This was a collaborative project between the National Institute of Neurological Disorders and Stroke (NINDS) at the NIH, Bethesda, MD, USA and the Centre for Brain Research of the Medical University in Vienna, Austria. A Material Transfer Agreement between the NIH and the University of Vienna was signed from both institutions.
The samples used for this study derive from two patients with multiple sclerosis, designated Patients MS-1 and MS-2 hereafter, and one non-multiple sclerosis donor. All the samples were obtained from NINDS.
None of the patients were seen in the NIH-multiple sclerosis clinic. Details of their clinical history derive from the retrospective evaluation of clinical charts (F.K.C.) and from clinical history collected retrospectively from family members.
In addition, to rule out possible Alzheimer's confounder pathology, haematoxylin and eosin, Bielschowsky silver impregnation and amyloid-β and -tau AT8 stains were performed on tissues from all three cases at the Centre for Brain Research, Medical University, Vienna, Austria.
Patient MS-1, a Caucasian male, had a disease course consistent with relapsing–remitting multiple sclerosis evolving into secondary progressive multiple sclerosis. Onset of multiple sclerosis occurred at the age of 40 years with an episode of left optic neuritis. After partial recovery, the patient had 2 months of ‘forgetfulness’ and recovered full vision at the age of 42 years. Between the ages of 42 and 51 years, the patient had 11 clinical relapses involving the spinal cord, the brainstem and the cerebellum with varying amounts of recovery during remissions. Gradually, he developed bladder symptoms and erectile dysfunction treated with an implanted penile prosthesis. At the age of 48 years, he began using a cane and gait progressively worsened thereafter. He needed automobile hand controls at the age of 51 years, and used a scooter, wheel chair and, for a limited period of time, a walker at the age of 52 years. Subsequently, he developed progressively worse motor function, bladder control, constipation and cognitive impairment. At the age of 65 years, he was admitted to a nursing home, bedridden with a permanent Foley catheter and evidence of nutritional deterioration. By the age of 66 years, his cognitive impairment progressed to pronounced dementia. He had several episodes of sepsis due to urinary tract infections. He was described as demented with euphoria at the age of 67 years and non-verbal at the age of 70 years. He died with pneumonia at the age of 70 years in March 2005.
Spinal fluid examination at the age of 44 years was positive for oligoclonal bands. Early in his disease course, intermittent glucocorticoid treatments had been discontinued because of acute changes in mentation. He had not tolerated cyclosporine.
Apart from multiple sclerosis, this patient had labile hypertension by the age of 63 years and intermittent atrial fibrillation and non-atrial fibrillation sustained tachycardia at the age of 69 years. Chest X-ray shortly before death showed pneumonia and borderline cardiac enlargement.
At autopsy, the patient showed cardiomegaly, atherosclerosis of the aorta and coronary arteries, and prostatic adenocarcinoma in situ
. The brain weighed 1225 g and had a smooth surface without signs of infarction. There was severe atherosclerosis of the Circle of Willis and major branches. Patient MS-1 did not fulfil Braak's histopathological for Alzheimer's diagnosis (Braak and Braak, 1997
). In line with chronic multiple sclerosis pathology (Dal-Bianco et al., 2008
), a few neurofibrillary tangles within the entorhinal cortex (basal temporal lobe) were observed. The haematoxylin and eosin staining of the hippocampus revealed profound neuronal loss in the CA1 region (sommer sector) due to hypoxic brain injury.
Case MS-2, a Caucasian female, had a disease course consistent with a relapsing–remitting multiple sclerosis rapidly progressing to secondary progressing multiple sclerosis and preponderant spinal cord involvement. She presented with right optic neuritis at the age of ~37 years. Shortly, thereafter, she had an episode of bilateral hand paraesthesias followed by an episode of gait disturbance. She developed progressively worse gait disturbance and by the age of 39 years required the use of a cane and then progressed to using a rollator. By the age of 50 years, she was restricted to a wheelchair and had poor bladder control. A baclofen pump was implanted. At the age of 59 years, her progressive disability required assistance with her activities of daily living. On physical examination, she showed spastic quadriplegia with retained ability to partially lift the arms. She had abnormal movements suggestive of dystonic posturing. In the subsequent 2 years, she required a tracheotomy and nocturnal use of a ventilator because of progressively worse dysphagia, frequent aspiration, pulmonary insufficiency and pulmonary infections. She died of pneumonia at the age of 61.5 years in February 2009. During her lifetime, she was treated with multiple courses of intravenous methylprednisolone, interferon β-1 a, interferon β-1 b, intravenous immunoglobulins, intrathecal methotrexate and autologous bone marrow stem cell transplantation. Apart from multiple sclerosis, the patient was treated for mild hypothyroidism. Autopsy showed numerous multiple sclerosis plaques in the brain and spinal cord. Microscopic examination of several plaques showed loss of myelin and oligodenrocytes, astrocytosis and a few macrophages consistent with chronic lesions. There were no signs of cerebrovascular disease. Brain weight was 1140 g with normal ventricular size.
As with Patient MS-1, Patient MS-2 did not fulfil Braak's histopathological criteria for Alzheimer's diagnosis (Braak and Braak, 1997
The brain of the non-multiple sclerosis case was from a Caucasian male with severe combined immunodeficiency syndrome secondary to recombination activating gene 1 (RAG1) deficiency. His disease course was characterized by multiple infections and progressive granulomatous disease involving pharynx, palate, nose, skin, nasopharyngeal mucosa, lungs and colon. At 5 years of age, he was diagnosed with myasthenia gravis treated with thymectomy and had 6 years of intravenous immunoglobulin infusions. During his lifetime, he was treated with multiple courses of steroids and infliximab, cytoxan and rituximab. He had a history of drug abuse requiring three hospitalizations for overdose. Cause of death at the age of 19 years was due to overdose of phenergan and gabapentin. Autopsy of the brain showed no gross or microscopic abnormalities and brain weight was 1450 g.