Results of a multinational study suggest the need for rapid diagnosis and early antiviral treatment at the onset of herpetic meningoencephalitis.

Data in the literature regarding the factors that predict unfavorable outcomes in adult herpetic meningoencephalitis (HME) cases are scarce. We conducted a multicenter study in order to provide insights into the predictors of HME outcomes, with special emphasis on the use and timing of antiviral treatment. Samples from 501 patients with molecular confirmation from cerebrospinal fluid were included from 35 referral centers in 10 countries. Four hundred thirty-eight patients were found to be eligible for the analysis. Overall, 232 (52.9%) patients experienced unfavorable outcomes, 44 died, and 188 survived, with sequelae. Age (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.02 to 1.05), Glasgow Coma Scale score (OR, 0.84; 95% CI, 0.77 to 0.93), and symptomatic periods of 2 to 7 days (OR, 1.80; 95% CI, 1.16 to 2.79) and >7 days (OR, 3.75; 95% CI, 1.72 to 8.15) until the commencement of treatment predicted unfavorable outcomes. The outcome in HME patients is related to a combination of therapeutic and host factors. This study suggests that rapid diagnosis and early administration of antiviral treatment in HME patients are keys to a favorable outcome.

Successful use of tocilizumab and casirivimab/imdevimab in a twin pregnancy with critical COVID-19 - A case report.

COVID-19 in pregnancy is associated with increased maternal morbidity and mortality as well as higher risk for hospitalization in intensive care unit and mechanical ventilation. We present a 38-year-old 21+5week pregnant unvaccinated woman with twins and critical COVID-19 pneumonia caused by Delta SARS-CoV-2 strain. Because of rapid worsening of respiratory condition despite standard of care treatment with steroids, she received a combination of casirivimab/imdevimab and tocilizumab. After therapy we noticed respiratory improvement and after 10 days she was extubated. Due to selective fetal growth restriction of one of the twins, a planned caesarean section was performed at 34+6 weeks. Presented case indicates favorable outcome and safe use of casirivimab/imdevimab and tocilizumab in critical COVID-19, as no severe or minor signs or symptoms in the case presentation were observed neither in the mother nor in infants during the time of observation.

Herpesviridae and Atypical Bacteria Co-Detections in Lower Respiratory Tract Samples of SARS-CoV-2-Positive Patients Admitted to an Intensive Care Unit.

Shortly after the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), cases of viral, bacterial, and fungal coinfections in hospitalized patients became evident. This retrospective study investigates the prevalence of multiple pathogen co-detections in 1472 lower respiratory tract (LRT) samples from 229 SARS-CoV-2-positive patients treated in the largest intensive care unit (ICU) in Slovenia. In addition to SARS-CoV-2, (rt)RT-PCR tests were used to detect cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), varicella zoster virus (VZV), and atypical bacteria: Chlamydia pneumoniae, Mycoplasma pneumoniae and Legionella pneumophila/spp. At least one co-detection was observed in 89.1% of patients. EBV, HSV-1, and CMV were the most common, with 74.7%, 58.1%, and 38.0% of positive patients, respectively. The median detection time of EBV, HSV-1, and CMV after initial SARS-CoV-2 confirmation was 11 to 20 days. Bronchoalveolar lavage (BAL) and tracheal aspirate (TA) samples showed equivalent performance for the detection of EBV, CMV, and HSV-1 in patients with both available samples. Our results indicate that SARS-CoV-2 infection could be a risk factor for latent herpesvirus reactivation, especially HSV-1, EBV, and CMV. However, additional studies are needed to elucidate the clinical importance of these findings.

Adult patients with tetanus in Slovenia 2006-2021 : Results of a national cohort study.

INTRODUCTION: The aim of the present study was to determine the demographic, epidemiological and clinical characteristics of adult patients with tetanus in Slovenia between 2006 and 2021, as well as to determine the therapeutic approaches which have been successfully used in the intensive care unit (ICU) of the Infectious Diseases Department in the University Medical Centre Ljubljana (UMC). METHODS: We included all adult patients who were treated for tetanus in the ICU of the Department of Infectious Diseases Ljubljana between January 1st, 2006, and December 31th, 2021, in the retrospective study. Available epidemiological and clinical characteristics were reviewed from the medical documentation. RESULTS: There were 31 patients included in the study, four (12.9%) males and 27 (87.1%) females. The vast majority of patients required mechanical ventilation (MV) (87.1%) which lasted (±â€¯SD) on average 35.4 ±â€¯16.0 days. Autonomic dysfunction was present in 29 (93.5%) patients and was statistically significantly associated with shorter disease evolution (p = 0.005) and presence of healthcare-associated infection (p = 0.020). During the hospitalization, 27 (87.1%) patients acquired at least one healthcare-associated infection, most commonly ventilator-associated pneumonia. The average length of stay in the ICU (±â€¯SD) was 42.5 ±â€¯21.3 days. With increasing age, MV lasted statistically significantly longer (p = 0.001), length of stay was longer (p = 0.015), and healthcare-associated infections occurred (p = 0.003) more frequently. Four patients (12.9%) died. CONCLUSIONS: Although the tetanus incidence rate in Slovenia is high in comparison to other European countries on average, our therapeutic approach resulted in a good survival rate and low mortality.

The role of high-income countries in the establishment and development of modern critical care in low resource settings: A Slovenian model.

BACKGROUND: Critical care medicine is a young branch of medicine, of which the development was much faster in High Income Countries (HICs) than in Low Resources Settings (LRS). Slovenia, as one of the successor states of former Yugoslavia, passed the process of transition and joined the European Union successfully. On the contrary, Bosnia and Herzegovina (B&H) went through the extremely difficult process of transition (four years of civil war), which left a deep scar to the healthcare system, including critical care medicine. OBJECTIVE: To examine the impact of HICs on the development of critical care in LRS. METHOD: This review examined the process of growing up the first modern Medical Intensive Care Unit (MICU) in the Republic of Srpska. RESULTS: The five-year process of transferring critical care knowledge from Slovenia to the health care system of Republic of Srpska has contributed to the existence of modern and state of the art MICU with tremendous social effects. CONCLUSION: The model of using the impact of HICs for improving critical care in LRS can be extrapolated to other similar settings.

Severe human granulocytic anaplasmosis transmitted by blood transfusion.

A 36-year-old woman acquired severe human granulocytic anaplasmosis after blood transfusion following a cesarean section. Although intensive treatment with mechanical ventilation was needed, the patient had an excellent recovery. Disease caused by Anaplasma phagocytophilum infection was confirmed in 1 blood donor and in the transfusion recipient.

Necrotizing fasciitis caused by Serratia marcescens after venous access port implantation in a child with acute lymphoblastic leukemia.

Necrotizing fasciitis is a potentially life-threatening infection of deep skin layers and subcutaneous tissues that can easily spread across the fascia plate and is usually the result of a combined infection with anaerobic and aerobic microorganisms. The patient typically complains of excruciating pain, which is not necessarily in accordance with clinical signs. Early recognition of the condition is very important, and aggressive treatment with a combination of antibiotics and surgical procedure is crucial. We present a case of a 15-year-old girl with acute lymphoblastic leukemia who developed necrotizing fasciitis after venous access port implantation during induction chemotherapy.

The Predictive Value of Oxidative Stress Index in Patients with Confirmed SARS-COV-2 Infection.

Disbalance balance between oxidants and antioxidants is called oxidative stress and could be presented as oxidative stress index (OSI). OSI is determined by the reactive oxygen metabolites (d-ROM test) to assess oxidants and the plasma antioxidant capacity test (PAT test) to measure antioxidants. The aim of the study was to evaluate the predictive value of OSI in the disease COVID-19. d-ROMs results were the highest in the SARS-CoV-2 POSITIVE group (365+/-112), lower in the SARS-CoV-2 NEGATIVE group (314+/-72.4), and the lowest in an INTENSIVE CARE UNIT group (ICU) (277+/-142) U.Carr. PAT test values were the lowest in the SARS-CoV-2 POSITIVE group (2762+/-387), higher in the ICU group (2772 +/-786), and the highest in the SARS-CoV-2 NEGATIVE group (2808+/-470), and are not statistically significantly different (P>0.05), while OSI was: healthy with average value of 49 and the critical ill with average value of 109 (P = 0.016). Cut-offs for predicting ICUs admission was at OSI 62, with 80.0% sensitivity and 68.2% specificity.

Effect of CytoSorb Coupled with Hemodialysis on Interleukin-6 and Hemodynamic Parameters in Patients with Systemic Inflammatory Response Syndrome: A Retrospective Cohort Study.

Excessive release of cytokines during systemic inflammatory response syndrome (SIRS) often leads to refractory hypotension and multiple organ failure with high mortality. Cytokine removal with hemoadsorption has emerged as a possible adjuvant therapy, but data on interleukin-6 (IL-6) reduction and outcomes in clinical practice are scarce. We aimed to evaluate the effect of CytoSorb hemoadsorption on laboratory and clinical outcomes in shocked patients with SIRS. We designed a retrospective analysis of all patients with SIRS treated with CytoSorb in intensive care units (ICU). IL-6, laboratory and hemodynamic parameters were analyzed at approximate time intervals during CytoSorb treatment in the whole cohort and in a subgroup with septic shock. Observed and predicted mortality rates were compared. We included 118 patients with various etiologies of SIRS (septic shock 69%, post-resuscitation shock 16%, SIRS with acute pancreatitis 6%, other 9%); in all but one patient, CytoSorb was coupled with renal replacement therapy. A statistically significant decrease in IL-6 and vasopressor index with an increase in pH and mean arterial pressure was observed from 6 h onward. The reduction of lactate became significant at 48 h. Results were similar in a subgroup of patients with septic shock. Observed ICU and in-hospital mortalities were lower than predicted by Sequential Organ Failure Assessment (SOFA) (61% vs. 79%, p = 0.005) and Acute Physiology and Chronic Health Evaluation (APACHE) II (64% vs. 78%, p = 0.031) scores. To conclude, hemoadsorption in shocked patients with SIRS was associated with a rapid decrease in IL-6 and hemodynamic improvement, with improved observed vs. predicted survival. These results need to be confirmed in a randomized study.

The effects of antibiotic cycling and mixing on acquisition of antibiotic resistant bacteria in the ICU: A post-hoc individual patient analysis of a prospective cluster-randomized crossover study.

BACKGROUND: Repeated rotation of empiric antibiotic treatment strategies is hypothesized to reduce antibiotic resistance. Clinical rotation studies failed to change unit-wide prevalence of antibiotic resistant bacteria (ARB) carriage, including an international cluster-randomized crossover study. Unit-wide effects may differ from individual effects due to "ecological fallacy". This post-hoc analysis of a cluster-randomized crossover study assesses differences between cycling and mixing rotation strategies in acquisition of carriage with Gram-negative ARB in individual patients. METHODS: This was a controlled cluster-randomized crossover study in 7 ICUs in 5 European countries. Clinical cultures taken as routine care were used for endpoint assessment. Patients with a first negative culture and at least one culture collected in total were included. Community acquisitions (2 days of admission or less) were excluded. Primary outcome was ICU-acquisition of Enterobacterales species with reduced susceptibility to: third- or fourth generation cephalosporins or piperacillin-tazobactam, and Acinetobacter species and Pseudomonas aeruginosa with reduced susceptibility for piperacillin-tazobactam or carbapenems. Cycling (altering first-line empiric therapy for Gram-negative bacteria, every other 6-weeks), to mixing (changing antibiotic type every empiric antibiotic course). Rotated antibiotics were third- or fourth generation cephalosporins, piperacillin-tazobactam and carbapenems. RESULTS: For this analysis 1,613 admissions were eligible (855 and 758 during cycling and mixing, respectively), with 16,437 microbiological cultures obtained. Incidences of acquisition with ARB during ICU-stay were 7.3% (n = 62) and 5.1% (n = 39) during cycling and mixing, respectively (p-value 0.13), after a mean of 17.7 (median 15) and 20.8 (median 13) days. Adjusted odds ratio for acquisition of ARB carriage during mixing was 0.62 (95% CI 0.38 to 1.00). Acquired carriage with ARB were Enterobacterales species (n = 61), Pseudomonas aeruginosa (n = 38) and Acinetobacter species (n = 20), with no statistically significant differences between interventions. CONCLUSIONS: There was no statistically significant difference in individual patients' risk of acquiring carriage with Gram-negative ARB during cycling and mixing. These findings substantiate the absence of difference between cycling and mixing on the epidemiology of Gram-negative ARB in ICU. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov, registered 10 January 2011, NCT01293071.

Procalcitonin in hantavirus infections.

In hantavirus infections levels of serum leukocytes or C-reactive protein are usually elevated to levels found in serious bacterial infections. However, procalcitonin in patients infected with hantavirus has not yet been discussed in the literature. A total of 29 adult patients with hantavirus infection, 30 with sepsis, and 19 with tick-borne encephalitis were included in this observational retrospective study. The median procalcitonin level in patients with hantavirus infection was 0.53 µg/L (range 0.09-11.71 µg/L), in the group with sepsis 4.33 µg/L (range 0.08-161.1 µg/L) and in patients with viral meningitis 0.08 µg/L (range 0.05-0.12 µg/L). The difference between all three groups was statistically significant (p < 0.001). A higher procalcitonin level was found in patients with hemorrhagic fever with renal syndrome caused by Dobrava virus (0.74 µg/L; range 0.09-2.83 µg/L) than in those with Puumala virus infections (0.50 µg/L; range 0.10-11.71 µg/L). However, the difference was not statistically significant (p = 0.895). This study confirmed previous findings demonstrating the association of elevated procalcitonin with bacterial infection. However, increased procalcitonin serum level was also found in hantavirus infections with overlapping results between viral and severe bacterial infections.

Micafungin for Candida infections in Slovenia and Romania: A multicenter, observational, prospective study.

INTRODUCTION: An echinocandin, such as micafungin, is recommended as first-line treatment for invasive Candida infections in immunocompromised patients. This multicenter, observational, prospective, non- interventional study evaluated the real-world use of micafungin in clinical practice in Slovenia and Romania, as this remains unexplored. METHODOLOGY: The primary endpoint was evaluation of micafungin use, including rationale for prescription, treatment duration, and daily dose. Secondary endpoints included recordings of patient baseline characteristics and evaluations of efficacy and safety. Across 11 centers in two countries, 118 patients (18 children [< 16 years] and 100 adults [≥ 16 years]) received micafungin for the first time according to their clinic's standard practice. RESULTS: Micafungin was prescribed for treatment in 57.6% of patients and for prophylaxis in 40.7% of patients. The median (range) treatment duration was 9.0 (0 - 54) days and 13.0 (2 - 6)] days, respectively. The median dose of micafungin was higher than recommended for children receiving prophylaxis or treatment for invasive candidiasis and for adults receiving prophylaxis. Fever was the most commonly observed clinical sign at baseline (16 children [88.9%] and 31 adults [31%]) and hematologic malignancy was the most frequent primary diagnosis at admission (11 children [61.1%] and 40 adults [40%]). Candida species were the most commonly identified causal agents of invasive fungal infections (2 children [11.1%] and 48 adults [48%]). CONCLUSIONS: The efficacy and safety profiles of micafungin use in Slovenia and Romania based on clinician's own experiences in local clinical practice were consistent with those reported in other real-world studies.

Severe immune thrombocytopenia in a critically ill COVID-19 patient.

The novel coronavirus SARS-CoV-2 can cause a severe and even fatal respiratory illness named COVID-19. Apart from respiratory failure, COVID-19 may be associated with various autoimmune complications. We present a case of a critically ill patient with COVID-19 who developed severe immune thrombocytopenia that was successfully treated with a concomitant use of corticosteroids and intravenous immunoglobulins.

Usefulness of presepsin as diagnostic and prognostic marker of sepsis in daily clinical practice.

INTRODUCTION: Sepsis represents a major cause of morbidity and mortality in critically ill patients. Early diagnosis and appropriate treatment have a crucial influence on survival. The aim of this study was to evaluate the diagnostic and prognostic role of presepsin (sCD14) in patients with sepsis. METHODOLOGY: Fifty-four consecutive adult patients with sepsis and 26 patients with aseptic meningitis as a control group were included in this prospective observational study. In all patients included in the study, levels of C-reactive protein (CRP), presepsin, lactate, and a count of leukocytes and neutrophils were determined on admission. In those with suspected bacterial infection, two separate blood cultures were obtained and procalcitonin (PCT) concentration was detected. Plasma presepsin and PCT concentrations in septic group patients were followed on days 2, 3 and 7 after enrollment. RESULTS: The median presepsin serum concentration in patients with sepsis was 1614 pg/mL and in the control group it was 203 pg/mL (p < 0.001). Presepsin levels in patients with septic shock were higher than in sepsis patients (p < 0.014). The mean presepsin concentrations were higher in deceased than in surviving patients (p = 0.009). The trend of changes in presepsin concentrations in deceased patients was significantly different than in the surviving patients (p = 0.018). There were no statistically significant differences in the concentration of presepsin or other biomarkers in patients with Gram negative or Gram positive bacteria. CONCLUSIONS: Presepsin may be used as a diagnostic marker of systemic bacterial infection and can predict the severity and outcome of sepsis.

Severe Clostridium difficile-associated disease in children.

Three cases of Clostridium difficile-associated disease in children were detected within a short time interval. Intensive therapy was required in 2 cases with colectomy in one of them. One of the severe cases was community-acquired. Two patients had underlying diseases (Hirschprung disease, Down syndrome) and also tested positive for enteric viruses (rotavirus, calicivirus).

The effects of antibiotic cycling and mixing on antibiotic resistance in intensive care units: a cluster-randomised crossover trial.

BACKGROUND: Whether antibiotic rotation strategies reduce prevalence of antibiotic-resistant, Gram-negative bacteria in intensive care units (ICUs) has not been accurately established. We aimed to assess whether cycling of antibiotics compared with a mixing strategy (changing antibiotic to an alternative class for each consecutive patient) would reduce the prevalence of antibiotic-resistant, Gram-negative bacteria in European intensive care units (ICUs). METHODS: In a cluster-randomised crossover study, we randomly assigned ICUs to use one of three antibiotic groups (third-generation or fourth-generation cephalosporins, piperacillin-tazobactam, and carbapenems) as preferred empirical treatment during 6-week periods (cycling) or to change preference after every consecutively treated patient (mixing). Computer-based randomisation of intervention and rotated antibiotic sequence was done centrally. Cycling or mixing was applied for 9 months; then, following a washout period, the alternative strategy was implemented. We defined antibiotic-resistant, Gram-negative bacteria as Enterobacteriaceae with extended-spectrum ß-lactamase production or piperacillin-tazobactam resistance, and Acinetobacter spp and Pseudomonas aeruginosa with piperacillin-tazobactam or carbapenem resistance. Data were collected for all admissions during the study. The primary endpoint was average, unit-wide, monthly point prevalence of antibiotic-resistant, Gram-negative bacteria in respiratory and perineal swabs with adjustment for potential confounders. This trial is registered with ClinicalTrials.gov, number NCT01293071. FINDINGS: Eight ICUs (from Belgium, France, Germany, Portugal, and Slovenia) were randomly assigned and patients enrolled from June 27, 2011, to Feb 16, 2014. 4069 patients were admitted during the cycling periods in total and 4707 were admitted during the mixing periods. Of these, 745 patients during cycling and 853 patients during mixing were present during the monthly point-prevalence surveys, and were included in the main analysis. Mean prevalence of the composite primary endpoint was 23% (168/745) during cycling and 22% (184/853) during mixing (p=0·64), yielding an adjusted incidence rate ratio during mixing of 1·039 (95% CI 0·837-1·291; p=0·73). There was no difference in all-cause in-ICU mortality between intervention periods. INTERPRETATION: Antibiotic cycling does not reduce the prevalence of carriage of antibiotic-resistant, Gram-negative bacteria in patients admitted to the ICU. FUNDING: European Union Seventh Framework Programme.

Usefulness of procalcitonin to differentiate typical from atypical community-acquired pneumonia.

BACKGROUND: The value of elevated serum procalcitonin concentration for differentiating between typical and atypical community-acquired pneumonia was assessed and compared with other parameters that are usually used in clinical practice. PATIENTS AND METHODS: Thirty consecutive adult patients with community-acquired bacterial pneumonia admitted to the Department of Infectious Diseases, University Medical Center Ljubljana, Slovenia, were included in this prospective study. Only those patients for whom the etiology of bacterial pneumonia was confirmed participated in the study. RESULTS: The median serum procalcitonin level in patients with typical pneumonia was 7.64 ng/ml (range 0.26-63.16) and in the group with atypical pneumonia 0.80 ng/ml (range 0.13-34.90). A significant difference between the typical and atypical pneumonia groups was found only for the procalcitonin serum concentration on admission. The standard laboratory markers of bacterial infections, such as C-reactive protein, total leukocyte count and immature polymorphonuclear cells, did not discriminate between typical and atypical etiology. Median procalcitonin levels were significantly higher among patients with bacteremic pneumonia. CONCLUSIONS: Determination of the procalcitonin level may provide useful additional diagnostic information on the etiology of pneumonia and could have a crucial influence on the initial antimicrobial therapy.

Severe tick-borne encephalitis in Slovenia in the years 2001-2005: time for a mass vaccination campaign?

The aim of this retrospective study was to assess some clinical, epidemiological and laboratory parameters of severe tick-borne encephalitis in Slovenia in the last five years, to compare them with published data, and to estimate need for providing a policy of active immunization. Thirty-three adult patients with a severe course of the disease, admitted to the intensive care unit of the Department of Infectious Diseases, University Medical Centre Ljubljana, Slovenia during a five year period, participated. All the patients had specific serum IgM antibodies against tick-borne encephalitis virus at admissions and IgG antibodies were present in 29 out of 33 patients. Twenty-two patients were admitted because of severe consciousness disturbances, nine suffered from spinal nerve paralysis, in two patients cranial nerve paralysis was observed, and one suffered from generalized tonic-clonic seizures. Ten patients were mechanically ventilated and three died. Leukocytosis in peripheral veins was found in twenty-one patients and nine had a C-reactive protein serum concentration over 50 mg/l. Nineteen patients had a cerebrospinal fluid leukocyte count exceeding 100 x 10(6)/l and a cerebrospinal fluid protein concentration was over the cut-off value of 0.45 g/l in majority. The findings of the present study confirmed some previous reports about clinical, epidemiological and laboratory characteristics of patients with severe tick-borne encephalitis. We have found that tick-borne encephalitis in Slovenia has a relatively low fatality rate. However, the severe course with long-lasting sequelae of the disease justifies vaccination of a risk population in endemic areas.

Herpes simplex virus infection limited to the brainstem.

Focal meningoencephalitis is commonly caused by Herpes simplex virus infection, which typically affects temporal or frontal lobes, and carries a mortality rate of 70% if untreated. On rare occasions, however, the infection is restricted to the brain stem. Polymerase chain reaction analysis of cerebrospinal fluid is the gold standard for the diagnosis of herpes simplex encephalitis. A 46-year-old male was admitted to the hospital with a three-day history of headache and fever up to 39 degrees C. Cerebrospinal fluid findings were in accordance with aseptic meningitis. On the third hospital day, the patient presented with double vision followed by confusion, and gaze paresis developed. The condition rapidly progressed from stupor to coma. A second examination of cerebrospinal fluid revealed a low glucose level (1.2 mmol/l) and cefotaxime with ampicillin were started empirically. All cerebrospinal fluid specimens were negative for bacteria and fungi. Serum IgG antibodies for herpes simplex virus type 1 were found with no intrathecal specific antibody synthesis. A polymerase chain reaction analysis of cerebrospinal fluid sample performed on the seventh day of his illness was negative for herpes simplex virus 1 and 2. A computer tomography scan of the brain did not show any abnormality. Despite antimicrobial and supportive intensive care, the condition of the patient progressively deteriorated and he died on the 11th day after admission. An autopsy revealed hemorrhagic and necrotic brainstem meningoencephalitis, and herpes simplex virus type 1 infection was confirmed by hybridization in situ. Herpes simplex virus encephalitis carries a mortality rate of 70% if untreated. The atypical location of the infection, as well as an atypical clinical manifestation with negative radiological and microbiological tests, could be the reasons for false diagnoses and mistreatment. Many authors advocate the use of empiric acyclovir in any patients with unexplained encephalopathy, since delay in treatment may greatly affect outcome. We describe a patient who died due to a herpes simplex virus 1 encephalitis affecting the brainstem, where nucleic acids were found post mortem by in situ hybridization. On rare occasions, the herpes simplex viral infection, as well as clinical manifestations and pathological changes, is restricted solely to the brainstem.