Timing of Mean Transit Time Maximization is Associated with Neurological Outcome After Subarachnoid Hemorrhage.

PURPOSE: Computed tomography perfusion (CTP) has gained significant relevance for the radiological screening of patients at risk of developing delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). Particularly, the impact of MTTPEAK, i.e., the maximal mean transit time value in a series of CTP measurements, for the prediction of long-term outcome has recently been demonstrated by our group. Complementing this recent work, the present study investigated how the timing of MTTPEAK affected the long-term outcome after aneurysmal subarachnoid hemorrhage. METHODS: CTP examinations from 103 patients with clinical deterioration attributed to DCI after aSAH were retrospectively analyzed for time interval between SAH ictus and onset of MTTPEAK in association with modified Rankin Scale (mRS) 23.1 months after SAH. RESULTS: Patients with unfavorable outcome (mRS > = 2) suffered significant earlier MTTPEAK onsets than patients with favorable outcome (mRS = 0 and 1). MTTPEAK within the first week was associated with significantly higher mRS scores compared to later MTTPEAK. Timing of MTTPEAK together with the value of MTTPEAK and initial World Federation of Neurosurgical Societies (WFNS) grade was a significant predictor for an unfavorable outcome (mRS > = 2). CONCLUSIONS: The current findings suggest a presumably higher vulnerability of the brain to early microcirculatory impairments after aSAH and highlight that timing of MTT elevations could be considered for the identification of patients at increased risk for poor neurological outcome due to DCI.

[Acute psychosis as a side effect of efavirenz therapy with metabolic anomalies: an important differential diagnosis of HIV-associated psychoses]. / Akute Psychose als Nebenwirkung der Therapie mit Efavirenz bei metabolischer Anomalie : Eine wichtige Differenzialdiagnose HIV-assoziierter Psychosen.

Among patients with human immunodeficiency virus (HIV) infections psychiatric disease poses a particular challenge for caregivers. Neuropsychiatric side effects of efavirenz have been described in up to 40% of patients showing dizziness, insomnia, unusual dreams, mood instability, personality alterations and thought disorders. In immigrants from Africa and South America these side effects may be related to elevated plasma concentrations of efavirenz due to polymorphisms of cytochrome P450 isozymes (especially G516T). Alleles for these polymorphisms are more frequent in African and South American patients. We report a case of a 52-year-old patient from Guinea who was referred to the department of neurology under the diagnosis of HIV-associated neurocognitive disorder (HAND). Since the start of combined antiretroviral therapy (cART) including efavirenz the patient had suffered severe personality alterations, acoustic and visual hallucinations and delusions which led to discrimination and reduced quality of life. Diagnostic procedures including magnetic resonance imaging (MRT) and spinal fluid analysis resulted in normal values and did not explain the disease. After switching to nevirapin instead of efavirenz the psychotic symptoms disappeared within 5 days.

Treatment of immigrants and residents suffering from neuro-AIDS on a neurological intensive care unit: epidemiology and predictors of outcome.

This study aimed at determining the clinical features and predictors for the outcome of patients with Neuro-Aids treated on a neurological intensive care unit (NICU) using retrospective analysis of all patients treated for Neuro-Aids in a tertiary Department of Neurology between 1996 and 2011. Chart review of the patients including the characteristics of intensive care was performed. As negative outcome, "death on the NICU or within 2 months following completion of NICU treatment" was defined. In total, 462 patients were identified of whom 87 were immigrants. 67 of all patients required NICU treatment (mean age 40.2 ± 0.8 years; 64% male). The median of the duration between diagnosis of HIV infection and the onset of treatment on NICU was 8 days for immigrants and 10 years for residents (p < 0.001). 34 of the patients on the NICU died due to severe neuromanifestations. Negative predictors for death were: (1) artificial ventilation; (2) antiretroviral-naïve immigrant; (3) primary cerebral lymphoma; (4) missing antiretroviral therapy upon admission to the NICU. Gender, age, ethnicity, CD4+ cell count, and viral load were no predictors of a negative outcome. The results indicated that the rate of death during treatment on a NICU is much higher as compared with treatment on an internal medicine ICU. A lot of research and effort will be necessary to improve this outcome especially for immigrants with Neuro-Aids.

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

BACKGROUND AND PURPOSE: 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. METHODS: We enrolled 94 patients (82 men and 12 women; mean age 45 ± 10 years) with HIV infection, but without opportunistic infections of the CNS. All patients underwent MRI and CSF analysis. The global pattern of white matter signal intensity abnormalities, the index of atrophy, the severity of periventricular white matter abnormalities, and the severity of basal ganglia signal changes were analyzed. We measured CSF markers of neurodegeneration (total tau, phospho-tau, beta-amyloid). The findings of this evaluation were correlated with demographic and infection parameters of the patients in blood and CSF. RESULTS: We found a highly significant correlation between the severity of global brain atrophy, basal ganglia signal changes, and cognitive impairment in HIV-infected patients. Furthermore, cognitive impairment was significantly correlated with total tau, but not with phospho-tau or A-beta-amyloid in CSF analysis. CONCLUSIONS: Our results confirm the significant correlation between MRI changes and cognitive impairment in HIV infection. Furthermore, we could show that global brain atrophy and signal changes in basal ganglia are the typical MRI pattern in HAND. The correlation between cognitive impairment and total tau, but not phospho-tau, supports the hypothesis that HAND are not a subtype of Alzheimer's dementia.

Depression associated with antiretroviral drug therapy in HIV: case report and overview.

Depression is the main psychiatric symptom in patients living with HIV. Genetic predisposition, stress from disease as well as the antiretroviral therapy itself are discussed as pathogenic factors. We report a 35-year-old HIV-positive man suffering from bipolar disorder who developed major depression shortly after commercing combination antiretroviral therapy (cART) on three occasions. The first two times the patient ceased therapy autonomously, and the depression disappeared completely. The close connection between cART and major depression in the present case supports the depression-inducing potential of cART. Additionally, we present an overview of literature.

[Modern CT and PET/CT imaging of the liver]. / Moderne CT- und PET/CT-Bildgebung der Leber.

Computed tomography (CT) is now widely available and represents an important and rapid method for the diagnostics of acute liver disease, characterization of focal liver lesions, planning of interventional therapy measures and postintervention control. In recent years CT has not become less important despite the increasing value of magnetic resonance imaging (MRI). By the use of different contrast medium phases good characterization of space-occupying lesions can be achieved. For the diagnostics of hepatocellular carcinoma (HCC) a triphasic examination protocol should always be implemented. The introduction of dual energy CT increased the sensitivity of imaging of hypervascularized and hypovascularized liver lesions and by the use of virtual native imaging it has become possible to avoid additional native imaging which reduces the x-ray exposition of patients. Positron emission tomography (PET) has an advantage for imaging in oncology because nearly the complete body of the patient can be screened and this is the main indication for PET/CT (whole-body staging). For purely hepatic problems 18F-fluorodeoxyglucose (FDG)-PET/CT using diagnostic CT data has a higher precision than CT alone but is inferior to MRI.

[Treatment of neuro-AIDS on a neurological intensive care unit: epidemiology and predictors of outcome]. / Behandlung von Neuro-Aids auf der neurologischen Intensivstation : Epidemiologie, Outcome und Prädiktoren des Verlaufs.

BACKGROUND: Investigations concerning the outcome for patients suffering from neuro-AIDS treated on a neurological intensive care unit and specific predictors indicating "dead" were analyzed. MATERIAL AND METHODS: A total of 56 patients with a mean age of 39 ± 0.7 years, a mean CD4+ cell count of 130 ± 166 CD4+ cells/µl and viral load of 146,520 ± 198,059 copies/ml were treated on a neurological intensive care unit due to different forms of neuro-AIDS. RESULTS: Of the patients, 34% were immigrants of whom 74% came from sub-Saharan regions. In 57% of the patients the diagnosis of HIV infection was made during therapy on the neurological intensive care unit. The median for the time between diagnosis of HIV infection and the treatment on the neurological intensive care unit was 8 days for immigrants and 10 years for residents. The most common manifestations of neuro-AIDS were cerebral toxoplasmosis, cryptococcosis and progressive multifocal leukoencephalopathy (PML). Fifty per cent of the patients (n=28) died during treatment on the neurological intensive care unit. Negative predictors for the outcome "dead" were (a) artificial ventilation, (b) antiretroviral naïve immigrant, (c) primary cerebral lymphoma and (d) missing antiretroviral therapy as a result of admission to the intensive care unit. DISCUSSION: The rate of death during treatment of neuro-AIDS on a neurological intensive care unit is much higher than during treatment of internal medicine problems of HIV infection. Antiretroviral naïve immigrants show a much higher rate of death compared to residents in Germany. A lot of research and effort is necessary to improve the availability of the Highly Active Anti-Retroviral Therapy (HAART) worldwide in order to improve the outcome especially for immigrants with neuro-AIDS treated on a neurological intensive care unit.

Gadofosveset-enhanced MR imaging for the preoperative evaluation of potential living kidney donors: correlation with intraoperative findings.

PURPOSE: The purpose of this study was to evaluate the blood pool contrast agent gadofosveset for MR angiography (MRA) of the renal vasculature in living kidney donors (LKD). MATERIALS AND METHODS: Of the 28 consecutive potential LKDs (13 men, 15 women; mean age 55.14 years ± 11.97) initially included in this prospective study, 20 patients underwent surgery and were considered for further evaluation. 7 acquisitions of a 3D T 1-weighted FLASH sequence were performed following administration of gadofosveset for the assessment of the vascular anatomy and collecting system at predefined time points at 1.5 T. All MR exams were prospectively analyzed by 2 radiologists in consensus mode prior to surgery. In addition, ROI-based relative SNR measurements were performed in the vena cava inferior and abdominal aorta. RESULTS: MR image acquisition was completed in all 20 potential living donors. In 8 donors an additional CT scan was available for further comparison with the collateral anatomy, resulting in a total of 28 analyzed kidneys. MRA disclosed 36 renal arteries, since 8 accessory arteries were found in 8 subjects. One accessory artery and one case of fibromuscular dysplasia were missed by MRA. The venous anatomy and the collecting system were assessed correctly with MRI. In addition, MRI diagnosed two renal cell carcinomas. The overall sensitivity and positive predictive value of gadofosveset-enhanced MRI on a per kidney basis were 92.9 % and 100 %, respectively. CONCLUSION: Gadofosveset enables accurate evaluation of potential LKDs.

[Cartilage quality in finger joints: delayed Gd(DTPA)²-enhanced MRI of the cartilage (dGEMRIC) at 3T]. / Knorpelqualität an den Fingergelenken: delayed Gd(DTPA)²-enhanced MRI of the cartilage (dGEMRIC) bei 3T.

PURPOSE: To evaluate the feasibility of molecular cartilage MRI in finger joints. MATERIALS AND METHODS: Delayed Gd(DTPA)²-enhanced MRI of the cartilage (dGEMRIC) using a variable flip angle approach (VFA) was performed for the metacarpophalangeal (MCP) joints II and III in nine healthy volunteers and eighteen patients with rheumatoid arthritis (RA). The cartilage thickness was measured. Additionally, dGEMRIC was performed on proximal interphalangeal joints (PIP) in two patients with finger osteoarthritis (OA). RESULTS: the dGEMRIC index of the four evaluated cartilage areas was significantly decreased in RA patients compared to healthy subjects. The dGEMRIC index of MCP II phalangeal cartilage was 389.6 ± 85.5 msec vs. 558.7 ± 74.4 msec in healthy subjects. The metacarpal MCP II cartilage dGEMRIC index was 357.3 msec ± 97.1 msec vs. 490.0 ± 86.6 msec. The dGEMRIC indices of MCP III were: phalangeal 436.2 ± 113.6 msec in RA, 558.8 ± 115.5 msec in healthy subjects and metacarpal 398.0 ± 97.6 msec in RA and 529.6 ± 111.0 msec in healthy subjects. Age and cartilage thickness were not significantly different. In PIP joints of finger osteoarthritis patients, low dGEMRIC indices were noted, compared to the controls. CONCLUSION: The dGEMRIC of finger joints is feasible in patients with RA and finger OA. Morphologically normal cartilage shows significantly decreased dGEMRIC values in RA, pointing towards cartilage degeneration on a molecular level. Further studies are needed to establish the usefulness of this technique for early diagnosis, prognosis and therapy monitoring.

Early detection of bony alterations in rheumatoid and erosive arthritis of finger joints with high-resolution single photon emission computed tomography, and differentiation between them.

OBJECTIVE: To evaluate high-resolution multi-pinhole single photon emission computed tomography (MPH-SPECT) for the detection of bony alterations in early rheumatoid arthritis (ERA), early osteoarthritis (EOA) of the fingers and healthy controls. METHODS: The clinically dominant hands of 27 patients (13 ERA, nine EOA, five healthy controls) were examined by MPH-SPECT and bone scintigraphy. Additionally, magnetic resonance imaging (MRI) was performed in the ERA patients. Number of affected joints, localisation, pattern of tracer distribution and joint involvement were scored. Quantitative analysis was achieved by measurement of the region of interest (ROI) in all patients. The MPH-SPECT and MR images were fused in the ERA group. RESULTS: Bone scintigraphy detected fewer joints (26 joints,13/22 patients) with increased tracer uptake than did MPH-SPECT (80 joints, 21/22 patients). Bone scintigraphy did not show recognisable uptake patterns in any group of patients. With MPH-SPECT central tracer distribution was typical in ERA (10/13 patients, EOA 2/9). In contrast, an eccentric pattern was found predominantly in EOA (7/9, ERA 2/13). Normalised counts were 4.5 in unaffected joints and up to 222.7 in affected joints. The mean uptake values in affected joints were moderately higher in the EOA patients (78.75, and 62.16 in ERA). The mean tracer uptake in affected joints was approximately three-times higher than in unaffected joints in both groups (ERA 3.64-times higher, EOA 3.58). Correlation with MR images revealed that bone marrow oedema and erosions matched pathological tracer accumulation of MPH-SPECT in 11/13. MPH-SPECT demonstrated increased activity in 2/13 patients with normal bone marrow signal intensity and synovitis seen on MR images. CONCLUSION: MPH-SPECT is sensitive to early changes in ERA and EOA and permits them to be distinguished by their patterns of uptake.

[Severe aseptic leucoencephalopathy. Manifested as immune reconstitution inflammatory syndrome in Caucasian and African patients]. / Schwere Leukenzephalopathie. Manifestationsform des aseptischen Immune-reconstitution-inflammatory-Syndroms bei Kaukasiern und Afrikanern.

BACKGROUND: We hypothesize that CNS immune reconstitution inflammatory syndrome (IRIS) after highly active antiretroviral therapy (HAART) in HIV-1-positive patients may become manifest without any opportunistic infection as an aseptic leucoencephalopathy. This opens a window of opportunity for successful treatment with corticosteroids. DESIGN: We describe a case series of immunocompromised HIV-1-positive patients who were started on HAART. All of them had clinical laboratory follow-up tests and cerebral MRI in order to investigate the course and the underlying pathophysiology of this aseptic form of IRIS. One African patient died and we performed a neuropathological examination. RESULTS: No infectious agent was detected before and during HAART. Three of four immunocompromised patients were successfully treated with corticosteroids while HAART was never interrupted and have survived up to now. One African patient died within 2 days despite intensive care due to cerebral oedema. CONCLUSIONS: Starting HAART, HIV-1-positive patients may develop an aseptic type of IRIS of the CNS without any detectable opportunistic infection, a finding that has not yet been published. This makes them susceptible for successful treatment with corticosteroids. Perhaps IRIS has a higher incidence in African patients and the patients have a poorer outcome than Caucasians.

[Epidemiology and therapy of pain and depression during HIV and AIDS]. / Epidemiologie und Therapie von Schmerzen und Depression bei HIV und Aids.

Pain is one of the most common reasons for admission to hospital for patients suffering from AIDS. Pain and other symptoms very often cover depressive episodes. Pain induced by AIDS therapy represents a progressive problem and induces the necessity to alter the highly active antiretroviral therapy (HAART). Of HIV-infected people 90% complain of headaches. Headache may result from opportunistic infections, from side-effects of HAART or from the HIV in the CNS itself but also the high burden of idiopathic headaches must be considered. Up to 20% of all neuropathies in HIV-infected people are caused by HAART. In most cases changing of HAART is necessary. Problems of interactions between HAART and the substances used for pain therapy via the cytochrome P450 system represents a special therapeutic problem during HAART in order to avoid development of resistance by the HIV.

[Bony pathologies of the metacarpophalangeal joints in early rheumatoid arthritis: comparison of MRI and high-resolution SPECT]. / Knöcherne Pathologien der Metacarpophalangeal-Gelenke bei früher rheumatoider Arthritis: Vergleich zwischen MRT und hochauflösender SPECT.

AIM: Comparison of MRI with a newly developed high-resolution multi-pinhole single photon emission computed tomography (MPH-SPECT) regarding the detection of bony pathologies of the metacarpophalangeal (MCP) joints in patients with early rheumatoid arthritis (ERA). MATERIALS AND METHODS: The clinically dominant hand of 15 patients with ERA (disease duration 6 months) was examined using MRI and MPH-SPECT. The evaluation of MRI was achieved according to RAMRIS criteria and for the MPH SPECT regarding pathological tracer uptake and distribution. Image fusions of MRI and MPH-SPECT were provided and the two methods were compared. RESULTS: In MRI 12 of 15 patients showed arthritic joint pathologies, while 8 patients exhibited soft tissue and bony changes. 4 patients had only soft tissue inflammation (synovitis) with a normal bone signal. In MPH-SPECT 10 of 15 patients showed pathologically increased bone metabolism. The fusion images presented a high agreement of the pathological changes in both methods, while areas with increased bone metabolism were not only present in the case of erosions, but also in the case of bone edema. In 2 patients increased bone metabolism was detectable in areas of MR tomographic normal bone, while a clear surrounding synovitis was present in each case here. CONCLUSION: The comparison of MPH-SPECT with MRI proves that the latter is a sensitive procedure for the detection of bony pathologies of MCP joints in ERA. A normal bone signal in MRI does not exclude early changes in bone metabolism in cases of severe synovialitis.

[Highly active antiretroviral therapy of neuro-AIDS. Side effects on the nervous system and interactions]. / Hochaktive antiretrovirale Therapie bei Neuro-AIDS. Nebenwirkungen auf das Nervensystem und Interaktionen.

Highly active antiretroviral therapy (HAART) has increased the mean survival time in the AIDS stage to sometimes more than 10 years. Five different groups of antiretroviral medications are known, of which integrase inhibitors and CCR5 antagonists represent the newest and most modern substances. The long AIDS survival time implies that side effects and interactions become relatively more important and must be differentiated from the symptoms of HIV itself. Side effects of HAART concern the central and peripheral nervous system and the muscles. The neurotoxicity of the components in HAART varies considerably and depends on the substance itself. Knowledge of side effects and interactions of HAART with antiepileptics, antidepressants, and analgetics are essential for the treatment of patients with neuro-AIDS.

Frequency of seizures and epilepsy in neurological HIV-infected patients.

BACKGROUND: Infection with the human immunodeficiency virus (HIV) is associated both with infections of the central nervous system and with neurological deficits due to direct effects of the neurotropic virus. Seizures and epilepsy are not rare among HIV-infected patients. We investigated the frequency of acute seizures and epilepsy of patients in different stages of HIV infection. In addition, we compared the characteristics of patients who experienced provoked seizures only with those of patients who developed epilepsy. METHODS: The database of the Department of Neurology, University of Münster, was searched for patients with HIV infection admitted between 1992 and 2004. Their charts were reviewed regarding all available sociodemographic, clinical, neurophysiological, imaging and laboratory data, therapy and outcome. Stage of infection according to the CDC classification and the epileptogenic zone were determined. RESULTS: Of 831 HIV-infected patients treated in our department, 51 (6.1%) had seizures or epilepsy. Three of the 51 patients (6%) were diagnosed with epilepsy before the onset of the HIV infection. Fourteen patients (27%) only had single or few provoked seizures in the setting of acute cerebral disorders (eight patients), drug withdrawal or sleep withdrawal (two patients), or of unknown cause (four patients). Thirty-four patients (67%) developed epilepsy in the course of their HIV infection. Toxoplasmosis (seven patients), progressive multifocal leukencephalopathy (seven patients) and other acute or subacute cerebral infections (five patients) were the most frequent causes of seizures. EEG data of 38 patients were available. EEG showed generalized and diffuse slowing only in 9 patients, regional slowing in 14 patients and regional slowing and epileptiform discharges in 1 patient. Only 14 of the patients had normal EEG. At the last contact, the majority of the patients (46 patients=90%) were on highly active antiretroviral therapy (HAART). Twenty-seven patients (53%) were on anticonvulsant therapy (gabapentin: 14 patients, carbamazepine: 9 patients, valproate: 2 patients, phenytoin: 1 patient, lamotrigine: 1 patient). Patients with only provoked seizures had no epilepsy risk factors except HIV infection, and were less likely to be infected via intravenous drug abuse. CONCLUSIONS: Seizures are a relevant neurological symptom during the course of HIV infection. Although in some patients seizures only occur provoked by acute disease processes, the majority of patients with new onset seizures eventually develops epilepsy and require anticonvulsant therapy. Intravenous drug abuse and the presence of non-HIV-associated risk factors for epilepsy seem to be associated with the development of chronic seizures in this patient group.

Comorbidity of restless legs syndrome and HIV infection.

BACKGROUND: The lifetime prevalence of restless legs syndrome (RLS) is about 10 % in the general population. The association of RLS with HIV infection is unknown. We aimed to investigate the prevalence of RLS in HIV positive patients and to define predictors. METHODS: A standardized questionnaire was presented to 228 HIV infected patients of the HIV outpatient clinic at the Department of Neurology,University of Münster, Germany. 129 patients (57% recall; 15% female, 44 +/- 9 years; mean CD4(+) cell count 333 +/- 274/microl, 82% under highly active antiretroviral treatment) were included in the statistical analysis. 100 age- and sex-matched controls (20 % female, 42 +/- 13 years) were recruited from waiting relatives of surgical patients. Beside demographic and disease-specific data, the questionnaire included the diagnostic questions for RLS and the RLS severity scale by the International RLS Study Group. Diagnosis of RLS was confirmed by experienced neurologists. RESULTS: 33.3% of the HIV infected patients and 7% of the controls (p <0.001) fulfilled the diagnostic criteria for RLS. The mean RLS severity score was higher in HIV infected patients (19.5 +/- 7.2) than in controls (7.3 +/- 1.5; p <0.001) and correlated inversely with the CD4(+) cell count (r = -0.381; p = 0.024) and the BMI (r = -0.548; p <0.001) but not with other disease-specific factors. CONCLUSIONS: HIV infected patients show a significantly higher prevalence rate for RLS than the general population. The HIV infection itself with its immunological changes and involvement of the central nervous system may predispose for a risk of RLS in HIV infected patients.

Neurophysiological abnormalities in HIV-infected long term survivors.

BACKGROUND: HIV is a neurotropic virus causing neuronal damage independent of opportunistic infections. A subgroup of patients suffer from long-term infection without developing significant disease symptoms requiring antiretroviral therapy (long-term survivors, LTS). We investigated the prevalence and severity of neurophysiological abnormalities in LTS. METHODS: The outpatient database of the Dept. of Neurology, University of Münster, was searched for HIV-infection LTS (infection for more than 9 years, no antiretroviral therapy since infection, stable CD4-positive lymphocyte count of more than 400/ul). Their neurophysiological test results (nerve conduction studies, event-related potentials, EEG) were compared to a control group of patients with similar disease duration not fulfilling the criteria for LTS. RESULTS: Sixteen LTS patients and 22 control patients were investigated. Median age at examination was 35 years. There were no significant differences between the groups regarding age, sex, duration of the disease and way of infection. By definition, CD4+-lymphocyte counts differed between LTS and both control groups. Standard nerve conduction studies of the peroneal or the sural nerve were abnormal in 1 LTS patient and 3 control patients. Sural nerve paired stimulation amplitude showed abnormal findings in 4 LTS patients and 4 control patients. P300 latency was prolonged in 4 LTS patients and 4 control patients. EEG background frequency was normal in all but one patient (LTS). There were no differences between groups regarding any of the parameters. CONCLUSION: Sensitive methods showed subtle affection of the nervous system in HIV-infected outpatients infected for more than 9 years. However, there was no difference between patients fulfilling accepted criteria of LTS, and those who did not. LTS most likely form the extreme end of a continuum of disease severity.