Rush University Medical Center
Neurology

Author Of 2 Presentations

Comorbidities Poster Presentation

P0442 - Cerebrovascular disease and Alzheimer’s disease neuropathology in multiple sclerosis. (ID 422)

Speakers
Presentation Number
P0442
Presentation Topic
Comorbidities

Abstract

Background

Multiple sclerosis (MS) is associated with an increased risk of ischemic stroke and this association is not accounted for by traditional vascular risk factors. Few neuropathologic human studies have examined the relation of MS to cerebrovascular disease (CVD) and other common neuropathology of aging.

Objectives

To examine associations of MS with pathologically-proven CVD and Alzheimer’s disease (AD), among community-dwelling persons with and without MS who died and came to autopsy.

Methods

Participants were enrolled in one of two clinical-pathologic studies of aging, the Rush Memory and Aging Project and the Religious Orders Study. We matched (1:2) all autopsied MS subjects (n=14) with persons without MS (n =28), on gender, balancing by race, years of education, and age of death. MS was identified by the medical history or postmortem neuropathological examination. Pathological diagnosis of MS was made when one or more areas of primary demyelination were encountered in the periventricular white matter in the cerebrum or brainstem. Uniform neuropathologic examination documented brain infarcts, and separately gross and microscopic infarcts, and cerebral vessel pathologies including atherosclerosis. A global AD score was based on a modified Bielschowsky silver stain detecting plaques and neurofibrillary tangles, and immunohistochemistry documented amyloid load and tangle density. Analyses employed the generalized estimating equation for categorical variables and linear mixed model of a logarithmic scale for continuous variables.

Results

In the total group (n=42), participants were 79% female, 93% white, with a mean age-at-death of 85.0 years (SD=8.2). Five patients had a clinical diagnosis of MS, seven a pathological diagnosis, and two both diagnoses. MS cases were more likely to have one or more brain infarcts (10/14 (71.4%) MS cases and 7/28 (25.0%) controls, OR=7.02, 95% CI[2.44, 20.17], p=0.0003), and more likely to have one or more gross infarcts (8/14 (57.1%) MS cases and 5/28 (17.9%) controls, OR=5.92, 95% CI [2.49, 14.10], p=<0.0001). There was no difference in number of microinfarcts (p=0.07) or severity level of vessel pathologies including atherosclerosis (p=0.56), arteriolosclerosis (p=0.99), or cerebral amyloid angiopathy (p=0.09). Cases had higher levels of global AD pathology than controls (Coefficient (SE)=1.10(0.49), p=0.03). There were no significant differences in amyloid load (p=0.13) or tangles density (p=0.50).

Conclusions

In keeping with clinical studies showing that MS is associated with stroke, we found that persons with MS were more likely to have neuropathologically-confirmed brain infarcts, and gross infarcts in particular. There was no difference in cerebral vessel pathology. MS was also associated with AD pathology. This study was limited by a small sample size. Further studies will elucidate pathways linking MS to neuropathology of aging, stroke, and cognitive impairment.

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Observational Studies Poster Presentation

P0872 - Efficacy and Safety of Intravenous and Subcutaneous Cladribine in Relapsing and Progressive Multiple Sclerosis: a 24-year retrospective (ID 1243)

Speakers
Presentation Number
P0872
Presentation Topic
Observational Studies

Abstract

Background

Intravenous and subcutaneous cladribine has been used in multiple sclerosis since 1993. While oral cladribine is now approved by the EMA and FDA, the dosing of intravenous and subcutaneous cladribine is equivalent to twice that given with oral cladribine and in half the time. Based upon its mechanism of action, prolonged effect, and significant CNS penetration, we felt MS patients with aggressive or progressive disease would be ideal candidates for this medication and have been using cladribine since 1995.

Objectives

This study reports the efficacy and safety of a large cohort of multiple sclerosis (MS) patients receiving intravenous or subcutaneous cladribine. The primary objective is assessing the clinical outcomes. The secondary objective is assessing hematologic abnormality, infection, and cancer rates.

Methods

This is a retrospective cohort study of relapsing-remitting (RRMS), secondary progressive (SPMS), and primary progressive (PPMS) MS patients treated with intravenous or subcutaneous cladribine at the Rush Multiple Sclerosis Center from January 1995 to May 2019. Each round of cladribine was 0.7 mg/kg given over 5 days. Subsequent rounds were given once the total white blood cell count was normal. Full course consists of 4 rounds, or a total dose of 2.8 mg/kg (equivalent to 5 mg/kg of oral cladribine). Additional intravenous or subcutaneous doses were administered based upon new clinical or MRI activity.

Results

There were 247 patients in the cohort with 2198 patient-years of follow-up. Mean age of patients and disease duration at the time of first dose was 42.9 and 11.2 years, respectively. Mean follow-up after the first dose was 7.6 years. RRMS and active SPMS comprised 51.2% while non-active SPMS and PPMS made up 43.9% of patients. A full course was completed by 77.3% of patients. At least one additional dose of cladribine was given to 24.6% of patients at a mean of 3.5 years after the fourth round. Clinical outcomes were 46.4% had sustained clinical improvement, 37% were stable, and 16.7% continued to progress. Mean duration for stability or improvement after a full course was 2.3 and 3.6 years, respectively. Mean nadir of the white blood cell count was 3.3 K/uL. Mean maximum time to Grade 1 leukopenia was 0.6 months. Mean nadir lymphocyte count was 0.27 K/uL. Mean maximum time to Grade 0-1 lymphopenia was 8.7 months. For serious adverse events, there were 13 cases of cancer (0.59 cases per 100 patient-years), 3 serious infections, 6 cases of herpes zoster, 2 cases of myelodysplastic syndrome, and 14 deaths.

Conclusions

Intravenous and subcutaneous cladribine resulted in most patients having temporary clinical stability or improvement of their most disabling MS symptoms. Most patients experienced a transient leukopenia and lymphopenia. Overall, the treatment was well tolerated with no unexpected serious adverse events.

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Presenter Of 1 Presentation

Observational Studies Poster Presentation

P0872 - Efficacy and Safety of Intravenous and Subcutaneous Cladribine in Relapsing and Progressive Multiple Sclerosis: a 24-year retrospective (ID 1243)

Speakers
Presentation Number
P0872
Presentation Topic
Observational Studies

Abstract

Background

Intravenous and subcutaneous cladribine has been used in multiple sclerosis since 1993. While oral cladribine is now approved by the EMA and FDA, the dosing of intravenous and subcutaneous cladribine is equivalent to twice that given with oral cladribine and in half the time. Based upon its mechanism of action, prolonged effect, and significant CNS penetration, we felt MS patients with aggressive or progressive disease would be ideal candidates for this medication and have been using cladribine since 1995.

Objectives

This study reports the efficacy and safety of a large cohort of multiple sclerosis (MS) patients receiving intravenous or subcutaneous cladribine. The primary objective is assessing the clinical outcomes. The secondary objective is assessing hematologic abnormality, infection, and cancer rates.

Methods

This is a retrospective cohort study of relapsing-remitting (RRMS), secondary progressive (SPMS), and primary progressive (PPMS) MS patients treated with intravenous or subcutaneous cladribine at the Rush Multiple Sclerosis Center from January 1995 to May 2019. Each round of cladribine was 0.7 mg/kg given over 5 days. Subsequent rounds were given once the total white blood cell count was normal. Full course consists of 4 rounds, or a total dose of 2.8 mg/kg (equivalent to 5 mg/kg of oral cladribine). Additional intravenous or subcutaneous doses were administered based upon new clinical or MRI activity.

Results

There were 247 patients in the cohort with 2198 patient-years of follow-up. Mean age of patients and disease duration at the time of first dose was 42.9 and 11.2 years, respectively. Mean follow-up after the first dose was 7.6 years. RRMS and active SPMS comprised 51.2% while non-active SPMS and PPMS made up 43.9% of patients. A full course was completed by 77.3% of patients. At least one additional dose of cladribine was given to 24.6% of patients at a mean of 3.5 years after the fourth round. Clinical outcomes were 46.4% had sustained clinical improvement, 37% were stable, and 16.7% continued to progress. Mean duration for stability or improvement after a full course was 2.3 and 3.6 years, respectively. Mean nadir of the white blood cell count was 3.3 K/uL. Mean maximum time to Grade 1 leukopenia was 0.6 months. Mean nadir lymphocyte count was 0.27 K/uL. Mean maximum time to Grade 0-1 lymphopenia was 8.7 months. For serious adverse events, there were 13 cases of cancer (0.59 cases per 100 patient-years), 3 serious infections, 6 cases of herpes zoster, 2 cases of myelodysplastic syndrome, and 14 deaths.

Conclusions

Intravenous and subcutaneous cladribine resulted in most patients having temporary clinical stability or improvement of their most disabling MS symptoms. Most patients experienced a transient leukopenia and lymphopenia. Overall, the treatment was well tolerated with no unexpected serious adverse events.

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