Doris Reichelt

Effect of a Novel Free Radical Scavenger, Edaravone (MCI-186), on Acute Brain Infarction

Edaravone, a novel free radical scavenger, demonstrates neuroprotective effects by inhibiting vascular endothelial cell injury and ameliorating neuronal damage in ischemic brain models. The present study was undertaken to verify its therapeutic efficacy following acute ischemic stroke. We performed a multicenter, randomized, placebo-controlled, double-blind study on acute ischemic stroke patients commencing within 72 h of onset. Edaravone was infused at a dose of 30 mg, twice a day, for 14 days. At discharge within 3 months or at 3 months after onset, the functional outcome was evaluated using the modified Rankin Scale. Two hundred and fifty-two patients were initially enrolled. Of these, 125 were allocated to the edaravone group and 125 to the placebo group for analysis. Two patients were excluded because of subarachnoid hemorrhage and disseminated intravascular coagulation. A significant improvement in functional outcome was observed in the edaravone group as evaluated by the modified Rankin Scale (p = 0.0382). Edaravone represents a neuroprotective agent which is potentially useful for treating acute ischemic stroke, since it can exert significant effects on functional outcome as compared with placebo.

Ischaemic Cerebrovascular Events in HIV Infection

Several case reports and series described ischaemic cerebrovascular events in HIV infection. However, the exact prevalence and the clinical features of these events are unknown. We performed a cohort study on 772 consecutive HIV infected patients and evaluated the rate of transient ischaemic attacks (TIA) and of completed stroke. A total prevalence of 1.9% for TIA (0.8%) and stroke (1.2%) was calculated resulting in an annual incidence rate of 216 per 100,000. The prevalence was highest in the later stages of the infection. Stroke patients had a poorer immunological state than the TIA and the cohort patients. Probable (n = 3) and possible (n = 2) vasculitis and cardiogenic embolism (n = 2) could be detected as aetiology, the remaining patients had a cryptogenic event. Our data suggest that ischaemic cerebrovascular events are more common in HIV infected patients than in the general population and that a part of these events might be caused by HIV associated vasculitis or vasculopathy.

Cognitive impairment in HIV infection is associated with MRI and CSF pattern of neurodegeneration.

Biomarkers as indicators for the progression of human immunodeficiency virus (HIV)‐associated neurocognitive disorders (HAND) remain still elusive. We performed a cross‐sectional study to analyze the correlation between cognitive impairment, abnormalities in magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) markers of neurodegeneration in HIV‐infected patients.

The impact of HIV infection on primary headache. Unexpected findings from retrospective, cross-sectional, and prospective analyses

Abstract Headache is one of the most important factors influencing the quality of life in patients infected with the human immunodeficiency virus type 1 (HIV). However, only symptomatic headache but not changes or primary headache types during HIV infection have been studied to date. Therefore, we aimed to determine the impact of an HIV infection on frequency and semiology of different primary headache types. Patients with confirmed HIV type 1 infection underwent a neurological examination, neuroimaging or EEG, and a standardized interview. Time pattern and symptoms of headaches (cross‐sectional analysis), changes of headaches preexisting to their infection (longitudinal retrospective analysis), and changes of primary headaches during a 2‐year follow‐up (longitudinal prospective analysis) were evaluated as were the correlations between these headache patterns and different markers of HIV infection. One hundred thirty‐one consecutive HIV‐infected patients without evidence of a cerebral manifestation except mild encephalopathy were enrolled. The point prevalence of migraine was 16.0% (confidence interval (CI) 10.1–25.4%), of headache with a semiology of tension‐type headache 45.8% (CI 33.7–62.2%), and of other headache types 6.1% (CI 3.0–12.5%). During the natural course of infection, the migraine frequency significantly decreased in the retrospective and in the prospective analyses, whereas the frequency of the headache with a semiology of tension‐type headache significantly increased in all three analyses. In 20% of all patients, the tension‐type headache could be considered as symptomatic due to the infection but not due to focal or general cerebral lesions. Changes of primary headache were significantly associated with different stages of the infection and with the presence of mild encephalopathy but not with antiretroviral treatment or CD4 cell count. HIV infection seems to be associated with a progressive decrease in migraine frequency and intensity which probably is related to the immunological state of the patients. Tension‐type headache becomes more frequent during HIV infection. However, this can in part be related to secondary headache caused by the HIV in less than 50% of patients with tension‐type headache. The progressing immunological deficiency of HIV‐infected patients seems to influence pain processing of primary headache types in different ways.

CSF Penetration by Antiretroviral Drugs

Severe HIV-associated neurocognitive disorders (HAND), such as HIV-associated dementia, and opportunistic CNS infections are now rare complications of HIV infection due to comprehensive highly active antiretroviral therapy (HAART). By contrast, mild to moderate neurocognitive disorders remain prevalent, despite good viral control in peripheral compartments. HIV infection seems to provoke chronic CNS injury that may evade systemic HAART. Penetration of antiretroviral drugs across the blood–brain barrier might be crucial for the treatment of HAND. This review identifies and evaluates the available clinical evidence on CSF penetration properties of antiretroviral drugs, addressing methodological issues and discussing the clinical relevance of drug concentration assessment. Although a substantial number of studies examined CSF concentrations of antiretroviral drugs, there is a need for adequate, well designed trials to provide more valid drug distribution profiles. Neuropsychological benefits and neurotoxicity of potentially CNS-active drugs require further investigation before penetration characteristics will regularly influence therapeutic strategies and outcome.

Prevention of AIDS dementia by HAART does not depend on cerebrospinal fluid drug penetrance.

The impact of the cerebrospinal fluid (CSF) penetrance properties of different highly active antiretroviral therapy (HAART) regimes on cognitive processing in AIDS dementia is still undetermined. We therefore designed a retrospective cross-sectional and prospective longitudinal analysis of event-related potentials in HIV-infected patients with different combinations of HAART or without antiretroviral treatment. A total of 353 consecutive patients without secondary CNS manifestation of HIV infection were enrolled in the cross-sectional study and 135 consecutive patients without secondary CNS manifestations of HIV infection were enrolled in the longitudinal study. HAART in different combinations (n = 306) or no antiretroviral treatment (n = 47) was given for at least 6 months in the retrospective cross-sectional study. HAART in different combinations (n = 110) or no antiretroviral treatment (n = 25) was given for 1 year in the prospective longitudinal study. We evaluated the latency and amplitude of the P3 component of visually evoked event-related potentials and mean choice reaction time as measures of cognitive processing. Patients receiving HAART had decreased P3 latencies as compared to those patients not receiving HAART but P3 latency and P3 amplitude were not correlated with the amount of CSF penetrance of the different HAART combinations in either statistical analysis. However, mean choice reaction time was significantly correlated with the amount of CSF penetrance. In HIV-infected patients, the CSF penetrance properties of HAART do not have any significant influence on cognitive processing as measured by event-related potentials.

Impact of Highly Active Antiretroviral Therapy on Cognitive Processing in HIV Infection: Cross-Sectional and Longitudinal Studies of Event-Related Potentials

Patients with HIV infection often complain of cognitive disturbances, which can be related to AIDS dementia or HIV-associated encephalopathy (HIVE). We investigated the impact of highly active antiretroviral therapy (HAART) in comparison with other therapeutic regimens on the progression of these cognitive disturbances as measured by visual event-related potentials (ERP). In a cross-sectional study, 214 patients without secondary neuromanifestation of their infection were divided into four groups with respect to their treatment status for 1 year before examination: (1) without antiretroviral treatment, (2) zidovudine monotherapy, (3) zidovudine in combination with didanosine, zalcitabine, or lamivudine, and (4) HAART. In a prospective longitudinal study, we divided 54 patients into three groups: (1) without antiretroviral treatment, (2) zidovudine monotherapy, and (3) HAART. Latencies of the P2, N2, and P3 components and the amplitude of the P3 component were evaluated. A significant negative correlation between CD4(+) lymphocyte cell count and P3 latency was found in all patients (p < 0.004). In the cross-sectional study, P3 latency was significantly decreased in the HAART group as compared with patients with no antiretroviral treatment (p < 0.01). During the 1-year period of the prospective longitudinal study, the P3 latency significantly increased in patients with no antiretroviral treatment (p < 0.05) and significantly decreased in patients with HAART (p < 0.05). In summary, these results suggest that HAART has an improving therapeutic effect on cognitive processing in HIV-infected patients and is superior to zidovudine monotherapy or dual antiretroviral treatment. Because prolongation of ERP might in part reflect HIVE, we conclude that this condition represents an indication for HAART.

Cidofovir (Vistide®) in der Therapie der Progressiven multifokalen Leukoenzephalopathie (PML) bei AIDS Literaturübersicht und Beschreibung zweier Fälle

ZusammenfassungDie Progressive Multifokale Leukoenzephalopathie (PML), eine durch das JC-Virus hervorgerufene Enzephalitis, tritt bei etwa 4%–5% aller HIV-1-infizierten Personen auf und hat mit einer mittleren postdiagnostischen Überlebenszeit von 3 bis 6 Monaten eine äußerst schlechte Prognose. Bis heute existiert keine effektive Therapie der PML, Therapieversuche an kleineren Kollektiven mit a-Interferon, Didanosin und Arabinosid hatten nur wenig Erfolg. In einer kontrollierten Studie mit Cytarabin konnte keine Wirksamkeit dieses Medikamentes gegen die PML beobachtet werden. Erste Einzelfallbeschreibungen über eine Therapie der PML mit Cidofovir (Vistide®), einem für die Zytomegalie-Retinitis bei AIDS-Patienten ohne renale Dysfunktion zugelassenen Nukleotid-Analogon, zeigten positive Ergebnisse. Wir berichten über zwei weitere Fälle der Behandlung einer AIDS-assoziierten PML mit Cidofovir. Von 22 in der Literatur beschriebenen Fällen einer Behandlung der AIDS-assoziierten PML mit Cidofovir – einschließlich der beiden hier beschriebenen Fälle – haben sich 16 Patienten unter der Therapie gebessert, 2 Patienten zeigten eine stabile Symptomatik und nur 4 Patienten verschlechterten sich weiterhin fulminant. Diese Ergebnisse deuten darauf hin, daß Cidofovir einen antiviralen Effekt auch auf das JC-Virus ausübt, der in der Therapie der PML bei Patienten mit AIDS genutzt werden sollte, da bisher kaum therapeutische Alternativen bestehen. Ob andere Faktoren für die klinische Verbesserung der 16 bisher beschriebenen Fälle unter einer Therapie mit Cidofovir mitverantwortlich sind oder ob die klinische Verbesserung ein alleiniger Effekt der Therapie mit Cidofovir ist, muß letztlich offen bleiben und in einer randomisierten, kontrollierten Studie mit großer Patientenzahl geklärt werden.SummaryThe progressive multifocal leukoencephalopathy (PML), a complication of the acquired immunodeficiency syndrome (AIDS) in 4%–5% of all cases, is an encephalitis caused by the JC papovavirus. The prognosis is very poor with a mean survival time after diagnosis of 3 to 6 months. No effective therapy is known to date. Therapeutic trials in small groups of patients with a-interferon, didanosine, and arabinoside were of minor success. A controlled study with cytarabine did not show any efficacy. Single case reports on a therapy with cidofovir (Vistide®), an approved nucleotide-analogone in the therapy of cytomegalovirus-retinitis in AIDS-patients without renal dysfunction, showed positive results. We describe 2 more cases of a therapy of cidofovir in AIDS-associated PML. Out of 22 cases described in the literature, including these 2 cases, with a therapy of cidofovir in AIDS-associated PML, 16 patients improved under therapy, 2 remained stable, and only 4 patients still worsened fulminantly. These results indicate an additive antiviral effect of cidofovir against JC-virus. This may be used in the therapy of PML in AIDS-patients because no alternative antiviral therapy of PML is available at present. The efficacy of cidofovir for the therapy of PML is suggested by case reports. The exact mechanisms leading to an improvement under a therapy with cidofovir in the 16 cases described so far should be evaluated in a randomised, controlled study with an adequate size of cohorts.

Sleepiness and sleep quality in patients with HIV infection.

OBJECTIVES Patients with HIV infection frequently complain of sleep disturbances and daytime sleepiness. Only few data on these problems evaluated by standardized measures is available. METHODS A sample of 180 consecutive patients with HIV infection referred to the internal and to the neurological HIV clinics at the University of Münster was enrolled in this study. The data were compared to a sample of 120 age- and sex-matched control subjects. We used the Epworth Sleepiness Scale (ESS), the Pittsburgh Sleep Quality Index (PSQI), and the Becks Depression Inventory (BDI). In addition, the clinical and immunological data of the patients were registered. RESULTS All scores of the ESS, the PSQI, and the BDI were significantly increased in the HIV infected patients as compared to the control group. There were no significant correlations between any of the immune parameters and the scores. Only a higher BDI score was correlated with both the ESS score and the PSQI score. CONCLUSIONS Patients with HIV infection and not using evavirenz show an increased daytime sleepiness and a decreased quality of sleep. These findings could not be related to the immunological state of the patients. The only specific factor influencing daytime sleepiness in HIV infected patients is probably treatment with HAART. The most important factor determining sleepiness and sleep quality in HIV infected patients is depression which was found to be independent from the immunological state and HAART of the patients.

Impact of antiretroviral treatment on AIDS dementia: a longitudinal prospective event-related potential study.

We investigated the impact of antiretroviral treatment on event-related potentials (ERP) as a possible marker of AIDS dementia. A total of 154 HIV-infected patients without central nervous system (CNS) neoplasm or opportunistic infection were examined and randomized to receive either zidovudine 500 mg/day or no antiretroviral treatment. The participants were prospectively examined by visually evoked ERP in a longitudinal design. Latencies and amplitudes of ERP were evaluated at the beginning of the study, after 1 year, and after 2 years. After 1 year, 98 patients could be analyzed, 47 of whom were taking zidovudine. In the treatment group, P3 latency was 419 +/- 55 msec at baseline and 424 +/- 52 msec at follow-up (not significant). In the patients without treatment, P3 latency was 437 +/- 42 msec at baseline and 462 +/- 53 msec at follow-up (p < .0001, Wilcoxon test). A significant inverse correlation existed between P3 latency and CD4 cell count in both groups. The increase of P3 latency in untreated patients and a stable P3 latency in treated patients could be confirmed in a subgroup analysis of 21 patients with a follow-up of three examinations in a 2-year period. Our data suggest that zidovudine has a positive impact on AIDS dementia as measured by ERP. This finding was observed in patients in different stages of HIV infection, thus suggesting that zidovudine is indicated in all stages of HIV infection to treat encephalopathy.