Daclizumab high-yield process reduced the evolution of new gadolinium-enhancing lesions to T1 black holes in patients with relapsing-remitting multiple sclerosis.

BACKGROUND AND PURPOSE: In the SELECT study, treatment with daclizumab high-yield process (DAC HYP) versus placebo reduced the frequency of gadolinium-enhancing (Gd(+) ) lesions in patients with relapsing-remitting multiple sclerosis (RRMS). The objective of this post hoc analysis of SELECT was to evaluate the effect of DAC HYP on the evolution of new Gd(+) lesions to T1 hypointense lesions (T1 black holes). METHODS: SELECT was a randomized double-blind study of subcutaneous DAC HYP 150 or 300 mg or placebo every 4 weeks. Magnetic resonance imaging (MRI) scans were performed at baseline and weeks 24, 36 and 52 in all patients and monthly between weeks 4 and 20 in a subset of patients. MRI scans were evaluated for new Gd(+) lesions that evolved to T1 black holes at week 52. Data for the DAC HYP groups were pooled for analysis. RESULTS: Daclizumab high-yield process reduced the number of new Gd(+) lesions present at week 24 (P = 0.005) or between weeks 4 and 20 (P = 0.014) that evolved into T1 black holes at week 52 versus placebo. DAC HYP treatment also reduced the percentage of patients with Gd(+) lesions evolving to T1 black holes versus placebo. CONCLUSIONS: Treatment with DAC HYP reduced the evolution of Gd(+) lesions to T1 black holes versus placebo, suggesting that inflammatory lesions that evolved during DAC HYP treatment are less destructive than those evolving during placebo treatment.

4-Aminopyridine in multiple sclerosis: prolonged administration.

In an earlier study, we demonstrated efficacy of single oral doses of 4-aminopyridine (4-AP) in improving motor and visual signs in multiple sclerosis (MS) patients for a mean of 4.97 hours. We attempted to determine whether efficacy could safely be prolonged using multiple daily doses over several days by administering 7.5 to 52.5 mg 4-AP to 17 temperature-sensitive MS patients in one to three daily doses at 3- to 4-hour intervals over 1 to 5 days in a double-blind study. Nine of these patients were also tested with identically appearing placebo. Thirteen of the 17 patients (76%) given 4-AP showed clinically important motor and visual improvements compared with three of nine in the placebo group. Average peak improvement scores were 0.40 for 4-AP and 0.12 for placebo. Seventy percent of the daily 4-AP improvements lasted 7 to 10 hours. The improvements for two consecutive doses of 4-AP lasted a mean of 7.07 hours (83% of the average 8.53-hour treatment-observation period) compared with 2.36 hours for placebo (26% of the average 9.06-hour treatment-observation period). No serious side effects occurred. 4-AP is a promising drug for the symptomatic treatment of MS.

Plasmapheresis decreases neuroelectric blocking activity in multiple sclerosis.

Serum neuroelectric blocking factor activity diminished after plasmapheresis in five of seven patients with MS but returned to baseline levels in 2 to 3 weeks. In the other two patients changes were insignificant. All patients studied had progressing symptoms. Five plasma exchanges of 2 liters were performed in 10 days. Two patients improved clinically, whereas five did not. There was no correlation between the level of neuroelectric blocking activity and changes in clinical status.

Evaluation of cervical stimulation for chronic treatment of spasticity.

Electrical stimulation of the spinal cord (SCS) to reduce spasticity was evaluated in seven patients who, along with their physicians, perceived significant and prompt benefit from stimulation. In two 24-hour test periods, on or off stimulation, we used two independent methods of evaluation: quantitative measures of joint compliance and stretch reflexes, and a standardized neurologic examination. Neither method did better than chance in determining whether SCS was actually being received. Problems with the experimental protocol are discussed, but the results cannot be interpreted as supporting the efficacy of SCS as a treatment for spasticity.

Validation of the functional assessment of multiple sclerosis quality of life instrument.

Based on scientific literature and interviews with clinicians and patients, we developed a quality of life instrument for use with people with MS called the Functional Assessment of Multiple Sclerosis (FAMS). The initial item pool consisted of 88 questions: 28 from the general version of the Functional Assessment of Cancer Therapy quality of life instrument, plus 60 generated by patients, providers, and literature review. The validation samples comprised a mail survey cohort (N = 377) and a clinical cohort (N = 56). Both cohorts provides evidence for internal consistency of the derived subscales, test-retest reliability, content validity, concurrent validity, and construct validity. Principal components and Rasch measurement model analyses were applied sequentially to survey sample data, reducing test length to 44 questions, divided into six subscales: mobility, symptoms, emotional well-being (depression), general contentment, thinking/fatigue, and family/social well-being. Fifteen initially rejected questions were added back as miscellaneous (unscored) questions for their potential clinical and empirical value. The mobility subscale was strongly predictive of the Kurtzke Extended Disability Status Scale and the Scripps Neurologic Rating Scales. The other five subscales were not, indicating they measure aspects of patient quality of life not captured by the neurologic exam. The final 59-item English language instrument (FAMS version 2) is available for inclusion in clinical trials and clinical practice.

T cell-depleted autologous hematopoietic stem cell transplantation for multiple sclerosis: report on the first three patients.

Multiple sclerosis (MS) is a disease of the central nervous system characterized by immune-mediated destruction of myelin. In patients with progressive deterioration, we have intensified immunosuppression to the point of myeloablation. Subsequently, a new hematopoietic and immune system is generated by infusion of CD34-positive hematopoietic stem cells (HSC). Three patients with clinical MS and a decline of their Kurtzke extended disability status scale (EDSS) by 1.5 points over the 12 months preceding enrollment and a Kurtzke EDSS of 8.0 at the time of enrollment were treated with hematopoietic stem cell (HSC) transplantation using a myeloablative conditioning regimen of cyclophosphamide (120 mg/kg), methylprednisolone (4 g) and total body irradiation (1200 cGy). Reconstitution of hematopoiesis was achieved with CD34-enriched stem cells. The average time of follow-up is 8 months (range 6-10 months). Despite withdrawal of all immunosuppressive medications, functional improvements have occurred in all three patients. We conclude that T cell-depleted hematopoietic stem cell transplantation can be performed safely in patients with severe and debilitating multiple sclerosis. Stem cell transplantation has resulted in modest neurologic improvements for the first time since onset of progressive disease although no significant changes in EDSS or NRS scales are evident at this time.

Nonhomogeneous distribution of 5-hydroxyindoleacetic acid and homovanillic acid in the lumbar cerebrospinal fluid of man.

The volume of the lumbar sac measured in 4 subjects was found to be 15.5 ml. Exactly 15 ml of lumbar cerebrospinal fluid (L-CSF) was permitted to flow freely out during a lumbar puncture in 20 neurological patients and small samples of the L-CSF were collected in the beginning (sample 1), at the middle (sample 2), and at the end (sample 3) of this procedure either for 5-HIAA or HVA measurement. The concentrations of 5-HIAA and HVA increased in an exponential manner from sample 1 to sample 3. These results indicate that CSF in the lumbar sac is not a homogeneous fluid as is generally believed and that certain rules have to be followed in the sampling of the L-CSF to obtain reproducible biochemical data.

Development of somatizing responses in multiple sclerosis.

Chronic medical illness may produce emotional stress of a variety which encourages the development of patterns of somatization. Discussed here are patterns of somatization in multiple sclerosis. The long-term uncertainty and changing nature and severity of symptoms raises the likelihood that people will become absorbed in their bodies, will demonstrate heightened responses to minor physical change, and may come to experience psychic conflict through the language of physical symptomatology. Case examples are discussed as well as recommendations for treatment.

Meningiomas with conspicuous plasma cell-lymphocytic components: a report of five cases.

Five meningeal neoplasms grossly resembling meningiomas but histologically containing meningothelial cells together with abundant plasma cells and lymphocytes are reported. These masses are regarded as meningiomas with extensive plasma cell--lymphocytic infiltrates.

Orally administered 4-aminopyridine improves clinical signs in multiple sclerosis.

4-Aminopyridine (4-AP), a potassium channel blocker, restores conduction in blocked, demyelinated animal nerve. Its administration to multiple sclerosis (MS) patients produces transient neurological improvements. Vision improves after either oral or intravenous administration, whereas motor function improvement has been reported only with the latter. To assess further its potential as a practical symptomatic treatment, we studied the efficacy of single, oral doses of 4-AP on both visual and motor signs in MS. Twenty temperature-sensitive male MS patients were given either 10 to 25 mg of 4-AP or identically appearing lactose placebo capsules. Static quantitative perimetry, critical flicker-fusion, visual acuity, visual evoked potentials, and videotaped neurological examinations were monitored. All of 15 MS patients given 4-AP mildly to markedly improved. Motor functions (power, coordination, gait) improved in 9 of 13 involved, vision in 11 of 13, and oculomotor functions in 1 of 2. Improvements developed gradually at doses as low as 10 mg, usually beginning within 60 minutes after drug administration, and reversed gradually over 4 to 7 hours. No serious adverse effects occurred. No significant changes were observed in 5 MS patients given placebo. We conclude that orally administered 4-AP produces clinically important improvements in multiple, chronic deficits in MS. Further studies are warranted to assess efficacy and safety of prolonged administration.

Acute improvement in exacerbating multiple sclerosis produced by intravenous administration of mannitol.

The mode of action of adrenocorticotropic hormone (ACTH) treatment in exacerbating multiple sclerosis was studied by short-term infusions of agents that mimic specific and limited pharmacological actions of ACTH and observing for temporally phase-locked clinical changes. The study was double blinded, and agents were administered while the patients were being treated with a standard course of 10-day intramuscular ACTH therapy (40 U twice daily). Antiedema, alkalotic-hypocalcemic, extraadrenal, and sodium-retaining actions were studied using infusions of mannitol, sodium bicarbonate, ACTH, and sodium chloride, respectively. Seven of 8 patients receiving placebo infusions (2.5% glucose) showed no significant clinical change and 1 exhibited an equivocal improvement. Five of 9 patients receiving mannitol showed definite signs of clinical improvement phase-locked to drug administration, with subsequent gradual reversal to baseline. Similar improvements occurred with infusions of NaHCO3 in 5 of 8 patients and of ACTH in 4 of 8 patients. Three of 7 patients given NaCl infusion showed possible mild improvements. The results indicate that mannitol and NaHCO3 induced transient acute improvement in signs at the 95% confidence level in patients with exacerbating multiple sclerosis, with ACTH having a similar effect at the 90% confidence level. These agents mimic some of the known effects of ACTH, which may be important in the therapeutic action of ACTH in multiple sclerosis. A possible role for mannitol and high-dose ACTH in the treatment of demyelinating disease warrants further study.

4-Aminopyridine improves clinical signs in multiple sclerosis.

Twelve temperature-sensitive male patients with multiple sclerosis and 5 normal men were monitored before, during, and after the intravenous injection of 7 to 35 mg of 4-aminopyridine (4-AP) in 1- to 5-mg doses, every 10 to 60 minutes. Static quantitative perimetry, flicker-fusion frequency, visual acuity, and videotaped neurological examinations were performed. Ten of the 12 patients showed mild to marked improvement. Vision improved in 7 patients, oculomotor function in 5, and motor function (power, coordination, gait) in 5. Improvements developed gradually within minutes of drug injection at doses as low as 2 mg, and gradually reversed around 2 to 4 hours after the peak drug effect. No effects were observed in 5 patients given saline injections. No serious side effects occurred in either the normal subjects or the patients receiving 4-AP. It is concluded that 4-AP lessens multiple neurological deficits in multiple sclerosis and, furthermore, that the K+ channel is functional in demyelinated central nervous system axons in humans. The improvements with 4-AP are substantial enough to be of transient therapeutic benefit in selected patients.

Selective blockade of components of potassium activation in Myxicola axons.

The K+ conductance in Myxicola giant axons activates in two phases which are pharmacologically separable. The fast phase of K+ activation is specifically inhibited by 4-aminopyridine and by the substitution of D2O for H2O. We suggest Myxicola giant axons, like the amphibian node of Ranvier, may possess more than one variety of K+ channel.

Partial plasma protein replacement in therapeutic plasma exchange.

We wished to determine whether subtotal replacement of protein in plasma removed at plasma exchange would be adequate to prevent hypovolemia and hypoproteinemia. Seven well nourished outpatients with chronic progressive multiple sclerosis underwent 60 plasma exchanges in which two liters of plasma were replaced with 750 ml saline followed by 1250 ml of a 5% albumin solution (62.5% albumin replacement). Total serum protein, protein electrophoresis, and immunoglobulin levels were measured before and after each exchange. Clinically, the exchanges were well tolerated. Total serum protein dropped by a mean of only 18% during the study and mean preexchange serum albumin levels were unchanged, even though immunoglobulins decreased by 57-72%. We conclude that in well nourished patients, partial albumin replacement of this magnitude is an adequate substitute for plasma removed in a plasma exchange.

Correlation between diffuse EEG abnormalities and cerebral atrophy in senile dementia.

Thirty-five elderly patients were investigated because of clinical signs of dementia. The presence or diffuse cerebral atrophy, and its severity, were determined by the use of computed tomography (CT scan). All of the patients were also examined by electroencephalography (EEG), and the presence of diffuse abnormalities, especially diffuse slowing, was noted. Specifically, patients with normal or near-normal EEGs were compared with those with severe diffuse slowing. No correlation between the presence or severity of diffuse EEG abnormalities and the degree of cerebral atrophy as measured by CT scan was found. Though the EEG is clearly identifying physiological dysfunction of nerve cells in demented patients it does not appear to be reliable tool for the prediction of diffuse cerebral atrophy in this population.

Myogenic and central neurogenic factors in fatigue in multiple sclerosis.

Short episodes of electrical stimulation were applied to the right quadriceps muscle of patients with multiple sclerosis (MS) and healthy subjects at different times during 60 sec sustained voluntary muscle contractions at 0 to 100% levels of maximal voluntarily generated joint torque. The amplitude of electrically induced increments of torque (delta T) has been shown to depend upon both the level of muscular contraction and time from the beginning of the contraction. The dependence of delta T upon the time from the beginning of contraction has been assumed to reflect muscle fatigue. Patients with MS demonstrated an apparent involvement of central neurogenic mechanisms in fatigue manifested as a drop in muscle torque during sustained contractions at 75 and 100% levels when electrical stimulation was able to induce considerable increments in muscle torque. These patients also demonstrated a dependence of delta T upon the contraction level suggesting that they did not produce maximal voluntary contraction torque in the pre-trial. Fatigue in MS is due to central, neurogenic factors and does not seem to involve any myogenic factors such as might be related to secondary muscle changes due to the long-standing disorder. The subjective feeling of tiredness ('fatigue') may be related to a dissociation between central motor commands ('effort') and their mechanical consequences.

Treatment of autoimmune disease by intense immunosuppressive conditioning and autologous hematopoietic stem cell transplantation.

Multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis are immune-mediated diseases that are responsive to suppression or modulation of the immune system. For patients with severe disease, immunosuppression may be intensified to the point of myelosuppression or hematopoietic ablation. Hematopoiesis and immunity may then be rapidly reconstituted by reinfusion of CD34(+) progenitor cells. In 10 patients with these autoimmune diseases, autologous hematopoietic stem cells were collected from bone marrow or mobilized from peripheral blood with either granulocyte colony-stimulating factor (G-CSF) or cyclophosphamide and G-CSF. Stem cells were enriched ex vivo using CD34(+) selection and reinfused after either myelosuppressive conditioning with cyclophosphamide (200 mg/kg), methylprednisolone (4 g) and antithymocyte globulin (ATG; 90 mg/kg) or myeloablative conditioning with total body irradiation (1,200 cGy), methylprednisolone (4 g), and cyclophosphamide (120 mg/kg). Six patients with multiple sclerosis, 2 with systemic lupus erythematosus, and 2 with rheumatoid arthritis have undergone hematopoietic stem cell transplantation. Mean time to engraftment of an absolute neutrophil count greater than 500/microL (0.5 x 10(9)/L) and a nontransfused platelet count greater than 20,000/microL (20 x 10(9)/L) occurred on day 10 and 14, respectively. Regimen-related nonhematopoietic toxicity was minimal. All patients improved and/or had stabilization of disease with a follow-up of 5 to 17 months (median, 11 months). We conclude that intense immunosuppressive conditioning and autologous T-cell-depleted hematopoietic transplantation was safely used to treat these 10 patients with severe autoimmune disease. Although durability of response is as yet unknown, all patients have demonstrated stabilization or improvement.