Innovations In Clinical Neuroscience

JAN-FEB 2018

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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O R I G I N A L R E S E A R C H 29 ICNS Innovations in Clinical Neuroscience • January–February 2018 • Volume 15 • Number 1–2 myelopathy, namely human T-leukemia virus type I (HTLV-I), in which the immunomodulatory therapy intravenous immunoglobulin (IVIG) has shown some benefit. A small Japanese open- label clinical trial showed marked improvement with infusion of IVIG in 10 out of 14 patients with HTLV-I myelopathy. 10 The therapeutic effects were seen within one week after IVIG infusion, and the effects were sustained for more than three weeks in some patients. Inspired by these results, we sought to obtain preliminary evidence for the efficacy and safety of IVIG in an open-label pilot study of 17 patients with HIVM. 11 Following IVIG infusion, there was a trend toward improved lower-extremity strength scores at 14 days post- infusion, which became statistically significant by Day 28. However, given that time and labor-intensive treatments, such as intravenous (IV) infusions, can be associated with a strong placebo effect, we sought to investigate these findings further in the current study. This randomized, double-blind, placebo-controlled feasibility study was designed to evaluate the safety and tolerability of IVIG (2g/kg) infused over two days for the treatment of HIVM, as well as provide preliminary evidence of its efficacy. The specific issues of feasibility on which we focused were recruitment and randomization (given that IVIG is commercially available and may be obtained outside the study), retention for follow-up assessments after the infusion, and the suitability of muscle dynamometry as a primary outcome measure for the study of HIVM. Although muscle dynamometry has not been used as an outcome in prior studies of HIVM, it has been used in other neurologic conditions, including other forms of myelopathy (spinal cord injury [SCI] in particular), stroke, motor neuron disease, and cerebral palsy. 12–14 Muscle dynamometry has also been used in the assessment of non-neurologic conditions, such as frailty in older adults. 15 In the case of SCI, lower-extremity dynamometry has been validated based on its association with clinically meaningful outcomes, such as walking function. 16 METHODS Participants and recruitment. This was a single-center study conducted at a large academic medical center in New York City, which is the center of a large healthcare system that provides services for approximately10,000 HIV-infected patients in a network of five primary care HIV clinics. Participants were recruited from three main sources: the clinical NeuroAIDS practices of the investigators, pre-existing observational research studies (Manhattan HIV Brain Bank and the CNS HIV Antiretroviral Effects Research [CHARTER]); and a referral network of regional and national HIV care providers. Included participants were HIV-infected adults (age ≥18 years) who were diagnosed with HIVM by a neurologist using the criteria of at least two symptoms and at least two signs. Eligible symptoms (as reported by the participant) included paresthesias and/ or numbness in the lower extremities or in all four limbs; weakness of the limbs, with predominance in the lower extremities; unsteady, stiff, or uncoordinated gait; sensation of electrical shock through the back or the legs upon flexion of the neck (L'Hermitte's sign); stiffness or spasm in the lower extremities; urinary frequency, urgency, incontinence, or retention; fecal incontinence or retention; and sexual dysfunction, with erectile impairment in men. Eligible signs (as documented on neurologic examination) were reduction in vibratory or position sensation in the lower extremities, hyperactive deep tendon reflexes in the lower limbs, abnormal response to plantar stimulation (Babinski sign), weakness in the lower extremities or in all four limbs, and spastic or ataxic gait. In addition, it was required that participants be on a stable CART regimen for at least two months prior to entry of the study; women of child-bearing potential have a negative urine pregnancy within 14 days prior to study entry; and all subjects agree to practice abstinence or a highly effective method of birth control. Finally, we required the following laboratory parameters (within 14 days of study entry): Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase less than five times the upper limit of normal (ULN); total bilirubin 2.5mg/dL or less; creatinine 2.3 or less; and serum vitamin B12 level 200pg/mL or greater. The following conditions were exclusionary: presence of active opportunistic infection within two weeks before randomization; evidence of another contributing cause for myelopathy; pregnancy, breast-feeding or planning a pregnancy; any medical, psychiatric or substance use condition that in the opinion of the investigators would interfere with the subject's ability to adhere to the protocol; contraindication to IVIG (e.g., cardiac, pulmonary, or renal disease that would place the subject at risk for fluid overload; known hypersensitivity to immunoglobulin, or IgA, deficiency); vaccination with live viruses within the past 90 days; or receipt of IVIG or other immunomodulatory agent within the past 90 days. Study procedures . Participants were seen for a total of eight visits. Visit 1 was the screening visit, which began with the informed consent process followed by assessment of eligibility. A comprehensive medical history was recorded, physical and neurological examinations were performed, and the participant's most recent spinal magnetic resonance imaging (MRI) (within the prior six months) was reviewed to confirm the absence of a visible alternative cause of myelopathy. Blood was collected for the following tests (unless available from clinical records within the prior 14 days): CD4+ cell count, plasma HIV viral load, HTLV-I and II, venereal disease research laboratory (VDRL), complete blood count (CBC), blood urea nitrogen (BUN), creatinine, liver function tests (LFTs), urinalysis, quantitative immunoglobulins, and serum pregnancy test in women of childbearing potential. The screening visit was also used as a training session for muscle dynamometry in order to accustom the participants to the procedures involved. Quantitative lower-extremity muscle dynamometry was performed using a Microfet 2 dynamometer (Pro Healthcare Products, Park City, Utah), a load-cell device that records the force and the duration of muscle contraction. The dynamometer was mounted on an adjustable arm, permitting its placement in an ideal location for each of the muscle groups to be tested and allowing adjustment for differing lower limb lengths of the participants. A similar apparatus was shown to be reliable in a test-retest study of lower-limb muscle groups in an elderly population. 15 We tested bilateral hip flexors, knee flexors, and ankle dorsiflexors. Participants were tested in a seated position with the hip and knee flexed to 90 degrees. For hip flexion, the pad of the dynamometer was placed 2cm proximal to the femoral condyle; for knee flexion, the dynamometer pad was 4cm proximal to the lateral malleolus; and for ankle dorsiflexion, the dynamometer pad was

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