achieved ≥20% versus <20% improvement on the 6MW. The correlation between change in walking speed over time and subgroup (by change in distance walked) was evaluated. The tolerability of dalfampridine was assessed based on the prevalence of treatment-emergent adverse events (TEAEs). FINDINGS In the post hoc analysis, the percentage of patients with an improvement in 6MW distance that met or exceeded the MCID was significantly greater with dalfampridine ER 10 mg BID relative to placebo (37.3% vs 12.2%; nominal P = 0.004). Similarly, the percentage with an improvement in 6MW distance of ≥20% was significantly greater with dalfampridine 10 mg BID relative to placebo (45.1% vs 14.3%; nominal P < 0.001). Regardless of treatment allocation, improvement in MSWS-12 was significantly greater in the subgroup that achieved a ≥20% improvement on the 6MW compared with the subgroup with <20% improvement (mean changes, -15.5 vs -7.2; nominal P = 0.041). The prevalences and types of TEAEs were consistent with those reported in previous studies. IMPLICATIONS Based on the MCID for 6MW, the use of dalfampridine ER 10 mg BID but not 5 mg BID was associated with statistically significant and clinically meaningful improvements in walking relative to placebo. The correlation between improvement on MSWS-12 and the 20% increase in 6MW distance suggests that an improvement on MSWS-12 is clinically relevant. These results, although highlighting a lack of efficacy of dalfampridine ER 5 mg BID, suggest that the 10-mg BID dose is effective for improving walking speed, as observed on short timed-walk tests, and for increasing distance walked over longer timed-walk periods. ClinicalTrials.gov identifier: NCT01328379.

Effect of Eszopiclone on Sleep Disturbances and Daytime Fatigue in Multiple Sclerosis Patients

The prevalence of moderate-to-severe sleep problems is significantly higher among people with multiple sclerosis (MS) than in the general population. In 2002, we found a significant relationship between fatigue and disrupted sleep in patients with relapsing-remitting MS (RRMS). The objectives of this study were to determine whether eszopiclone (Lunesta; Sunovion Pharmaceuticals Inc, Marlborough, MA) was superior to placebo in improving sleep among patients with MS-related fatigue and sleep complaints (primary end point); and to assess the impact of improved sleep on daytime fatigue and functioning (secondary end point). This was a double-blind, placebo-controlled pilot trial lasting 7 weeks. Thirty ambulatory adults under age 65 years with RRMS, fatigue, and sleep disturbances were randomized to receive either eszopiclone or placebo. The outcome measures included subjective and objective changes in sleep-onset latency (SOL), total sleep time (TST), wakefulness after sleep onset (WASO), sleep efficiency (SE), fatigue scales, and neuropsychological measures of daytime functioning. Compared with placebo, eszopiclone was superior only in increasing TST. Fatigue improved in both groups, but there was no statistically significant correlation between increased TST and improved fatigue, and no statistically significant differences were observed between the two groups. Thus, in this study, eszopiclone did not improve sleep sufficiently to improve fatigue in MS patients. This result may be due to the multifactorial nature of sleep disturbances and fatigue in people with MS.

Evaluation of Dalfampridine Extended Release 5 and 10 mg in Multiple Sclerosis A Randomized Controlled Trial

BACKGROUND Dalfampridine extended-release (ER) tablets, 10 mg twice daily, have been shown to improve walking in people with multiple sclerosis. We evaluated the safety and efficacy of dalfampridine-ER 5 mg compared with 10 mg. METHODS Patients were randomized to double-blind treatment with twice-daily dalfampridine-ER tablets, 5 mg (n = 144) or 10 mg (n = 143), or placebo (n = 143) for 4 weeks. Primary efficacy endpoint was change from baseline walking speed by the Timed 25-Foot Walk 3 to 4 hours after the last dose. At 40% of sites, 2-week change from baseline walking distance was measured by the 6-Minute Walk test. RESULTS At 4 weeks, walking speed changes from baseline were 0.363, 0.423, and 0.478 ft/s (placebo, dalfampridine-ER 5 mg, and dalfampridine-ER 10 mg, respectively [P = NS]). Post hoc analysis of average changes between pretreatment and on-treatment showed that relative to placebo, only dalfampridine-ER 10 mg demonstrated a significant increase in walking speed (mean ± SE): 0.443 ± 0.042 ft/s versus 0.303 ± 0.038 ft/s (P = .014). Improvement in 6-Minute Walk distance was significantly greater with dalfampridine-ER 10 mg (128.6 ft, P = .014) but not with 5 mg (76.8 ft, P = .308) relative to placebo (41.7 ft). Adverse events were consistent with previous studies. No seizures were reported. CONCLUSIONS Dalfampridine-ER 5 and 10 mg twice daily did not demonstrate efficacy on the planned endpoint. Post hoc analyses demonstrated significant increases in walking speed relative to placebo with dalfampridine-ER 10 mg. No new safety signals were observed.

MRI and encephalography in fatal eastern equine encephalitis

Eastern equine encephalitis (EEE) is the most severe of the mosquito-borne encephalitides, with a case fatality rate estimated at 36%.1 We describe 2 fatal cases of seropositive EEE in men. In both patients, EEG monitoring revealed periodic 0.25- to 0.5-Hz transients with lower voltages (∼20–40 μV) than typically seen in herpes encephalitis (∼100–500 μV), and MRI revealed a symmetric pattern of T2 hyperintensity in the lentiform nuclei, as previously noted1,2 (figure). Considered together, these MRI and EEG findings suggest a distinctive pattern that may be pathognomonic for EEE in the appropriate clinical context.

Syndrome of transient headache and neurologic deficits with cerebrospinal fluid lymphocytosis presenting as acute neurological emergencies

Background The syndrome of transient headache and neurologic deficits with cerebrospinal fluid lymphocytosis (HaNDL) is a self-limited benign disorder of unclear pathogenesis, with diverse clinical manifestations. Cases We report two unusual presentations of this entity. The first case developed a catastrophic picture, characterized by acute elevation of intracranial pressure, necessitating emergency life support. The second case presented with hyperacute-onset mixed aphasia and facial droop, masquerading as acute ischemia of the middle cerebral artery territory. Both patients made full recoveries. Conclusion The possibility of HaNDL should be considered in individuals presenting with unusual patterns of headaches and transient neurological symptoms. Our report will expand the spectrum of this disorder, which will help physicians not only to recognize the unusual manifestations of this rare disorder, but also consider potential therapeutic interventions.

The Clinical Overlap of Multiple Sclerosis and Headache

Multiple sclerosis (MS) and migraine headache coexist in many young female patients. Whether this is coincidental or causally linked remains unclear. The presenting symptoms and signs of MS relapse and migraine aura can be similar and should be differentiated by careful history and examination to ensure proper diagnosis and treatment. White matter lesions on magnetic resonance imaging have specific patterns for each entity and also need to be interpreted carefully. Although a clear link has not been established between migraine and MS, numerous studies have been reported assessing risks, prevalence, and causation. Complicating these assessments are the disease‐modifying therapies used to treat MS which have been known to be implicated in causing headache. The recent development of novel treatment options for MS requires practitioners to be aware of polypharmacy and potential drug interactions.

Altered gastrointestinal motility involving autoantibodies in the experimental autoimmune encephalomyelitis model of multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system that, in addition to motor, sensory, and cognitive symptoms, also causes constipation, which is poorly understood. Here, we characterize gastrointestinal (GI) dysmotility in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS and evaluate whether autoantibodies target the enteric nervous system (ENS) and cause dysmotility.