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Objective: To determine the effect of dalfampridine (4-aminopyridine), a broad-spectrum, voltage-dependent potassium channel blocker, on patients with trigeminal nerve dysfunction due to multiple sclerosis (MS)., Methods: We reviewed histories of 71 patients in our clinic with clinically definite MS who were treated with dalfampridine for at least 2 to 3 months. Of the 71 patients, 5 had a history of either trigeminal neuralgia or altered facial sensation., Results: Of these 5 patients, 3 with preexisting trigeminal neuralgia had a marked worsening of facial pain in close proximity to starting dalfampridine. One patient with altered facial sensation developed trigeminal pain after being on dalfampridine for 18 months. Pain in this individual rapidly subsided when dalfampridine was discontinued. Pain in the worsened 3 patients persisted, became more refractory to previously effective medications, and in one instance required trigeminal surgery for pain control., Conclusions: Dalfampridine should be used with caution in persons with trigeminal neuralgia due to MS., Classification of Evidence: This study provides Class IV evidence that treatment with dalfampridine may precipitate or exacerbate preexisting trigeminal neuralgia., (© 2014 American Academy of Neurology.)

Objective: To explore whether high-dose atorvastatin can be administered safely to persons with relapsing-remitting multiple sclerosis (MS) taking thrice weekly, 44 microg dose subcutaneous interferon beta-1a., Methods: Persons with clinically stable, relapsing-remitting MS, on standard high-dose subcutaneous interferon beta-1a, were randomized in a double-blind fashion to receive either placebo or atorvastatin at dosages of 40 or 80 mg/day for 6 months. Blinded neurologic examinations and brain MRI readings were obtained at months 0, 3, 6, and 9. Laboratory blood testing was performed monthly. Main outcome measures were the determination of drug toxicity using blood tests and ECG and determination of MS-related disease activity, either clinical relapses or new or contrast-enhancing lesions on MRI., Results: Twenty-six subjects received at least one dose of study drug. Ten of 17 subjects on either 80 mg or 40 mg of atorvastatin per day had either new or enhancing T2 lesions on MRI or clinical relapses. One of the nine subjects on placebo had a relapse with active lesions on MRI. The subjects receiving atorvastatin were at greater risk for either clinical or MRI disease activity compared to placebo (p = 0.019). Significant changes in blood tests were noted only for lower cholesterol levels in subjects receiving atorvastatin., Conclusion: The combination of 40 or 80 mg atorvastatin with thrice weekly, 44 microg interferon beta-1a in persons with multiple sclerosis resulted in increased MRI and clinical disease activity. Caution is suggested in administering this combination.

This multicenter, stratified, randomized, placebo-controlled, double-blind trial evaluated tizanidine for use in the United States for spasticity secondary to MS. The 15-week trial was divided into baseline (weeks 0 and 1), titration (2 mg to a maximum of 36 mg/d; weeks 2 to 4), and plateau (weeks 5 to 13) phases, followed by dose tapering (week 14) and a final visit (week 15). Primary efficacy parameters were scores on muscle tone (Ashworth Scale) and type and frequency of muscle spasms (patient diaries). All efficacy parameters were evaluated by the physician/assessor, and the physician/prescriber was responsible for all dosage adjustments. The patient, physician/assessor, and physician/prescriber made global evaluations of antispastic efficacy. Tizanidine produced a significantly greater reduction than placebo in spasms and clonus (patient diaries) but no significant differences in Ashworth scores. Patients and physician/prescribers, but not physician/assessors, gave significantly better scores in the overall assessment of efficacy and tolerability. No significant differences in other secondary efficacy parameters were noted. Adverse events were reported for 66 (61%) of the 109 placebo-treated patients and 101 (91%) of the 111 tizanidine-treated patients; 6 (6%) and 14 (13%) discontinued treatment, respectively. Patient and physician perception of improvement demonstrated more consistent differences between groups than did the Ashworth Scale, perhaps because of inexperience with this measure or failure to consider time between drug administration and assessment.

Multiple sclerosis is a disease in which immune abnormalities are present both in the CNS and peripheral blood. Whether these changes are primary or secondary to the disease process is not known. We tested T-cell clones derived from activated lymphocytes in the blood and CSF of MS patients and controls for their capacity to regulate T-cell responses to alloantigens. A wide spectrum of regulatory functions were observed, ranging from marked enhancement to almost complete suppression. Clones from different patient populations and anatomic sites were equivalent in their regulatory functions with the net effect of clones in each compartment being suppression. However, certain clones from CSF and peripheral blood had the capacity to stimulate autologous T cells. Percentages of such clones in the peripheral blood of MS patients were significantly higher than in controls, while percentages in MS and other neurologic diseases (OND) CSF were equivalent. Our data suggest that (1) functional suppressor cells are not lost from the blood or CSF or MS and OND patients, (2) lymphocytes that have entered the CNS in patients with MS and other CNS diseases have equivalent regulatory functions, (3) MS may be an illness in which peripheral immunologic events are important in perpetuating the disease process, and (4) responses to autologous antigens may also play a role in this perpetuation.

We evaluated 48 relapsing-remitting multiple sclerosis (R/R MS) sibling pairs derived from 44 families for age and date of onset of MS symptoms, clinical course, and family history of MS. Age- and sex-matched R/R MS clinic patients provided a statistical comparison group. The age of onset tended to cluster within multiplex families. The initial symptom of MS occurred within 5 years of age in 30/48 sibling pairs compared with 16/48 controls. A positive family history of MS (other than siblings) was present in 43% of the multiplex families compared with 20% among simplex controls. In 1st-, 2nd-, and 3rd-degree relatives who had lived into the age at risk, 22/1,134 family members of multiplex sibling pairs had probable or definite MS compared with 10/1,215 control family members. Age of onset clustering in siblings concordant for R/R MS and an increased risk of MS in other family members suggest that factors influencing disease onset may be in part inherited in these kindreds.

We enrolled 116 patients in a multicenter, randomized, double-blind controlled trial of an 8-week course of 11 plasma exchange (PE) treatments in exacerbations of MS. The control group received sham PE, and both groups received identical treatment with IM ACTH and oral cyclophosphamide. Serum IgG decreased in the PE and sham treatment groups by 76% versus 22% by treatment 5, and by 64% versus 14% by treatment 11. PE also produced significant reductions in IgA, IgM, C3, and fibrinogen. PE patients had moderately enhanced improvement at 2 weeks relative to the sham group. PE patients with relapsing/remitting disease had significantly enhanced improvement at 4 weeks and there was also an increased improvement at 12 months, although this latter effect disappeared when we analyzed relapsing/remitting patients as a separate subgroup. Life table analysis showed the median time to recover preattack disability status was shorter in PE- than in sham-treated relapsing/remitting patients (4 vs. 13 weeks), a result confirmed by raw disability status scores in which there was recovery to their average preattack disability score by 3 months. PE given with ACTH plus cyclophosphamide enhances recovery from an exacerbation of disease in relapsing/remitting patients, although we observed no clear long-term benefits.

B-cell differentiation was studied in patients with MS and in age- and sex-matched controls, using a pokeweed mitogen (PWM)-stimulated in vitro culture system. Peripheral blood lymphocytes were obtained and separated into T-cell and non-T-cell fractions. Autologous and allogeneic combinations of T cells and B cells were cultured in the presence of pokeweed mitogen for 7 days. Numbers of plaque-forming cells (PFC) were measured at the end of the culture period. T cells from MS patients before and after a 10-day course of adrenocorticotropic hormone (ACTH) were able to cooperate fully in the generation of PWM-generated PFC. B cells from MS patients showed a decreased ability to differentiate into PFC in the presence of either autologous or allogeneic T cells. No significant change in differentiation was observed after a 10-day course of intravenous ACTH. We were thus unable to demonstrate any alteration in T-cell function in MS but were able to demonstrate a decreased ability of MS B cells to differentiate into immunoglobulin-secreting cells. ACTH had no significant effect on these abnormalities.

Recently published reports have suggested that multiple sclerosis (MS) may be associated with human retrovirus infection. Indeed, an autonomously proliferating T-cell clone was isolated from the CSF of an MS patient, an observation interpreted as indicating an infection with human T lymphotropic virus I (HTLV I). In view of these findings, we undertook a systematic search for autonomously proliferating cells in the spinal fluids of MS patients and those with other neurologic diseases (OND). In vivo activated blast cells were isolated from the CSF of six MS patients and six OND controls. A total of 442 clones were grown from these cells and assayed for their ability to proliferate independently, without the need for T cell-produced lymphokines. No autonomously proliferating clones were detected. Thus, while our data do not exclude the possibility that HTLV I transformed cells may exist in the CSF of MS patients, they do suggest that such cells are exceptional.