Slavenka Kam-Hansen

Altered Placebo and Drug Labeling Changes the Outcome of Episodic Migraine Attacks

In 459 migraine attacks, information provided to patients (from negative to neutral to positive) modified placebo and medication outcomes in a progressive fashion. Placebo and Medication Effects in Episodic Migraine Placebo and medication effects are intimately related in clinical practice and drug development. In new work, Kam-Hansen et al. investigated how information—ranging from “negative” to “neutral” to “positive”—provided to patients, who received either active drug or placebo, modified their headache pain as measured by patient-reported pain scores. In a randomized order over six consecutive attacks, 66 patients with episodic migraine received either placebo or Maxalt (10-mg rizatriptan) under three information conditions (told placebo, told Maxalt or placebo, told Maxalt). Each participant also reported on an initial no-treatment attack, yielding a total of 459 documented migraine attacks. Maxalt was superior to placebo for pain relief. Increasing information from negative to neutral to positive progressively enhanced the effects of both placebo and Maxalt. The efficacy of open-label placebo was superior to that of no treatment. Relative to no treatment, the placebo, under each information condition, accounted for more than 50% of the drug effect. The benefits of placebo persisted even when the placebo was honestly described. Whether treatment involves medication or placebo, the information provided to patients and the ritual of pill taking are important components of medical care. Information provided to patients is thought to influence placebo and drug effects. In a prospective, within-subjects, repeated-measures study of 66 subjects with episodic migraine, we investigated how variations in medication labeling modified placebo and drug effects. An initial attack with no treatment served as a control. In six subsequent migraine attacks, each participant received either placebo or Maxalt (10-mg rizatriptan) administered under three information conditions ranging from negative to neutral to positive (told placebo, told Maxalt or placebo, told Maxalt) (N = 459 documented attacks). Treatment order was randomized. Maxalt was superior to placebo for pain relief. When participants were given placebo labeled as (i) placebo, (ii) Maxalt or placebo, and (iii) Maxalt, the placebo effect increased progressively. Maxalt had a similar progressive boost when labeled with these three labels. The efficacies of Maxalt labeled as placebo and placebo labeled as Maxalt were similar. The efficacy of open-label placebo was superior to that of no treatment. Relative to no treatment, the placebo, under each information condition, accounted for more than 50% of the drug effect. Increasing “positive” information incrementally boosted the efficacy of both placebo and medication during migraine attacks. The benefits of placebo persisted even if placebo was honestly described. Whether treatment involves medication or placebo, the information provided to patients and the ritual of pill taking are important components of care.

B and T lymphocytes in cerebrospinal fluid and blood in multiple sclerosis, optic neuritis and mumps meningitis

B and T cells were defined in cerebrospinal fluid (CSF) and blood of 18 multiple sclerosis (MS), five optic neuritis, and 17 mumps meningitis patients by counting immunoglobulin‐bearing lymphocytes for B cells, and the capacity of rosette formation with sheep erythrocytes for T‐cell determination. Patients with MS and mumps meningitis had significantly higher T‐cell values in CSF compared to blood, while the B cell value was significantly lower in CSF in mumps meningitis only. MS patients also displayed significantly lower B‐cell values in blood compared to mumps meningitis patients and blood donors. No significant differences were observed between MS patients in exacerbation and in remission.

Chronic progressive myelopathy associated with HTLV‐I Oligoclonal IgG and anti‐HTLV‐I IgG antibodies in cerebrospinal fluid and serum

Among 22 patients with human T-lymphotropic virus type I (HTLV-I)-associated chronic progressive myelopathy, agarose isoelectric focusing (AIF) revealed oligoclonal IgG bands in 21: in 3 in CSF only; in 11 in CSF and to some extent in serum; and in 7, identical patterns in CSF and serum. By immunoblot after AIF of CSF and serum, we observed bands of anti-HTLV-I IgG antibodies in 19 patients: in 5 in CSF only; in 9 in CSF and partly in serum; and in 5, identical in CSF and serum. Oligoclonal anti-HTLV-I IgG antibody bands could only partly be traced to oligoclonal IgG bands. If, prior to AIF, serum and CSF were absorbed with HTLV-I antigen, practically all oligoclonal HTLV-I-specific IgG antibody activity was abolished, while the oligoclonal pattern of total IgG was affected only to a minor extent. Alongside with HTLV-I-specific oligoclonal B cell response, HTLV-I myelopathy is regularly accompanied by production of oligoclonal IgG of unknown antibody specificities.

Immunoglobulin-producing cells in CSF and blood from patients with multiple sclerosis and other inflammatory neurological diseases enumerated by Protein-A plaque assay

Using the Protein-A plaque assay, numbers of IgG + IgA + IgM producing cells determined in patients with multiple sclerosis (MS) were 0.1-5% in CSF and 0.1-0.7% in peripheral blood; interestingly, 7 of 11 MS patients had IgM producing cells in CSF. In patients with aseptic meningitis (AM), the corresponding values were 0.04-7.5% in CSF and 0.4-2.4% in peripheral blood. There were more Ig producing cells in peripheral blood from patients with AM and MS than in healthy subjects. A correlation between numbers of IgG producing cells in CSF and the concentrations of intrathecally produced IgG (CSF IgG index) was registered in patients with AM; the same was the true for IgA. The Protein-A plaque method, adopted for 20 X 10(3) lymphocytes, makes possible enumeration of Ig-producing cells in CSF and discrimination among cells secreting different Ig classes, thereby being a powerful tool for studying immune reactions in the CNS-CSF compartment.

Reduced in vitro response of CSF lymphocytes to mitogen stimulation in multiple sclerosis.

By means of a microculture technique and calculation of incorporation of 14C‐thymidine, cerebrospinal fluid (CSF) lymphocytes from multiple sclerosis (MS) patients showed low or absent proliferation when stimulated with phytohaemaggiutinin, concanavalin A, or pokeweed mitogen. in contrast to peripheral blood lymphocytes (PBL) obtained simultaneously and investigated in parallel. A lower proliferation of CSF lymphocytes compared with PBL was also found in acute aseptic meningitis, although it has been reported that CSF lymphocytes show greater proliferation than PBL when specifically stimulated. The low proliferation of MS CSF lymphocytes on mitogen stimulation may be a consequence of prolonged sensitization to an as yet unidentified antigen. The proliferation of MS CSF lymphocytes was not improved by adding irradiated PBL, making helper cell insufiiciency less likely. MS CSF had no inhibitory effect on proliferation of PBL. arguing against an inhibitory effect of soluble factors in the CSF as an explanation for the depressed response of CSF lymphocytes.

Reduced number of active T cells in cerebrospinal fluid in multiple sclerosis

Using a modification of the active rosette test of Wybran and Fudenberg, we found that the percentages of active T cells were significantly lower in the cerebrospinal fluid (CFS) of multiple sclerosis (MS) patients than in blood obtained simultanously from these patients, or in the CSF or blood from patients with other neurologic diseases. These results suggest that in MS there may be a depression or deficiency of a functional subpopulation of T lymphocytes confined to the central nervous system.

Immunoglobulin‐Producing Cells in Blood and Cerebrospinal Fluid during the Course of Aseptic Meningoencephalitis

The protein A plaque assay was used to quantitate the number of IgG‐, IgA‐, and IgM‐producing cells per 20 × 103 lymphocytes in cerebrospinal fluid (CSF) and peripheral blood (PB) from 23 patients with aseptic meningoencephalitis (AM) in the acute stage 1–10 days after onset (group 1) and during late convalescence after 19–38 days (group II) and in PB from healthy controls. In the acute stage, IgG‐ and IgM‐producing cells were found with significantly higher frequency in both CSF and PB than in the late convalescence. In both patient groups there were more Ig‐producing cells in PB than in CSF. The predominant Ig class in PB of AM patients was IgA, just as in healthy individuals. In CSF, IgA‐ and IgG‐producing cells predominated at similar frequencies. In the group I patients, there were positive correlations between numbers of Ig‐producing cells of each class and the corresponding CSF Ig index, an indicator of intrathecal Ig synthesis. Since high numbers of Ig‐producing cells could be found in CSF that was otherwise normal, enumeration of Ig‐producing cells is considered a more sensitive indicator of the immune response intrathecally than measurement of free Igs

Studies on the humoral and cell-mediated immune response in a patient with Mollaret's meningitis ☆

A patient with Mollarets meningitis with protracted course and a strong immune response within the central nervous system is described. The findings of IgG bands in agarose gel electrophoresis of CSF together with elevated CSF IgG index values are in accordance with intrathecal synthesis of IgG, possibly against an antigen persistent in the CNS. Subgrouping of CSF lymphocytes morphologically (B/T, active T cells) and functionally (stimulation with mitogens) showed that these cells differed from peripheral blood lymphocytes. A defect in the regulatory function of T cells may be responsible for the continuing pathologic process in Mollarets meningitis.

The 150-Year Anniversary of Multiple Sclerosis: Does Its Early History Give an Etiological Clue?

Multiple sclerosis (MS) is still an enigma. Despite being one of the major diseases of the central nervous system leading to the permanent disability of young adults in the United States and Europe, its etiology and pathogenesis remain unknown. The history of MS is short, the first pathoanatomical description appearing 150 years ago. But was MS really a new disease at that time? This article will focus on the early history of MS, that is, from the 1830s to the 1880s, and from this historical survey some facts will be extracted favoring the hypothesis that MS is a new disease that began 150 years ago. Based on this concept, a possible etiology will be discussed.

Production of Specific Antibodies by Cerebrospinal Fluid Lymphocytes in Patients with Herpes Zoster, Mumps Meningitis and Herpes Simplex Virus Encephalitis

We applied a new method consisting of short‐term culture (18 h) of lymphocytes from cerebrospinal fluid (CSF‐L) and peripheral blood (PBL) in viral antigen‐coaled ELISA plates and subsequent measurement of IgG and IgM antibodies bound to antigen. Utilizing mumps virus, herpes simplex virus (HSV), varicella zoster virus (VZV). and measles virus as antigens, we demonstrated production by CSF‐L. of antibodies against the aetiological agent only in all patients with mumps meningitis and HSV encephalitis and also in all patients with herpes zoster without central nervous system (CNS) symptoms. This might be considered as direct evidence that specific antibodies are produced within the CNS in inflammatory nervous system diseases. CSF‐L. usually produced higher amounts of antibodies than the corresponding number of PBL., In comparison with concentrations of free antibodies determined in parallel, our method had higher specificity and sensitivity and gave more precise information about the antibody response in infections of the nervous system.