Silvia Delgado

Morphometric analysis of the peripheral neuropathy of AIDS

A morphometric study of the peripheral nervous system at autopsy was undertaken in 11 AIDS patients and 10 controls. The left L4, L5, and S1 dorsal root ganglia (DRG) and samples of the sciatic nerve at the buttock, tibial nerve at the knee, and sural nerve at the ankle were collected. Indices of neuronal/axonal degeneration and of segmental demyelination/remyelination were measured at each level. The small number of cases and evidence of neuropathy in a number of the control cases resulted in statistical significance for only a limited number of comparisons. Nodules of Nageotte in the DRG were increased fivefold in AIDS cases compared with controls, and axonal degeneration in single‐teased nerve fibers was increased 9‐fold in the sciatic nerve, 28‐fold in the tibial nerve, and 12‐fold in the sural nerve. The ratios of AIDS to controls for the density of remaining DRG neurons and large myelinated axons were reduced to 0.71 in the DRG, 0.84 in the sciatic nerve, 0.84 in the tibial nerve, and 0.66 in the sural nerve. Axonal regeneration in single‐teased nerve fibers was increased threefold at the sciatic nerve level in AIDS, but was markedly reduced at distal levels. Acute segmental demyelination in single‐teased nerve fibers was present to a greater extent than in controls at all levels of the peripheral nerves in the AIDS cases. Remyelinating fibers were increased compared with controls only in the proximal sciatic nerve. No case showed the changes of cytomegalovirus infection. In a parallel immunohistochemical study of these AIDS peripheral nerves, T‐cell and macrophage infiltration, with cytokine expression, was demonstrated. The pathological process in the neuropathy of terminal AIDS appears to be a multifocal immunologically mediated inflammatory disease, with increased density of macrophages and T cells at all levels of the peripheral nervous system, producing segmental demyelination and axonal degeneration. Reparative processes (axonal regeneration and remyelination) occurred only at the most proximal levels of the nerves.

Hiv-1 Neuropathogenesis and Abused Drugs

HIV Associated Dementia (HAD) and peripheral neuropathy result from HIV-1 infection and several parameters impact on their initiation and course. These parameters include properties of the virus such as sequence heterogeneity of the envelope protein and virus and host gene expression in infected and uninfected macrophages in HIV infected individuals. The infection of brain cells such as macrophage/microglia may influence the course and duration of HAD through the elaboration of toxic molecules and viral host by-products of infection. Drugs of abuse complicate our interpretation of the resulting pathologies and affect the molecular and biochemical processes involved in HIV-1 infection and its life cycle. Furthermore, abused drugs may modulate the biology and function of macrophage/microglia as well as other cells in brain. Total HIV-1 virus load in the brain may also impact the clinical consequences of infection. Although specific strains of HIV-1 may inflict HAD by interactions at the molecular level, other mechanisms may operate in the initiation and development of peripheral neuropathy. An important aspect of these studies is the determination of their accuracy, specificity, sensitivity, and reproducibility. We describe important caveats involved in the performance, analysis, and interpretation of the results.

Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis

BACKGROUND Primary and secondary progressive multiple sclerosis (MS), collectively called progressive multiple sclerosis (PMS), is characterized by gradual progression of disability. The current anti-inflammatory treatments for MS have little or no efficacy in PMS in the absence of obvious active inflammation. Optimal biomarkers for phase II PMS trials is unknown. Ibudilast is an inhibitor of macrophage migration inhibitor factor and phosphodiesterases-4 and -10 and exhibits possible neuroprotective properties. The goals of SPRINT-MS study are to evaluate the safety and efficacy of ibudilast in PMS and to directly compare several imaging metrics for utility in PMS trials. METHODS SPRINT-MS is a randomized, placebo-controlled, phase II trial of ibudilast in patients with PMS. Eligible subjects were randomized 1:1 to receive either ibudilast (100mg/day) or placebo for 96weeks. Imaging is conducted every 24weeks for whole brain atrophy, magnetization transfer ratio, diffusion tensor imaging, cortical brain atrophy, and retinal nerve fiber layer thickness. Clinical outcomes include neurologic disability and patient reported quality of life. Safety assessments include laboratory testing, electrocardiography, and suicidality screening. RESULTS A total of 331 subjects were enrolled, of which 255 were randomized onto active study treatment. Randomized subjects were 53.7% female and mean age 55.7 (SD 7.3) years. The last subject is projected to complete the study in May 2017. CONCLUSION SPRINT-MS is designed to evaluate the safety and efficacy of ibudilast as a treatment for PMS while simultaneously validating five different imaging biomarkers as outcome metrics for use in future phase II proof-of-concept PMS trials.

Impaired retinal microcirculation in multiple sclerosis

Background: The transparent ocular structure enables quantitative analysis of microvasculature of retina, a neuronal tissue affected by multiple sclerosis (MS). Objective: The aim of this study was to determine whether the retinal blood flow velocity and flow volume at the macula are impaired in patients with relapsing remitting multiple sclerosis (RRMS). Methods: A total of 17 RRMS patients and 17 age- and gender-matched healthy subjects were assessed. A retinal function imager was used to measure the blood flow velocity of retinal arterioles and venules and to calculate the total perifoveal blood flow volume. Results: The blood flow velocities of the retinal arterioles (3.34 ± 0.89 mm/s) and venules (2.61 ± 0.6 mm/s) were significantly lower in MS patients than normal subjects (arteriole: 4.10 ± 0.87 mm/s; venule: 3.22 ± 0.65 mm/s, both p = 0.01). In addition, the total perifoveal blood flow volume in arterioles (3.74 ± 1.64 nL/s) and venules (3.81 ± 1.60 nL/s) were significantly lower in MS patients than in normal subjects (arteriole: 4.87 ± 1.41 nL/s, p = 0.02; venule: 4.71 ± 1.64 nL/s, p = 0.04). Conclusion: The impaired retinal microcirculation in RRMS patients indicates microvascular dysfunction in MS.

CNS demyelinating disorder with mixed features of neuromyelitis optica and multiple sclerosis in HIV-1 infection. Case report and literature review

An African-American male presented with bilateral visual impairment, gait difficulties, and bladder and bowel incontinence raising concerns for multiple sclerosis (MS) or neuromyelitis optica (NMO). He was identified to be HIV-1 infected with high viral load and low CD4+ counts. Magnetic resonance imaging (MRI) of the brain was abnormal, but atypical for MS. MRI of the cervical and thoracic spinal cord showed multiple areas of myelitis with a longitudinally extensive thoracic transverse myelitis that showed enhancement with gadolinium suggestive of NMO. Cerebrospinal fluid showed oligoclonal IgG bands but did not show reactivity to aquaporin 4. Patient underwent treatment for the acute exacerbation with intravenous corticosteroids and treatment of the HIV infection with highly active antiretroviral therapy (HAART). A year later, his viral load was <20 copies/ml and CD4+ counts were normal. Vision did not significantly improve, but his ambulation improved from a near total non-ambulatory state to ambulating without aids and resolution of the bladder and bowel incontinence. A demyelinating disorder of the central nervous system (CNS) like MS or NMO has been previously reported in the context of HIV infection. The remarkable improvement of symptoms has also been previously reported with HAART, and these observations have led to clinical trials of MS with HAART therapy in the absence of HIV infection. We reviewed the few cases of CNS demyelinating disorders with HIV infection reported in the literature and speculate on the mechanisms of pathogenesis.

In Vivo Characterization of Retinal Microvascular Network in Multiple Sclerosis.

Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system characterized by progressive neurodegeneration. Current management aims to reduce the inflammation through immunomodulation. However, the effectiveness of these treatments for preventing degeneration is unclear. Vascular alterations, which may be caused by inflammatory cerebral endotheliopathy, could play a role in neurodegeneration. Indeed, increased incidence of ischemic stroke and diffuse hypoperfusion in normal-appearing white and gray matter have been reported in MS patients. Thus, studying cerebral microvascular changes may reveal the underlying pathophysiology that connects inflammation and neurodegeneration. Because the retina is an extension of the brain, the cerebral and retinal vasculature shares similar anatomic

Human T-lymphotropic virus type I or II (HTLV-I/II) associated with recurrent longitudinally extensive transverse myelitis (LETM): two case reports.

We describe two patients with recurrent longitudinally extensive transverse myelitis (LETM) associated with human T-lymphotropic virus type I or II (HTLV-I/II) exposure, and with neuromyelitis optica (NMO) immunoglobulin G (IgG) antibody in one case. HTLV-I/II are well known retroviral agents of myelopathy and B-cell dysfunction in humans. NMO is an autoimmune, demyelinating disorder of the central nervous system (CNS), also linked to B-cell dysfunction. Therefore, the immunopathogenesis of NMO may in some cases be linked to human HTLV exposure. Awareness of a possible association with human retroviral exposure will contribute to the optimal diagnosis and management of patients presenting with LETM or NMO.

Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis.

BACKGROUND There are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll‐like receptor 4 and can cross the blood–brain barrier, with potential salutary effects in progressive multiple sclerosis. METHODS We enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal‐appearing brain tissue, the thickness of the retinal nerve‐fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis. RESULTS Of 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was ‐0.0010 per year with ibudilast and ‐0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain‐tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression. CONCLUSIONS In a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT‐MS ClinicalTrials.gov number, NCT01982942.)

Numb chin syndrome secondary to leptomeningeal carcinomatosis from gastric adenocarcinoma

Numb chin syndrome (NCS) can be a sign of malignancy. Its association with gastric adenocarcinoma is rare. We report a case of a 27-year-old Hispanic female that presented with complaint of left sided headache associated with numbness of the left side of chin and lower gingiva. Initial brain MRI, whole body gallium scan, high resolution CT of chest and elevated protein in the CSF were suggestive of sarcoidosis. She was treated with IV steroids with transient clinical improvement. Two weeks later, her symptoms worsened and further evaluation revealed the diagnosis of a poorly differentiated metastatic gastric adenocarcinoma with leptomeningeal involvement. This case report aims to emphasize the importance of identifying NCS as a possible indication of an underlying malignant condition. Reported cases of NCS associated with metastatic gastric adenocarcinoma are very rare.

Focal segmental glomerulosclerosis secondary to subcutaneous interferon β-1a treatment in a patient with multiple sclerosis

Interferon (IFN)-β is a first line treatment for patients with relapsing remitting multiple sclerosis (RRMS) that has been shown to decrease relapse rates, reduce magnetic resonance imaging (MRI) disease burden and possibly delay onset of disability (Arnason, 2005). There are few reports of nephrotic syndrome related to Minimal Change Disease (MCD) or Focal Segmental Glomerulosclerosis (FSGS) during treatment with IFN-α (Nishimura et al., 2002; Tola et al., 2003; Rettmar et al., 1995). There are fewer reports of nephrotic syndrome induced by IFN-β (Tola et al., 2003; Auty and Saleh, 2005; Kumasaka et al., 2006). We report a 41 year old African American woman with RRMS that developed FSGS after 3 months of treatment with IFN-β-1a 3 times weekly and review the previously published cases.