Subjecting acute ischemic stroke patients to continuous tube feeding and an intensive computerized protocol establishes tight glycemic control.

INTRODUCTION: Tight glycemic control (TGC) after ischemic stroke may improve clinical outcome but previous studies failed to establish TGC, principally because of postprandial glucose surges. The aim of the present study was to investigate if safe, effective and feasible TGC can be achieved with continuous tube feeding and a computerized treatment protocol. METHODS: We subjected ten acute ischemic stroke patients with admission hyperglycemia (glucose >7.0 mmol/l (126.0 mg/dl)) to continuous tube feeding and a computerized intensive protocol with insulin adjustments every 1-2 h. Two groups of regularly fed patients from a previous study with a similar design served as controls. These groups comprised hyperglycemic patients treated according to an intermediate protocol with insulin adjustments at standard intervals (N = 13), and normoglycemic controls treated according to standard care (N = 15). The primary outcome was the percentage of time within target (4.4-6.1 mmol/l (79.2-109.8 mg/dl)). Secondary outcome was the number of patients with hypoglycemic episodes (glucose <3.0 mmol/l (54.0 mg/dl)). RESULTS: Median time within target was 55% in the continuously fed intensive group compared to 19% in the regularly fed intermediate group, and 58% in normoglycemic controls. Hypoglycemic episodes occurred in 20% of patients in the continuously fed group-lowest glucose level 2.4 mmol/l (43.2 mg/dl). In contrast, in the regularly fed group, this was 31%-lowest glucose level 1.6 mmol/l (28.8 mg/dl). CONCLUSIONS: TGC after acute ischemic stroke is feasible with continuous tube feeding and a computerized intensive treatment protocol. Although glycemic control is associated with hypoglycemia, no severe hypoglycemia occurred in the continuous tube feeding group.

EFNS guideline on the management of community-acquired bacterial meningitis: report of an EFNS Task Force on acute bacterial meningitis in older children and adults.

Acute bacterial meningitis (ABM) is a potentially life-threatening neurological emergency. An agreed protocol for early, evidence-based and effective management of community-acquired ABM is essential for best possible outcome. A literature search of peer-reviewed articles on ABM was used to collect data on the management of ABM in older children and adults. Based on the strength of published evidence, a consensus guideline was developed for initial management, investigations, antibiotics and supportive therapy of community-acquired ABM. Patients with ABM should be rapidly hospitalized and assessed for consideration of lumbar puncture (LP) if clinically safe. Ideally, patients should have fast-track brain imaging before LP, but initiation of antibiotic therapy should not be delayed beyond 3 h after first contact of patient with health service. In every case, blood sample must be sent for culture before initiating antibiotic therapy. Laboratory examination of cerebrospinal fluid is the most definitive investigation for ABM and whenever possible, the choice of antibiotics, and the duration of therapy, should be guided by the microbiological diagnosis. Parenteral therapy with a third-generation cephalosporin is the initial antibiotics of choice in the absence of penicillin allergy and bacterial resistance; amoxicillin should be used in addition if meningitis because of Listeria monocytogenes is suspected. Vancomycin is the preferred antibiotic for penicillin-resistant pneumococcal meningitis. Dexamethasone should be administered both in adults and in children with or shortly before the first dose of antibiotic in suspected cases of Streptococcus pneumoniae and H. Influenzae meningitis. In patients presenting with rapidly evolving petechial skin rash, antibiotic therapy must be initiated immediately on suspicion of Neisseria meningitidis infection with parenteral benzyl penicillin in the absence of known history of penicillin allergy.

[Pharmacological treatment of Bell's palsy: favourable effects of prednisolone-based therapy now demonstrated]. / Medicamenteuze behandeling van bell-paralyse: gunstig effect van prednisolon nu aangetoond.

Bell's palsy accounts for two-thirds ofall acute facial palsies. Presumed reactivation of the herpes simplex virus and concurrent swelling of the facial nerve prompted the use of antivirals in combination with corticosteroids, although evidence supporting the effectiveness of this approach was weak. A recently published randomized placebo-controlled clinical trial assessed the effectiveness of adding valacyclovir to prednisolone; another larger primary-care-based study compared treatment with prednisolone, acyclovir or both with placebo. In patients with severe or complete facial palsy, the addition of valacyclovir improved the chance of complete recovery, but as this study was single-blinded, results should be interpreted with caution. Early treatment with prednisolone (25 mg twice daily for to days) significantly improved the chance of complete recovery at 3 and 9 months. Acyclovir, given alone or in addition to prednisolone, did not show any benefit.

[Confusion and abnormal liver enzyme levels: problems with diagnosing hepatic encephalopathy]. / Verwardheid en afwijkende leveruitslagen: de lastige diagnose 'hepatische encefalopathie'.

3 patients with liver failure developed hepatic encephalopathy. 2 patients, men aged 60 and 72 years, had chronic liver disease and presented with episodes of confusion. They recovered after being treated with lactulose. The third patient, a 37-year-old woman, became comatose shortly after the onset of acute liver failure due to acute autoimmune hepatitis. She died before a suitable donor liver became available. Hepatic encephalopathy is a syndrome of potential reversible neurological symptoms. Especially in the early stages of the condition, hepatic encephalopathy can be difficult to diagnose. Patients may present with mild cognitive impairment or episodes characterized by neurological symptoms. Hepatic encephalopathy is a clinical diagnosis. The pathophysiologic mechanism is only partly understood but toxicity of ammonia on the central nervous system seems to be of major importance. Raised ammonia concentrations or EEG findings consistent with metabolic encephalopathy may support but are not essential to the diagnosis. Episodes of hepatic encephalopathy are often elicited by an underlying disease such as infection or gastro-intestinal bleeding. It is important to recognize hepatic encephalopathy in its early stages because adequate treatment of the condition and any underlying disease reduces morbidity and mortality.

[Arguments against the pharmacotherapy of Bells' palsy]. / Tegen medicamenteuze behandeling van Bell-paralyse.

Bell's palsy is the most frequent type of peripheral facial paresis. Its cause is unknown. The prognosis is good in 85% of patients. Based on theories about its pathogenesis, antivirals and corticosteroids have been tried. In 6 studies with antivirals and 9 with corticosteroids (most ofthe studies were methodologically flawed), the efficacy of these treatments was not demonstrated.

Guidelines for the diagnosis and management of neurological complications of HIV infection.

The spectrum of neurological complications of HIV-infection has remained unchanged through the years, but its epidemiology changed remarkably as a result of the introduction of highly active antiretroviral therapy (HAART). Guidelines for the diagnosis and treatment of cerebral toxoplasmosis, cryptococcal meningitis, progressive multifocal leukoencephalopathy, CMV encephalitis, CMV polyradiculomyelitis, tuberculous meningitis, primary CNS lymphoma, HIV dementia, HIV myelopathy and HIV polyneuropathy are given with a grading of evidence and recommendations.

[Possible etiological role retroviruses and enteroviruses in the development of amyotrophic lateral sclerosis]. / Mogelijke etiologische rol van retrovirussen en enterovirussen bij het ontstaan van amyotrofische laterale sclerose.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with unknown pathogenesis. Loss of motor neurons leads to progressive weakness and, finally, respiratory failure with a mean survival of 3 years. A possible causal role of a retroviral infection has recently been suggested by studies of 7 HIV-infected patients who developed a rapid progressive ALS-like disorder as the first manifestation of their HIV-infection. All patients stabilised or improved with antiretroviral therapy. Other research groups have published on the detection of enterovirus RNA in the spinal cords of ALS-patients, also suggesting a viral aetiology of the disease. The results of these neuro-virological studies warrant further research into the possible role of viral infections as a cause of ALS, as well as clinical trials with anti-retroviral and anti-enteroviral drugs in ALS.

Kaposi's sarcoma and human herpesvirus 8 infection do not protect HIV-1 infected homosexual men from AIDS dementia complex.

OBJECTIVE: To examine the association between Kaposi's sarcoma (KS), human herpes virus 8 (HHV8) and AIDS dementia complex (ADC). DESIGN: A total of 599 HIV-1 infected homosexual men participated in a prospective cohort study (Amsterdam, 1984-1996). METHODS: The risk for ADC in patients with prior KS or HHV8 infection was estimated using the Cox proportional hazards method with adjustments for antiretroviral medication and low CD4 cell counts. RESULTS: Of the 599 participants, 290 (48.4%) had HHV8 antibodies, 99 (16.5%) had KS and 30 (5.0%) had ADC. ADC was diagnosed in 5.2% of participants with KS and 5.0% of those without KS, and in 4.8% of HHV8 seropositive compared to 5.2% seronegative individuals and thus was not associated with KS or HHV8 infection. Using a time-dependent Cox proportional hazards analysis with the date of KS as risk factor, the risk for ADC was 2.7 [95% confidence interval (CI), 0.92-7.96; P = 0.07) and when only definite ADC was considered it was 3.5 (95% CI, 1.00-12.26;P = 0.05). After adjusting for decreases in CD4 cell count and use of medication, the hazards ratio for participants with KS to develop ADC was 2.0 (95% CI, 0.66-5.77; P = 0.23) and 2.6 (95% CI, 0.73-9.12; P = 0.14), respectively. HHV8 seropositivity, adjusted for the same variables, showed a risk for ADC of 0.85 (95% CI, 0.41-1.77;P = 0.66) and for definite ADC 0.69 (95% CI, 0.27-1.73; P = 0.42). The expected neuroprotective effects of antiretroviral medication were observed. CONCLUSIONS: KS or HHV8 does not significantly influence the risk for developing ADC in a group with a uniform risk for developing KS therefore we recommend caution in searching for a KS-associated or HHV8-derived therapy for ADC.

Diagnostic investigation of patients with chronic polyneuropathy: evaluation of a clinical guideline.

OBJECTIVE: (1) To evaluate a clinical guideline for the diagnostic investigation of patients presenting with signs and symptoms (present for longer than 6 weeks) suggesting a chronic polyneuropathy. (2) To investigate the contribution of electrophysiological studies to a focused search for aetiology in these patients. METHODS: A chart review was carried out of a consecutive group of outpatients in 1993-7 at a university department of neurology, with signs and symptoms suggesting a polyneuropathy in whom the diagnostic investigation had been carried out according to a recently introduced guideline. Diagnostic tests were performed and final diagnoses were made. RESULTS: Unnecessary investigations were carried out in 108 (51%) of 213 patients and too few tests in 23 (11%) of these patients. In 82 (48%) of the 172 patients who fulfilled the inclusion criteria neurophysiological tests did not contribute to the final diagnosis. Neurophysiological criteria for demyelination were fulfilled in only 13 (8%) of the 172 patients. CONCLUSION: In patients presenting with signs and symptoms of chronic polyneuropathy the number of tests in the diagnostic investigation can be considerably reduced. In patients with signs and symptoms of polyneuropathy, providing the clinical phenotype is typical, in the presence of diabetes mellitus, renal failure, HIV infection, alcoholism, or use of potentially neurotoxic drugs further investigations are non-contributory. The significance of electrophysiological studies in the investigation of patients with polyneuropathy is rather to separate sensorimotor neuropathies from pure sensory neuropathies than to distinguish between demyelinating and axonal neuropathies.

Durable HIV-1 suppression with indinavir after failing lamivudine-containing double nucleoside therapy: a randomized controlled trial.

OBJECTIVE: To assess the durability of the antiretroviral effect in plasma and cerebrospinal fluid (CSF) of antiviral therapy intensification, produced by the addition of indinavir from week 12 onwards to the original regimen of zidovudine/lamivudine or stavudine/lamivudine, after 72 weeks of follow-up using an ultrasensitive HIV-1 RNA assay. To assess CSF concentrations of indinavir at week 48. DESIGN: In a prospectively, randomized, open, single-centre study, antiretroviral-naive patients (CD4 cell count > or =200 cells/microl and a plasma HIV-1 RNA level 10,000 copies/ml) were assigned to a combination of zidovudine/lamivudine or stavudine/lamivudine. Indinavir could be added to the double nucleoside analogue regimen from week 12 or thereafter in case the plasma HIV RNA level was insufficiently suppressed (>500 copies/ml). RESULTS: Forty-seven patients were enrolled (23 stavudine/lamivudine and 24 zidovudine/lamivudine), of whom 33 completed a follow-up of 72 weeks. Indinavir was added in 89% (42/47) of the patients. Only one discontinuation occurred due to virological failure. At week 72, the median plasma HIV-1 RNA levels in the zidovudine/lamivudine group had decreased from 4.80 log10 copies/ml to <500 copies/ml in 100% of patients and <50 copies/ml in 86.6% of the patients. In the stavudine/lamivudine group the plasma HIV-1 RNA decreased from 4.98 log10 copies/ml at baseline to <500 copies/ml in 100% of patients and <50 copies/ml in 66.7% of the patients. On an intent-to-treat basis these figures were 54.2 and 52.2% for zidovudine/lamivudine and stavudine/lamivudine, respectively, for the 50 copies/ml assay. The median CD4 cell count increased from 315 cells/microl, with 150 cells/microl in the zidovudine/lamivudine arm, and from 290 cells/microl, with 310 cells/microl in the stavudine/lamivudine arm (P=0.0001). However, the percentage of CD4 cells did not differ in each group. In the zidovudine/lamivudine group 9/10 and 5/5, and in the stavudine/lamivudine group 11/11 and 6/6 had a CSF HIV-1 RNA level <50 copies/ml at week 12 and 48, respectively. The CSF indinavir concentration ranged from 50 to 170 ng/ml. CONCLUSION: The long-term HIV-1 suppression observed in this study is remarkable, as adding a single antiretroviral agent to a failing regimen goes against current notions of adequate therapy.

[Sensory neuropathy in HIV infection: pathogenesis and therapy]. / Sensorische neuropathie bij HIV-infectie: pathogenese en therapie.

An axonal sensory neuropathy is a frequent complication in the course of HIV infection; more than 30% of all HIV-infected individuals will develop a polyneuropathy. Low CD4 cell counts and high HIV RNA loads increase the risk. This neuropathy causes pain, paresthesias and burning sensations and/or numbness in the feet, which sometimes occurs in the hands as well. Neurological examination reveals sensory deficits in a stocking and glove distribution and depressed or absent ankle reflexes, without severe paresis. The cause of the sensory neuropathy is unknown. Either the HIV infection or certain other infections, for example cytomegalovirus, may play a role in the pathogenesis; vasculitis may be a process associated with this. Some antiretroviral drugs within the nucleoside analogue group cause a neuropathy but the pathogenesis of this remains unclear. Amitriptyline, tramadol and carbamazepine can be used for symptomatic treatment. The efficacy of lamotrigine and gabapentin has yet to be confirmed.

Concentrations of human immunodeficiency virus type 1 (HIV-1) RNA in cerebrospinal fluid after antiretroviral treatment initiated during primary HIV-1 infection.

In 6 patients with primary human immunodeficiency virus type 1 (HIV-1) infection, concentrations of HIV-1 RNA and beta(2)-microglobulin were monitored in cerebrospinal fluid (CSF) and in plasma during antiretroviral therapy. Four patients had neurological symptoms. At baseline, the CSF of 5 patients had detectable levels of HIV-1 RNA (median, 3.68 log(10) copies/mL; range, <2.60-5.67 log(10) copies/mL), and the CSF of 3 patients had elevated levels of beta(2)-microglobulin. After 8 weeks of treatment, the median concentrations of HIV-1 RNA in CSF had decreased to <2.60 log(10) copies/mL (range, <1.60-3.00 log(10) copies/mL; P=.04) and in plasma to 3.07 log(10) copies/mL (range, 2.57-3.79 log(10) copies/mL; P=.03). Median concentration of beta(2)-microglobulin in CSF had decreased to 1.2 mg/L (range, 0.9-1.7 mg/L; P=.06) and, in plasma, to 1.7 mg/L (range, 1.1-2.2 mg/L; P=.03). After 48 weeks, HIV-1 RNA concentrations in 1 patient were still 1.97 log(10) copies/mL in CSF and 1.51 log(10) copies/mL in plasma, although beta(2)-microglobulin concentrations in CSF and plasma had normalized after 8 weeks.

Cerebrospinal fluid HIV-1 RNA during treatment with ritonavir/saquinavir or ritonavir/saquinavir/stavudine.

OBJECTIVE: To assess the HIV-1-RNA response and drug concentrations in cerebrospinal fluid (CSF) and serum during treatment with saquinavir (SQV)/ritonavir (RTV) or SQV/RTV plus stavudine (d4T) in HIV-1 -infected patients. DESIGN: A multicentre, open-label, randomized controlled trial. METHODS: A total of 208 protease inhibitor (PI) and d4T-naive, HIV-1-infected patients were treated with RTV 400 mg twice daily and SQV 400 mg twice daily with or without d4T 40 mg twice daily. Intensification with reverse transcriptase inhibitors was allowed if serum HIV RNA remained above 400 copies/ml after 12 weeks. In 27 volunteers, CSF and serum HIV RNA were measured at baseline, weeks 12 and 48, using the Roche Amplicor and the ultrasensitive assay. In 22 patients, serum and CSF drug concentrations were determined at week 12. RESULTS: The median baseline serum and CSF HIV-RNA concentrations were 4.81 and 3.21 log10 copies/ml, respectively. A difference in the proportion of patients with a CSF HIV-RNA level below the limit of quantification (< LLQ) after 12 weeks was found: four out of 14 (RTV/SQV) versus 12 out of 13 (RTV/SQV/d4T) (P = 0.001). The same results were found using the ultrasensitive assay. Patients with a baseline HIV-RNA level < LLQ in CSF remained < LLQ, regardless of the treatment regimen. Treatment with RTV/SQV alone was the only independent predictor of a CSF HIV-RNA level > LLQ at week 12 in logistic regression analysis (P = 0.005). CSF RTV and SQV concentrations were < LLQ in most patients. CONCLUSION: RTV/SQV alone cannot suppress detectable CSF HIV-1-RNA levels to < LLQ after 12 weeks of treatment in the majority of patients. CSF drug concentrations of RTV and SQV < LLQ may explain the suboptimal antiretroviral effect in the CSF.

Enhanced penetration of indinavir in cerebrospinal fluid and semen after the addition of low-dose ritonavir.

OBJECTIVE: Penetration of antiretroviral drugs into anatomical HIV-1 reservoirs such as the male genital tract and the central nervous system is important. Data on indinavir (IDV) concentrations in seminal plasma are lacking and IDV concentrations in cerebrospinal fluid are at best borderline. DESIGN: Thirteen patients were treated with zidovudine (or stavudine), lamivudine, abacavir, nevirapine and IDV (1000 mg three times daily). When nevirapine led to low IDV concentrations, IDV was changed into the combination IDV/ritonavir (RTV) 800/100 mg twice daily to improve the pharmacokinetic profile of IDV. METHODS: A serum pharmacokinetic profile, a semen sample and a cerebrospinal fluid sample were collected at weeks 8, 24, 48 and 72. RESULTS: Addition of RTV increased the median IDV trough concentration in serum from 65 to 336 ng/ml (P = 0.005). Median IDV concentration in seminal plasma increased from 141 to 1634 ng/ml (P = 0.002) (n = 9) and in cerebrospinal fluid from 39 (n = 12) to 104 (n = 7) ng/ml (P < 0.001). In six patients with samples collected both before and after the addition of RTV, the IDV concentration in seminal plasma increased 8.2 times [95% confidence interval (CI) 5.2-11.6], and in cerebrospinal fluid 2.4 times (95% CI 1.8-3.9). CONCLUSIONS: IDV penetrates well into the male genital tract. The addition of low-dose RTV not only increases IDV concentrations in serum but also in seminal plasma and cerebrospinal fluid, thereby probably improving the potency of the regimen in these anatomical HIV reservoirs. Higher serum trough levels alone can not sufficiently explain the observed increases in seminal plasma and cerebrospinal fluid concentrations. Inhibition of P-glycoprotein-mediated transport by RTV might be an additional mechanism.

Epstein-Barr virus and the nervous system.

The neurological complications of Epstein-Barr virus infection include viral meningitis, encephalitis and neuromuscular complications. The introduction of cerebrospinal fluid polymerase chain reaction for Epstein-Barr virus DNA has improved diagnosis of these conditions and of primary central nervous system lymphoma in acquired immune deficiency syndrome, and has enabled cerebrospinal fluid monitoring of therapy. Prognosis remains good for most Epstein-Barr virus-related neurological complications; for primary central nervous system lymphoma in acquired immune deficiency syndrome the prognosis is still poor.

Cytarabine and highly active antiretroviral therapy in HIV-related progressive multifocal leukoencephalopathy.

We assessed survival in AIDS-related progressive multifocal leukoencephalopathy (PML) and the effect of cytarabine and antiretroviral therapy in a retrospective analysis of a series of consecutive 35 patients with AIDS-related PML in an academic AIDS referral center over 15 years. Treatment regimens consisted of highly active antiretroviral treatment (HAART), intravenous cytarabine, or both. Median survival after diagnosis in the overall series was 88 days. Patients with low CD4 cell count tended to have shorter survival. Seven patients (20%) had prolonged survival (> 1 year). Cytarabine did not affect survival. Seven patients were treated with HAART, which did not significantly improve survival. We conclude that the prognosis of AIDS-related PML is still poor, with a median survival of 3 months.

Cerebrospinal fluid beta2-microglobulin, monocyte chemotactic protein-1, and soluble tumour necrosis factor alpha receptors before and after treatment with lamivudine plus zidovudine or stavudine.

CSF levels of beta2-microglobulin (b2m), monocyte chemotactic protein-1 (MCP-1), soluble tumor necrosis factor receptors (sTNFRs), and HIV-1 RNA were determined in 16 neurologically asymptomatic HIV-1 infected patients before and 12 weeks after treatment with lamivudine plus zidovudine or stavudine. b2m levels were significantly higher in patients (1.7 mg/l) compared with controls (0.8 mg/l) (P < 0.001), and decreased to 1.1 mg/l during treatment (P = 0.001). MCP-1 levels were low, and did not change during treatment. Levels of sTNFR type I were elevated in patients (0.92 ng/ml) compared to controls (0.30 ng/ml) (P = 0.03), but did not change during treatment. Levels of sTNFR type II were below the limit of detection in most patients and controls. In conclusion, CSF levels of b2m and HIV-I RNA, but not sTNFRs or MCP-1, are candidate surrogate markers of treatment efficacy in early CNS infection.

Increasing cerebrospinal fluid chemokine concentrations despite undetectable cerebrospinal fluid HIV RNA in HIV-1-infected patients receiving antiretroviral therapy.

Only limited data on cerebrospinal fluid (CSF) HIV-1 RNA responses and markers of local inflammation in CSF during antiretroviral therapy are available. HIV-RNA, soluble tumor necrosis factor (TNF)-receptor (sTNFr)-II, monocyte chemoattractant protein (MCP)-1, and interferon-gamma-inducible protein (IP)-10 were measured in the peripheral blood and CSF of 26 antiretroviral-naive HIV-1-positive patients, who were treated with ritonavir (RTV)/saquinavir (SQV) (n = 5), RTV/SQV/stavudine (d4T; n = 8) or zidovudine (AZT)/lamivudine (3TC)/abacavir/nevirapine/indinavir (n = 13). After 8 to 12 weeks of treatment, CSF HIV-RNA dropped to <400 copies/ml in 1 of 5 patients in the RTV/SQV group, 8 of 8 patients in the RTV/SQV/d4T group, and 9 of 10 patients in the five-drug group. CSF sTNFr-II and IP-10 levels increased in patients with detectable CSF HIV-RNA. However, increases in CSF chemokine and sTNFr-II concentrations were also observed in some patients with good CSF HIV-RNA responses. Moreover, CSF MCP-1 concentrations increased in the whole population after 2 months of treatment. Ongoing residual HIV replication in the central nervous system, which cannot be detected with CSF HIV-RNA measurements, may account for this phenomenon.