The relationship between objective parameters of sleep and measures of fatigue, depression, and cognition in multiple sclerosis.

BACKGROUND: People with multiple sclerosis (MS) often report poor sleep, fatigue, sleepiness, depression and cognitive dysfunction. Interrelationships between symptoms and sleep are poorly understood. OBJECTIVES: To document objective parameters of sleep measured by polysomnography (PSG) and multi-sleep latency tests (MSLTs) in patients experiencing fatigue or sleepiness and to determine whether they correlate with symptoms. METHODS: Thirty-two MS patients, not on therapy, with fatigue or sleepiness completed the Modified Fatigue Impact Scale, Fatigue Severity Scale, Epworth Sleepiness Scale, Beck Depression Index and NeuroTrax cognitive tests and underwent PSG and MSLTs. RESULTS: Sleep efficiency (SE) averaged 75.1%. wake after sleep onset (WASO), sleep onset latency and multi-sleep latency were 66.2, 43.4 and 10.43 min, respectively. Stage N3 and rapid eye movement sleep were absent in 10 and four patients, respectively. Increased limb movements were observed in eight patients. Obstructive sleep apnea was observed in 12 patients. Neither SE nor WASO correlated with fatigue or sleepiness. SE correlated with the global cognitive score and with executive function and information processing subscales. CONCLUSIONS: Overall, 30/32 MS patients reporting fatigue or sleepiness had evidence of one or more sleep disturbances. PSG should be considered in MS patients reporting fatigue or sleepiness in order to rule out treatable disturbances.

Serial evoked potential studies and MRI imaging in chronic progressive multiple sclerosis.

Measurements of serial evoked potential latencies and plaque burden on MRI scans are often obtained during clinical studies of multiple sclerosis patients to provide additional information to the disability-based primary endpoints. The ideal laboratory-based marker of progression would be expected to significantly change over the time period of study. Serial visual (VEP) and brainstem auditory evoked potentials (BAEP) and MRI scans of 11 chronic progressive MS patients were obtained over a 1.5 year period in a clinical study. Over this period, there was no significant change in disability as measured by the Kurtzke EDSS, Ambulation Index or Neurological Rating Score. The VEP P100 significantly progressed over the period of study. However, the MRI T(2) plaque burden and BAEP I-V intrapeak latency did not significantly progress over the 1.5 years. We conclude that, in chronic progressive MS, serial visual evoked potential tests may complement standard disability-based endpoints to assess disease progression.

A double-blind, placebo-controlled trial of extracorporeal photopheresis in chronic progressive multiple sclerosis.

Extracorporeal photopheresis is a safe therapy for cutaneous T-cell lymphoma and may have efficacy in certain autoimmune disorders. We performed a randomized, double-blinded, placebo-controlled trial of monthly photopheresis therapy in 16 patients with clinically definite multiple sclerosis (MS). All patients had progressed during the preceding year with entry Expanded Disability Status Scale (EDSS) scores between 3.0 and 7.0. Patients received photopheresis or sham therapy for 1 year and were followed for an additional 6 to 12 months. Patients were clinically evaluated by three disability scales: (1) EDSS; (2) Ambulation index and (3) Scripp's quantitative neurologic assessment. No serious side effects occurred in either group. There were no differences between the photopheresis and sham therapy groups by the disability measures. Additionally, there were no differences in progression of MRI plaque burden or evoked potential latencies. In this limited study, photopheresis was found to be safe but did not significantly alter the course of chronic progressive MS.

B cell receptor-induced apoptosis in primary transitional murine B cells: signaling requirements and modulation by T cell help.

Self-reactive immature B cells may be eliminated in the bone marrow (BM) after B cell receptor (BCR) engagement in a process known as negative selection. Immature B cells emigrating from the BM, the so-called transitional cells, remain sensitive to negative selection and are likely to be important targets of tolerance towards peripheral antigens. Transitional cells are deleted through apoptosis after BCR cross-linking in vitro. Using anti-Ig as a surrogate antigen, we determined the signaling requirements for the induction of apoptosis in transitional cells. Treatment with anti-Ig for only 20 min causes most cells to be apoptotic 16 h later. Furthermore, apoptosis of transitional cells is induced with low doses of anti-Ig while mature cell proliferation requires extended culture at 30-fold higher concentrations. For both populations of B cells, total surface Ig expression is equivalent, therefore indicating that the threshold of BCR signaling required to elicit these responses is different. T cell help can modulate B cell tolerance. However, specific help may not be available when apoptosis is triggered by a peripheral antigen. The opportunity to reverse apoptosis of transitional cells is surprisingly long. Even 8 h after anti-Ig treatment, IL-4 or anti-CD40 antibody can block apoptosis. The upper time limit of protection is concurrent with irreversibility of apoptosis as measured by DNA fragmentation. These findings indicate that B cell negative selection is more easily triggered than activation, and that the induction of apoptosis and its reversal by T cell help can be events that occur in distinct microenvironments.

Treatment of Guillain-Barré syndrome with intravenous immunoglobulin.

Guillain-Barré syndrome (GBS) is an acute polyneuropathy that typically presents as a progressive flaccid paralysis. The pathology is believed to be caused by both cellular and humoral immune processes. This inflammatory neuropathy has a mortality rate of 4-5%. About 30% of patients require mechanical ventilation, and these patients are often hospitalized for months before regaining the ability to walk. Immunomodulation is used to improve the recovery rate and shorten hospital stays. Plasma exchange was shown to be effective in improving recovery time in GBS in several controlled trials during the 1980s. In this decade, intravenous immunoglobulin (IVIg) therapy has been shown to be equally effective for therapy of GBS and its variants. Although the precise mechanisms of immunomodulation by IVIg are unknown, it probably directly inactivates specific anti-myelin antibodies and indirectly inhibits their production. IVIg offers some advantages over plasma exchange by being better tolerated in some patients and being easily administered without special equipment. However, because of the possibility of progression, the treatment of GBS patients requires qualified neurologic and supportive care.

Clinicopathologic study of paraneoplastic brainstem encephalitis and ophthalmoparesis.

We report three patients who exhibited ophthalmoparesis as an early manifestation of progressive paraneoplastic brainstem encephalitis. In two patients, anti-Hu antibodies were detected, whereas in a third, found at postmortem to have thyroid cancer, no antibodies were identified. Postmortem examination of two patients disclosed extensive gliosis, perivascular inflammation, and cell loss in the midbrain and pontine tegmentum. In one of these patients, there was selective neuronal loss within the third, fourth, and sixth nerve nuclei. We conclude that supranuclear or nuclear ophthalmoparesis may be the initial manifestation of paraneoplastic brainstem encephalitis. Our pathologic data suggest that the ophthalmoparesis may result from selective neuronal death within the brainstem tegmentum and ocular motor nuclei.

Renal cell carcinomatous meningitis: pathologic and immunohistochemical features.

We report the clinical, radiographic, pathologic, and immunohistochemical features of a patient with widespread meningeal carcinomatosis from renal cell carcinoma. Clear and spindle tumor cell subtypes infiltrated the meninges of the cauda equina, oculomotor nerve, spinal cord, and cerebral hemispheres, forming abortive glandular or tubular aggregates without evidence of parenchymal invasion. Cytokeratin epitopes were labeled immunohistochemically with Cam 5.2 antibodies, but epithelial membrane antigen and neuron-specific enolase were not present.

Basal expression of the human macrophage colony-stimulating factor (M-CSF) gene in K562 cells.

Macrophage colony-stimulating factor (M-CSF) functions in hematopoiesis and regulates mature monocytes. Untreated K562 leukemic cells transcribe M-CSF. Elements between bases -43 and -77 (NF-KB enhancer) and between -129 and -180 (Sp1 enhancer) of the M-CSF promoter were important for basal transcription. Gel Shift assays and ultraviolet crosslinking experiments showed a 50 kDa protein bound to the NF-KB element at -65 in a GTP-dependent fashion. Additionally, a K562 nuclear protein, specifically bound the Sp1 enhancer. Run-off transcription and half-life studies showed that M-CSF is regulated primarily at the post-transcriptional level.

Complex regulation of macrophage colony-stimulating factor in the HL-60 promyelocytic cell line.

The regulation of macrophage colony-stimulating factor (M-CSF) gene expression by phorbol esters and calcium ionophore (A23187) was studied in HL-60 cells. In untreated HL-60 cells, M-CSF transcripts were undetectable, but transcripts were present within 2 h of A23187 treatment or within 8 h of phorbol 12,13-dibutyrate (PdBu) treatment. Concurrent treatment of HL-60 cells with A23187 and cycloheximide (CHX) for 6 h led to a superinduction of message over A23187 treatment alone. But concurrent treatment with PdBu and CHX for 24 h abolished expression of the message normally present after 24 h of PdBu treatment. The role of new protein synthesis in transcriptional regulation of M-CSF was studied by run-on transcription assay. Untreated HL-60 cells or cells treated with CHX alone do not transcribe M-CSF mRNA. However, cells treated with A23187 for 6 h and CHX for 1, 3, or 6 h transcribed more M-CSF than cells treated with A23187 alone for 6 h. CHX also regulates M-CSF expression by message stabilization. The t1/2 of M-CSF mRNA was 45 min in cells treated with A23187 for 6 h or in cells treated with PdBu for 24 h, was over 2 h in HL-60 cells treated with A23187 for 6 h and CHX for 1 h, and was 3 h in cells treated with PdBu for 24 h and CHX for 1 h. We conclude that M-CSF gene expression can be differentially regulated in HL-60 cells and that new protein synthesis plays an important role in both the transcriptional and posttranscriptional regulation.

On the relation between seizures and brain lesions after intracerebroventricular kainic acid.

To analyze the relation between kainic acid-induced limbic seizures and the associated brain lesions, various doses of kainic acid (117-940 pmol) were administered intracerebroventricularly to unanesthetized rats. Rats which experienced status epilepticus developed lesions in several limbic, neocortical and thalamic regions. However, rats which experienced only temporally discrete seizures (less than 30 min each) suffered neuronal degeneration exclusively in the CA3-CA4 area ipsilateral to the kainic acid infusion, even when other regions exhibited the same total electrographic seizure duration. These results can best be explained by postulating that, in addition to evoking seizures, kainic acid also enhances the toxic effects of seizures on CA3-CA4 neurons.