Alastair Wilkins

Characterization of in vitro expanded bone marrow-derived mesenchymal stem cells from patients with multiple sclerosis.

Recent studies have investigated the potential of autologous bone marrow-derived mesenchymal stem cells (MSCs) as a therapy for multiple sclerosis. Whether MSCs from individuals with multiple sclerosis are functionally and/or phenotypically abnormal has received less attention. Through our Phase I clinical trial, SIAMMS, we were able to isolate and characterize MSCs from individuals with multiple sclerosis. The objective of the study was to demonstrate that MSCs from individuals with multiple sclerosis show no significant differences from MSCs derived from individuals without multiple sclerosis. MSCs were isolated from bone marrow aspirates from four SIAMMS participants. We were also able to isolate MSCs from bone marrow obtained during a total hip replacement operation on an individual with multiple sclerosis. Control MSCs were isolated from bone marrow acquired during total hip replacement operations on five individuals without MS. MSCs were characterized using standard criteria: plastic adherence, differentiation along adipogenic/osteogenic/chondrogenic lineages, and expression of specific cell surface antigens. We also determined their proliferation potential. MSCs from individuals with multiple sclerosis and individuals without multiple sclerosis were similar in proliferation, differentiation potential and cell surface antigen expression. This has relevance to scientific studies investigating the therapeutic potential of autologous MSCs which primarily utilize MSCs from individuals without multiple sclerosis, and relevance to clinical studies extrapolating from these scientific findings.

Cerebral amyloid angiopathy related vasculitis: successful treatment with azathioprine

Cerebral amyloid angiopathy (CAA) most frequently presents with recurrent intracerebral lobar hemorrhage in the elderly. There is, however, an important subset of patients who present instead with subacute cognitive decline, seizures, headaches and radiological as well as neuropathological evidence of CAA-associated perivascular inflammation [1, 2]. Here we report the first case of a patient with CAArelated vasculitis in which azathioprine has been associated with sustained clinical and radiological remission. A 70-year-old left-handed women with long-standing temporal lobe seizures presented with cognitive decline over 2 years. Examination revealed left homonymous hemianopia, gaze-evoked nystagmus, left upper limb ataxia and left-sided sensory inattention. She had difficulty following commands and her affect was altered. She scored 22/30 points on mini-mental state examination (MMSE). Brain MRI revealed a large area of increased T2 signal in the right hemisphere. An autoimmune screen, serum inflammatory markers and CSF analysis were unremarkable. EEG showed asymmetrical right-sided disorganization of background activity and mild slowing. Neuropathologic examination showed severe leptomeningeal and parenchymal amyloid angiopathy with evidence of predominately perivascular inflammation around the walls of many amyloid-laden blood vessels (Fig. 1). The patient was treated with a 5-day course of intravenous methylprednisolone (500 mg/day), which led to some improvement. MRI at 3 months showed improvement of the abnormalities in the right hemisphere, but repeat MRI at 9 months revealed progression of the white matter changes. Thirteen months after the initial presentation she noticed worsening visual problems as well as stiffness and weakness in her right leg. Her cognitive function had declined to 17/30 on MMSE. MRI showed clear disease progression (Fig. 2a–c). A second course of intravenous methylprednisolone resulted in symptomatic improvement. A further relapse at 15 months necessitated a third course of intravenous methylprednisolone. This led to a dramatic improvement in her walking and memory. At this point she was started on azathioprine, 75 mg once daily (lymphocyte counts maintained in the range of 0.8–1.1/ml). She remained neurologically stable with a partial resolution of her initial hemianopia. MRI 23 months after the initial presentation, when she had been on azathioprine for 8 months, confirmed partial resolution of the white-matter changes (Fig. 2d–f). At 25 months she was readmitted with a 2-week history of cognitive decline (MMSE 16/30), recurrence of her left hemianopia and left upper limb ataxia. It became clear that she had stopped taking her medication following the death of her husband 2 months earlier. Azathioprine treatment was reinstated and her symptoms started to improve again. At 45 months, 20 months after initiation of azathioprine, S. Luppe (&) N. Scolding A. Wilkins Department of Neurology, Frenchay Hospital, Bristol BS16 1LE, UK e-mail: Sebastian.Luppe@bristol.ac.uk

Symptomatic Treatment for Progressive Multiple Sclerosis

The symptoms of progressive MS are thought to be driven by neuronal loss within the CNS and the widespread distribution of the disease can manifest in a wide variety of symptoms. Typically, however, a stereotyped pattern emerges in progressive disease—an upper motor neuron syndrome with the character of a high spinal cord lesion and superimposed ataxia and cognitive impairment. This results in symptoms such as impaired mobility, spasticity, tremor and incoordination, bladder and bowel dysfunction and cognitive difficulties. In addition, fatigue, mood disturbance and paroxysmal symptoms such as trigeminal neuralgia may be troublesome. In the absence of a curative intervention for progressive disease, reducing the burden of symptoms will lead to improvement in quality of life for patients and carers, as well as reducing the significant socioeconomic impact of a chronic, disabling condition. Indeed, such a combined approach which prioritises the identification of disease modifying and improved symptom-relieving therapies is supported by the International Collaborative on Progressive MS Alliance [1].

What Is Disease Progression

The clinical course of multiple sclerosis (MS) represents a spectrum. The subdivision of MS, according to the clinical course, has become increasingly important in recent years, since therapeutic clinical trials have shown demonstrable reductions in the frequency of clinical relapses and of inflammatory lesions as demonstrated on magnetic resonance imaging (MRI). Measures of disease progression are more resistant to change and in patients with progressive MS, it has been more difficult to demonstrate positive benefits from therapeutic interventions.