[Direct costs for Parkinson's treatment in private neurology practices in Berlin]. / Direkte Kosten der Parkinson-Behandlung : Eine Erhebung in neurologischen Schwerpunktpraxen in Berlin.

BACKGROUND: Aim of this study was to assess the direct costs of Parkinson's disease (PD) within a 3-month period (i.e. the accounting period for the German statutory health insurance) in 12 neurological outpatient practices in Berlin during 2006. MATERIAL AND METHODS: A total of 425 patients (age 69.1+/-9.3 years, 185 females) were recruited, and sociodemographic and clinical data were obtained by a specific questionnaire. The distribution of costs was analyzed based on several clinical and patient parameters. The costs were calculated with different approaches: (1) prospectively, with the practices' accounting according to German uniform scales (GoA, EbM) and (2) retrospectively, with questionnaires for the Parkinson's patients. Costs were calculated according to current German guidelines of the statutory health insurance. Clinical parameters were assessed with a questionnaire for physicians. RESULTS: The direct medical costs totaled 1,667 EUR (range 1,436-1,995 EUR, CI 95%) per patient per 3 months. Charges by physicians were 42 EUR (39-45 EUR, CI 95%) for patients with statutory health insurance and 135 EUR (106-177 EUR, CI 95%) for those with private insurance. Disease severity and disease duration correlated with higher direct medical costs. Motor fluctuations and depression also were major factors influencing cost. CONCLUSION: Our study emphasizes the large economic burden caused mainly by PD medication and hospitalization. For the first time a direct comparison between costs and actual physicians' reimbursement was possible. In combination with further economic studies, this comparison will help to define shortcomings and excesses in PD health care services.

Conversion from valproic acid onto topiramate in adolescents and adults with epilepsy.

OBJECTIVE: To explore efficacy and tolerability outcomes of topiramate (TPM) in patients with epilepsy transitioning from valproic acid (VPA) because of insufficient efficacy and/or tolerability onto TPM. METHODS: Multicenter, open label, single arm, non-interventional study examining patients (> or =12 years) with epilepsy, transitioning onto TPM from baseline mono-or combination therapy with VPA. TPM was added onto the existing antiepileptic drug (AED) treatment and started at a dose of 25 mg once daily. The dose was titrated up with 25 mg/day increments, once every 1-2 weeks, until a final dose between 50-200 mg/day was reached. Based on clinical judgment, the treating physician decided whether or not and when the existing AED treatment especially with VPA could be withdrawn. Documented were type and frequency of seizures, TPM dose, quality of life (QOLIE-10 questionnaire), subjective perception of improvement, and adverse events (AE). RESULTS: One hundred and forty-seven patients (59% women, mean age 41 years) switched from baseline VPA treatment onto TPM because of insufficient efficacy (61%) and/or poor tolerability (81%). Average duration of follow-up was 20.3 weeks with an overall discontinuation rate of 16.3% of patients, mainly because of AE (in 8.2% of 147 patients). At study endpoint, the intended shift to TPM monotherapy was achieved in 70% of patients at a median dose of 150 mg/day. A seizure reduction of > or =50% was achieved in 75% of patients in the last scheduled period (week 8-20), and 51% of patients entering that period remained seizure-free. Quality of life improved significantly as compared with baseline for all domains of QOLIE-10 (P < 0.001). Most frequent AEs were weight decrease (4.8%), paraesthesia and fatigue (4.1% each), speech disorder and headaches (2.7% each). CONCLUSIONS: In patients with epilepsy not satisfactorily treated with VPA, conversion to TPM was associated with improved seizure control as well as improvement in several aspects of quality of life.

Tumor necrosis factor-alpha messenger RNA expression in patients with relapsing-remitting multiple sclerosis is associated with disease activity.

We determined the cytokine messenger RNA (mRNA) expression pattern of blood mononuclear cells in 29 patients with relapsing-remitting multiple sclerosis every 4 weeks over a period of 12 months. During this period 27 relapses occurred in 14 patients (48%). Progression of disease activity as assessed by the occurrence of new lesions on nonenhancing T2-weighted magnetic resonance images of the head was detected in 12 (48%) of 25 patients. Using a semiquantitative polymerase chain reaction we demonstrated significant increases in tumor necrosis factor-alpha mRNA expression in peripheral blood mononuclear cells prior to a relapse. In 24 (85%) of 27 relapses increased tumor necrosis factor-alpha mRNA expression preceded clinical symptoms by 4 weeks. A similar pattern was observed for lymphotoxin mRNA expression. At the same time, transforming growth factor-beta and interleukin-10 mRNA levels declined. Fluctuations in the mRNA expression of tumor necrosis factor-alpha were also observed in 6 patients with stable disease who had active magnetic resonance scans on follow-up. No correlation of disease activity was observed with interleukin-1 beta, -4, or -6, inferferon gamma or endothelin-1 mRNA expression. From these data it can be concluded that variations in cytokine mRNA expression in blood mononuclear cells are correlated with disease activity in relapsing-remitting multiple sclerosis. It may be a valuable parameter to monitor the immunological status of patients in future clinical trials.

Serial analysis of circulating adhesion molecules and TNF receptor in serum from patients with multiple sclerosis: cICAM-1 is an indicator for relapse.

We determined the serum levels for circulating adhesion molecules (circulating intercellular adhesion molecule-1 [cICAM-1], circulating endothelial leukocyte adhesion molecule-1 [cELAM-1], and circulating L-selectin [cL-selectin]) and circulating tumor necrosis factor receptor (cTNF-R) p60 in 29 patients with relapsing-remitting MS serially over a period of 12 months. During this period there were 27 relapses in 14 patients (48%). There was progression of disease activity in 12/25 patients (48%), as assessed by the occurrence of new lesions on nonenhancing, T2-weighted MRIs of the head. Clinically active patients with relapse or disease progression on MRI (n = 18) had frequent fluctuations in their serum levels for cICAM-1 if compared to patients with stable MS (n = 11). There were significant differences in the cumulative cICAM-1 production between the two groups (502 +/- 218 ng/ml in active versus 225 +/- 82 ng/ml in stable MS patients; p < 0.001). cTNF-R p60 serum levels were higher in patients with stable compared to active disease (2.3 +/- 0.5 ng/ml versus 1.5 +/- 0.6 ng/ml; p < 0.005). A significant increase in cICAM-1 levels was present at the time of a relapse (799 +/- 263 ng/ml versus 449 +/- 95 ng/ml; p < 0.001), whereas the highest serum levels for cTNF-R p60 occurred 4 weeks after the onset of a relapse (1.8 +/- 0.5 ng/ml at relapse versus 2.3 +/- 0.6 ng/ml 4 weeks after a relapse; p < 0.01). Interestingly, the cL-selectin serum levels in all MS patients were significantly higher than in healthy donors, whereas there were no differences for cELAM-1. These results reflect distinct changes of inflammatory variables in serum of patients with MS and revealed that cICAM-1 is an indicator for disease activity and that high serum levels for cTNF-R p60 are associated with remission.

Cytokine mRNA levels in mononuclear blood cells from patients with multiple sclerosis.

We determined the cytokine messenger RNA (mRNA) expression pattern of blood mononuclear cells in 45 patients with the relapsing-remitting form of MS and 32 patients with other neurologic diseases. Using a semiquantitative polymerase chain reaction method, we detected significantly higher levels of tumor necrosis factor-alpha and lymphotoxin mRNA in patients with relapsing compared to those with stable disease (p < 0.001), but transforming growth factor-beta and interleukin-10 mRNA expressions were higher in patients with stable disease.

Comparative analysis of intrathecal antibody synthesis and DNA amplification for the diagnosis of cytomegalovirus infection of the central nervous system in AIDS patients.

We evaluated 49 paired cerebrospinal fluid (CSF) and serum samples of 35 patients infected with the human immunodeficiency virus type 1 (HIV-1) for laboratory evidence of cytomegalovirus (CMV) infection. The patients were grouped according to clinical criteria as probable CMV encephalitis/polyradiculomyelitis, CMV retinitis, cerebral toxoplasmosis, progressive multifocal leukoencephalopathy, HIV-1-related cognitive/motor complex, HIV-1-associated myelopathy, and other neurological diseases. Paired CSF and serum samples were analysed for CMV deoxyribonucleic acid (DNA) by polymerase chain reaction (PCR), quantitative intrathecal synthesis of immunoglobulin G (IgG) antibodies specific for recombinant phosphoprotein 150 (pp150) of CMV and CMV-specific serum IgM. Intrathecal synthesis of pp150-specific IgG was detected in 26% of patients (9/35), serum IgM was found in 23% of patients (8/35), and PCR of CSF was positive in 11% of patients (4/35). Detection of CMV-specific DNA in CSF preceded the intrathecal antibody synthesis in three patients for whom serial samples were available. PCR results of the CSF became negative in one patient with CMV polyradiculomyelitis after successful therapy with 9-[2-hydroxy-1-(hydroxymethyl) ethoxymethyl] guanine (DHPG). PCR has a higher diagnostic specificity in the acute phase of CMV infection than intrathecal antibody synthesis. The serum IgM response to CMV cannot be used to monitor a compartmentalized immune response in the central nervous system while an intrathecal immune response seems to be associated with recovery either spontaneously or as a result of treatment.

Specific diagnosis of progressive multifocal leukoencephalopathy by polymerase chain reaction.

Using polymerase chain reaction (PCR), 34 cerebrospinal fluid (CSF) samples from 28 patients with progressive multifocal leukoencephalopathy (PML) were analyzed. As controls, 116 samples were evaluated from 82 human immunodeficiency virus type 1 (HIV-1)-infected patients and 1 HIV-1-negative patient. Of the HIV-1-positive patients, 23 had cerebral toxoplasmosis, 10 had HIV leukoencephalopathy, and 49 had other neurologic complications. Detection of JC virus (JCV) DNA in CSF was increased 10-fold by the addition of carrier DNA before phenol-chloroform-isoamyl alcohol extraction. The primer pair JC 26/29, from the VP1/large T region, had a limit of detection of 10(5) JCV DNA molecules/100 microL. The primer pair JC 36/39, located in the large T gene region, had a 100-fold lower limit of detection. With JC 26/29, the sensitivity was 43% (12/28) and specificity was 100%. Using JC 36/39, sensitivity increased to 82% (23/28), and false-positive results were not observed. Diagnosis of PML is greatly aided by PCR analysis of CSF.

Progressive multifocal leukoencephalopathy diagnosed by amplification of JC virus-specific DNA from cerebrospinal fluid.

OBJECTIVE: To study the diagnostic sensitivity and specificity of polymerase chain reaction (PCR) for the non-invasive diagnosis of progressive multifocal leukoencephalopathy (PML) in HIV-1-infected individuals. DESIGN: Retrospective analysis of stored cerebrospinal fluid (CSF) samples by PCR of HIV-1-infected patients. METHODS: Results of the PCR analysis of the CSF of three AIDS patients with autopsy-proven PML were compared with the results in 15 neurologically asymptomatic HIV-1-infected patients and with 15 AIDS patients with other opportunistic infections of the central nervous system (CNS). A polyclonal antiserum to simian virus 40 (SV40) cross-reacting with JC virus (JCV) late antigens was used for immunocytochemical confirmation of the diagnosis. Two different primer pairs, one taken from the VP1/large T gene and the other from the large T gene, were used to amplify JCV-specific DNA sequences from CSF. RESULTS: Five CSF samples were analysed and JCV-specific DNA found in three patients with autopsy-proven PML. No JCV-specific DNA was detected in 47 CSF samples, including serial samples from 14 of the 30 non-PML patients. The diagnosis of PML was confirmed in all three cases by immunocytochemistry. CONCLUSION: PML can be diagnosed by PCR analysis of CSF. The sensitivity and specificity of the method depends on the sensitivity of the primers used for amplification. Using a primer pair from the large T gene, JCV-specific DNA was amplified in three cases with PML as early as the day of presentation with the first neurological symptom of PML.

Acute diffuse leukoencephalitis in HIV-1 infection.

The clinical, neuroradiological, and cerebrospinal fluid findings of a case with acute diffuse leukoencephalitis, a demyelinating disease associated with human immunodeficiency virus infection of the brain, is reported. The patient presented with acute tetraparesis as the primary manifestation of a previously symptom free HIV infection. Cerebrospinal fluid analysis showed enhanced inflammatory abnormalities with high concentrations of P24 antigen. MRI showed diffuse white matter hyper-intensities in both hemispheres. In the follow up over 22 months, the neurological deficits disappeared after antiretroviral treatment in good correlation with improvements in MRI as well as in inflammatory cerebrospinal fluid abnormalities.

Acute demyelinating disease. Classification and non-invasive diagnosis.

Five young patients are described with biopsy-proven acute demyelinating disease. Two cases are classified as Schilder's disease, a particular childhood form of multiple sclerosis (MS) with atypical clinical manifestation, normal or atypical CSF-findings and large bilateral lesions in magnetic resonance imaging (MRI). Two further cases presented with a fulminant bout of MS with typical clinical picture and CSF-findings; they are classified as Marburg's disease. The last case was an acute second bout of classical MS. The biopsy seemed to be justified in 4 cases, but unnecessary in the last case. Localized proton magnetic resonance spectroscopy (MRS) performed in one case allowed us to examine the focal cerebral abnormalities directly and non-invasively. The spectra revealed a pattern typical of acute demyelination suggesting potential for a replacement of biopsy in the future.

Impact of magnetic resonance imaging (MRI) on the epidemiology of MS.

The availability of MRI has turned out to have less impact on the epidemiology of MS than originally expected. Only 3/69 patients diagnosed between 1986 and 1990 in the epidemiologic area of South Lower Saxony (Germany) would have been missed without MRI. However in 18/50 patients the diagnostic classification changed, mostly from possible to probable MS. As we included possible cases from the beginning of our studies, the overall figures remain essentially unchanged. Epidemiologists who excluded possible cases from their surveys may experience more problems with the introduction of MRI.

The use of recombinant antigens in ELISA procedures for the quantification of intrathecally produced HIV-1-specific antibodies.

An ELISA procedure is described for the quantification of intrathecally synthesized immunoglobulin G antibodies to human immunodeficiency virus (HIV) antigens. Recombinant p17, p24, endonuclease (END), reverse transcriptase (RT), a peptide from the transmembrane region of gp41 (ENV80) and a fusion protein containing HIV-1 and HIV-2 epitopes were compared with a commercially available ELISA. Using a reference serum, antibodies in serum and cerebrospinal fluid (CSF) to all of the antigens could be measured quantitatively in a reliable and reproducible fashion. Despite the fact that the titer varied up to 10(5)-fold between CSF and serum, interassay variability ranged from 3.87% for p17 to 8.41% for RT and intra-assay variability varied from 3.9% +/- 1.2% for p17 to 14.3% +/- 3.9% for the commercial ELISA. Antibody specificity indices (ASI) obtained by relating CSF/serum titers with reference to the corresponding IgG concentrations can be used to detect intrathecal synthesis of virus specific antibodies.

Progressive inflammatory lesions of the brain parenchyma in localized scleroderma of the head.

A patient with localized scleroderma of the head, uveitis, and Raynaud's phenomenon presented with generalized seizures, spastic hemiparesis, and local IgG production in the cerebrospinal fluid. Magnetic resonance imaging revealed progressive cortical and subcortical brain parenchymal lesions mainly adjacent to the cutaneous and bony lesions and probably of inflammatory origin.

Analysis of oligoclonal antibody bands against individual HIV structural proteins in the CSF of patients infected with HIV.

Intrathecal antibody responses to HIV were investigated by a highly sensitive immunoblot assay. Serum and CSF specimens were tested for reactivity with the recombinant HIV gag proteins p15, p17 and p24 and with the recombinant transmembrane protein p41. Autochthonous production of virus-specific IgG to one or more HIV structural proteins was seen in 8 of 10 asymptomatic seropositive subjects, in 3 of 4 men with AIDS-related complex, and in 9 of 13 patients with AIDS. These results were consonant with an elevated CSF/serum antibody ratio to total HIV antigen. The high frequency of local HIV-specific antibody synthesis in seropositive individuals without related clinical symptoms indicates an early involvement of the CNS in HIV infections.

Chronic HIV encephalitis--II. Clinical aspects.

Combined medical, neurological, and serological investigations were carried out in 59 patients infected with human immunodeficiency virus (HIV). In stage I clinical and neuropsychiatric testing did not reveal evidence for HIV encephalitis as diagnosed by local antibody production in CSF. Neuropsychiatric abnormalities, brain atrophy, memory and cognitive impairment reliably indicated HIV encephalitis in later stages. The commonest symptoms were cerebellar and brainstem signs, followed by dementia. Epileptic fits and hemiparesis always were associated with cerebral toxoplasmosis. A polyneuropathy was frequently found but other causes have to be considered.

Chronic HIV encephalitis--I. Cerebrospinal fluid diagnosis.

To establish a reliable procedure for the early detection of central nervous system involvement in HIV infection, paired cerebrospinal fluid and serum samples of 59 patients were analysed. Fifteen were HIV antibody positive without clinical symptoms (stage I), 12 had lymphadenopathy syndrome or AIDS-related complex (stage II), and 32 had AIDS (stage III). Intrathecal synthesis of HIV antibodies was determined by a modified ELISA. Antibodies in CSF and serum were evaluated at identical immunoglobulin G levels to correct for the actual blood-CSF-barrier permeability. A CSF/serum quotient above 1.5 is indicative of intrathecal antibody synthesis, which was found in 47% of the patients in stage I, 67% in stage II, and 84% in stage III. These findings indicate an early and frequent invasion of the CNS.

Cerebrospinal fluid immunoglobulins and virus-specific antibodies in disorders affecting the facial nerve.

Sixty-two patients with acute idiopathic peripheral facial nerve palsy (AIPFP) and 31 patients with lymphocytic meningoradiculitis (Garin-Bujadoux or Bannwarth's syndrome) are described. Results of cerebrospinal fluid (CSF) analysis, including the measurement of immunoglobulins (Ig) G, A, and M, indicate that pleocytosis and/or disturbance of the blood-CSF barrier (BCB) and/or local immunoglobulin synthesis within the central nervous system (CNS) do occur in about 25% of patients with AIPFP. The commonest finding is a slight to moderate breakdown of BCB function without evidence of intrathecal immunoglobulin synthesis. In only about 10% of patients, further support for an inflammatory process within the CNS is found by intrathecal synthesis of oligoclonal IgG and/or localized synthesis of IgG and/or IgA. The majority of cases (75%) do not show any signs of an inflammatory process within the CNS. In contrast, lymphocytic meningopolyradiculitis (LMR) has a characteristic CSF profile with early impairment of BCB permeability as well as with rapid and predominant intrathecal IgM synthesis, which helps to distinguish monosymptomatic LMR from AIPFP. By applying a sensitive enzyme-linked immunosorbent assay to identical concentrations of IgG in serum and CSF, evidence of intrathecal synthesis of virus-specific antibodies was found only in 2 of 13 patients with AIPFP. In contrast, all 4 patients with herpes zoster oticus and peripheral facial palsy (Ramsay Hunt syndrome) showed an intrathecal IgG synthesis to varicella zoster virus lasting for up to 4 months after onset of disease.

Intracellular and intraluminal aspects of renal calculosis in the marine mollusc Macrocallista nimbosa.

The intracellular and intraluminal development of renal calculi in the bivalved mollusc Macrocallista nimbosa was investigated by histologic techniques. The origin of calculi is within the renal tubule cell. Early events involve the formation of a stone precursor into which are incorporated calcium salts, heavy metals, and mucopolysaccharides. The stone is eventually extruded into the tubule lumen where it continues to grow by epitaxy and aggregation. Various forms of calcium phosphate calculi were identified, including hydroxylapatite, whitlockite, brushite, and chlorapatite.

Diagnosis of acute and inapparent hepatitis B virus infections by measurement of IgM antibody to hepatitis B core antigen.

IgM antibody to hepatitis B core antigen (anti-HBc) was determined by a reverse enzyme immunoassay. In all of 58 patients with transient hepatitis B surface antigen (HBsAg)-positive acute hepatitis, IgM anti-HBc was detected in high titer. In 79.3%, IgM anti-HBc disappeared within two years, but in the remaining 12, it was still detectable. In 20 of 21 patients who developed chronic hepatitis, IgM anti-HBc was present after two years. High titers of IgM anti-HBc were found in 13 patients with histologically confirmed hepatitis B in whom HBsAg could not be detected in the initial serum samples; 11 of them later developed antibody to HBsAg and/or e antigen. Furthermore, IgM anti-HGc was detected in eight (5.6%) of 142 HBsAg-negative blood donors with elevated levels of serum transaminases and in 11 (0.5%) of 2,400 HBsAg-negative blood donors with normal levels of serum transaminases. Thus, IgM anti-HBc might be a better indicator of hepatitis B than HBsAg and help differentiage acute from chronic infection in HBsAg-positive patients.