VACTERL with the mitochondrial np 3243 point mutation.

The VACTERL association of vertebral, anal, cardiovascular, tracheo-esophageal, renal, and limb defects is one of the more common congenital disorders with limb deficiency arising during blastogenesis. The cause is probably heterogeneous; a molecular basis has not yet been defined. We report on a family in which a female infant with VACTERL was born in 1977 and died at age 1 month due to renal failure. Because her mother and sister later developed classical mitochondrial cytopathy associated with the A-G point mutation at nucleotide position (np) 3243 of mitochondrial (mt) DNA, we performed a molecular analysis of mt DNA in preserved kidney tissue from the VACTERL case. We discovered 100% mutant mt DNA in multicystic and 32% mutant mt DNA in normal kidney tissue. Mild deficiency of complex I respiratory chain enzyme activity was found in the mother's muscle biopsy. Other maternal relatives were healthy but had low levels of mutant mt DNA in blood. This is the first report to provide a precise molecular basis for a case of VACTERL. The differing tissue pathology depending on the percentage of mutant mt DNA suggests a causal connection between the mutation and symptoms. VACTERL, and this type of multicystic renal dysplasia, are new phenotypes for the np 3243 point mutation. The possibility of a mitochondrial disorder should be born in mind and also that VACTERL may occur as a first manifestation of a mutation that has been present for generations. This would have major implications for patient management and for genetic counselling regarding both the risk of recurrence and risk of other mitochondrial syndromes in affected families.

Brain disease and molecular analysis in myotonic dystrophy.

Abnormal amplification of a CTG repeat on chromosome 19 is the molecular basis of myotonic dystrophy (DM). Expansion of the repeat has been correlated with severity of several clinical features of the disease. We performed extensive cognitive testing, cerebral magnetic resonance imaging (MRI) and a molecular analysis in 28 cases of DM to determine the relationship between the molecular defect and brain disease. Performance in two or more cognitive tests was pathological in 10 cases. Fourteen patients had subcortical white matter lesions on MRI, 14 had cerebral atrophy. Amplification of the CTG repeat showed a strong correlation with cognitive test deficits when exceeding a length of over 1000 trinucleotides. MRI lesions were associated with impaired psychometric performance, but MRI and molecular findings were only weakly related. Disease duration influenced the appearance and amount of white matter lesions on MRI. Quantification of CTG repeat size may allow an early estimate on the probability of brain involvement in DM; cognitive dysfunction is associated with white matter lesions and cerebral atrophy later on in the course.

Haemodynamic studies in early stroke.

We investigated prospectively a consecutive series of 81 patients suffering from acute middle cerebral artery (MCA) ischaemia by transcranial Doppler ultrasonography (TCD) within 24 h of the onset of symptoms. To monitor the haemodynamic changes follow-up recordings were carried out at short intervals during the next 2-3 weeks until stable haemodynamic status was achieved. In order to estimate the value of early TCD examinations in predicting the extent of brain damage seen later on, initial MCA flow reduction was correlated with infarction size and pattern on computed tomography. Fifty-three cases showed sufficient ultrasound penetration through the temporal bone. MCA flow asymmetries were recorded in 45 patients (85%); occlusion was observed in 17. Recanalization occurred in 11 patients followed by transient hyperaemia in 3, leaving residual stenosis in 2. Initial increase of flow velocities normalized within days or weeks in 7 out of 9 patients, while 2 developed residual MCA stenosis. Nineteen patients showed a considerable flow reduction on admission, which returned to normal in 9; transient hyperaemia was detected in 5 of these. Eight patients did not show any MCA flow asymmetry. Our study revealed very variable haemodynamic changes in acute stroke, which influenced further diagnostic and therapeutic management. The high rate of spontaneous recanalizations of MCA occlusions followed by transient hyperaemia in many cases has an important bearing on thrombolytic or rheological therapy. Flow velocity differences could be related to infarction pattern rather than to infarction volume. Early MCA flow asymmetry recorded by TCD within the first 24 h could not reliably predict the extent of persistent brain damage or clinical outcome.

Changes in CSF blood-brain barrier parameters in ischaemic cerebral infarction.

Total CSF protein and CSF/serum albumin and alpha 2-macroglobulin ratios as indicators of a disturbed blood-brain barrier were determined in 39 cases of ischaemic cerebral infarction proved by computed tomography (CT). About 50% of the patients had a barrier disturbance, whereat the CSF serum albumin ratio was shown to be the most sensitive parameter. A disturbed blood-brain barrier was more often found in cases of large infarction, as shown by CT, and occurred most frequently in the first 2 weeks of illness. No correlation was seen between enhancement in CT and disturbance of the blood-brain barrier.

CSF cyclic AMP and CSF adenylate kinase in cerebral ischaemic infarction.

The severity of neurological deficits, size of hypodense zone on CT, concentration of cAMP and activity of adenylate kinase in cerebrospinal fluid (CSF) were evaluated at predefined intervals in the acute stage of supratentorial cerebral ischaemic infarction in 52 patients. Patients with cerebral infarction had raised activities of adenylate kinase CSF as compared with normal persons. Patients with marked neurological deficits, only slight improvement of neurological signs and large infarction zones on CT had higher average activities of adenylate kinase and lower concentration of cAMP in CSF. Alterations of CSF adenylate kinase and CSF cAMP values were most distinct on the 3rd day after the stroke. Reasons for the changes may be metabolic disorders following brain ischaemia.

Magnetic resonance imaging of muscle and brain in myotonic dystrophy.

Myotonic dystrophy (MD) is characterized by myotonia, weakness and extramuscular symptoms, including intellectual impairment. We performed magnetic resonance imaging (MRI) of brain and muscle in 25 MD patients: 81% had cerebral atrophy (severe in 36%); 68% had focal white matter lesions, which were large and multiple in 27%. Brain MRI findings correlated with mental impairment; the severity of both correlated with disease duration. Changes in brain and muscle MRI were progressive with time, but independent of each other. Muscle MRI findings were fatty degeneration and loss of bulk. In the calves, the medial gastrocnemius muscles were involved earliest and the posterior tibial muscles relatively spared. In the thighs the vastus muscles were damaged most often and the rectus femoris least. Focal muscle damage was efficiently visualized, sometimes preceding clinical detection. Muscle MRI was less sensitive than conventional methods for early diagnosis, but ideal for follow-up, owing to its non-invasiveness and examiner-independence.

Stages and syndromes of neuroborreliosis.

To ascertain the varieties of neuroborreliosis, 330 patients were identified at the Departments of Neurology in Würzburg and Giessen from 1979 to 1994. Patients who fullfilled at least one of three strict case definitions based on clinical and laboratory criteria were included in the study. Ninety-one per cent of the patients had second-stage neuroborreliosis (duration of symptoms < or = 6 months). The most common syndrome was a painful spinal meningoradiculitis, alone (37%) or in combination with a cranial radiculitis (29%). Meningoradiculitis cranialis (9%), isolated meningitis (4%) and erythema chronica migrans-associated mono/polyneuritis (3%) were further stage II features. Central nervous system involvement occurred either as an acute meningomyelitis or meningomyeloradiculitis (5%) and meningoencephalitis or meningenocephaloradiculitis (4%). Less than 9% of the patients ran a chronic course (stage III) with a disease duration between 6 months and 9 years, either as acrodermatitis chronica atrophicans associated mono- or polyneuritis (2%) or a chronic progressive encephalomyelitis (6%). Cerebrovascular neuroborreliosis (1%) occurred in both stages; however, the primary nature of the course was a chronic one. Involvement of other organs except the skin was rare (joints 3%, heart 1%) but elevated hepatic enzymes were frequent. Our study demonstrates that neuroborreliosis has to be considered in the differential diagnosis of a wide variety of neurological conditions. Cerebrospinal fluid analysis and the search for specific intrathecal antibody production are important diagnostic procedures.

Stroke-like episodes in familial mitochondrial encephalomyopathy: clinical and biochemical aspects.

Acute episodes of focal neurological dysfunction are a well-recognized complication of the mitochondrial encephalomyopathies. Because of rapid remission, biochemical tests and other diagnostic procedures are mostly performed after the acute phase. We report the case of a patient suffering from mitochondrial disease manifesting primarily with seizures, progressive deafness and dementia, who experienced multiple stroke-like episodes. Other members of the family with evidence of mitochondrial dysfunction are presented briefly. EEG and biochemical findings in the acute stage are correlated with clinical symptoms, showing characteristics distinct from the chronic illness. The possible involvement of dietary factors in the provocation of stroke-like episodes is discussed and regulation of glucose intake suggested as a strategy in the prevention of stroke-like episodes.

[Estimation of regional cerebral blood flow with the gamma-camera (author's transl)]. / Die Bestimmung der regionalen Hirndurchblutung mit der Gammakamera

Using a computerized gamma camera regional cerebral blood flow and regional cerebral blood transit time are measured after injection of Xenon 133 and Technetium 99m respectively into the internal carotid artery. Equipment, technical procedures and methodology are described. Typical cases are presented to describe the usefullness of this procedure.

[Therapy of Lyme borreliosis]. / Therapie der Lyme-Borreliose.

Lyme Borreliosis is an infectious disorder caused directly by Borrelia burgdorferi. Secondary immunological mechanisms might play an additional pathogenetic role. The natural course of the disease in stage I and II is in most cases benign, therefore the influence of antibiotic therapy is difficult to assess. Double-blind, placebo-controlled randomized studies were performed rarely. However, by comparing untreated and treated patient groups it seems, that antibiotic therapy shortens the disease duration and prevents late complications. In stage III the course of the disease is usually chronic progressive (central nervous system, joint, skin), if no antibiotic therapy is applied. Currently performed clinical trials were up to now unable to determine the optimal antimicrobial agent, route of application, dosage and optimal duration of therapy for the different manifestations of the disease. Susceptibility testing, antimicrobial pharmacokinetic considerations (e. g. CSF penetration, half-life) and clinical experiences are therefore the basis of our recommendations. Stage I: Doxycyclin 2 x 100 mg p. o. or if contraindicated Cefuroxim 2 x 500 mg, at least 14 days. In case of systemic symptoms (e. g. fever) a intravenous therapy is indicated. Stage II and III: Ceftriaxon 1 x 2--2 x 2 g i. v. or Cefotaxim 3 x 2 g i. v., at least 14 days. Corticosteroids can be given in defined cases (pain syndrome!) additionally. Therapy failure was described regarding all used antibiotics, therefore clinical and laboratory follow up is mandatory. Residual symptoms can disappear over months and are usually not due to refractory disease.(ABSTRACT TRUNCATED AT 250 WORDS)

[Viral encephalitis. Experiences with 53 patients in Middle Hessia]. / Virale Enzephalitiden. Erfahrungen mit 53 Patienten aus Mittelhessen.

Clinical symptoms, course of disease, cerebrospinal fluid (CSF) and cranial CT of 53 patients suffering from acute or subacute encephalitis were evaluated retrospectively. The virus could be identified in 21 (39%) patients. Nine of them had herpes simplex virus-encephalitis. 16 patients, eight with herpes simplex virus-encephalitis, died due to the disease. Complete restitution could be observed in 73% of survivors. Disturbance of consciousness and severe focal neurological deficit worsened prognosis towards letality and functional recovery. Most patients had initially elevated number of cellular elements and/or pathological protein concentration in CSF. CSF protein profile showed disturbance of blood-CSF-barrier function in a great number of patients during the first week of the disease whereas autochthonous production of immunoglobulin G was observed predominantly during the second and third week. Elevated concentration of CSF-lactate was seen in herpes simplex virus-encephalitis and in letal cases. 28 (53%) patients had pathological CT-findings. Generalized brain edema, focal hypodensities, focal and cortical contrast enhancement and hemorrhagic imbibation were observed. With one exception patients with herpes simplex virus-encephalitis had hypodense lesions in the temporal lobe. Besides this CT-findings did not allow conclusions regarding the etiology of encephalitis. Prognosis of encephalitis caused by other than herpes simplex virus was worse in case of pathological CT.

[Combined nerve damage and drug-induced cutaneous embolism after faulty intragluteal injection]. / Kombinierte Nervenschäden und Embolia cutis medicamentosa nach intraglutäaler Fehlinjektion.

Injection-induced palsy of the ischiatic nerve with concomitant damage of other peripheral nerves occurred in two patients following intramuscular injection in the upper outer quarter of the large gluteal muscle. In close chronological connection skin changes developed in both cases representing drug-induced cutaneous embolism, and in one case extensive muscular necrosis was observed. In both cases the cause may be assumed to be ischaemic neuropathy following embolic occlusion of the vasa nervorum as a result of accidental intraarterial injection.

Assessment of intracranial venous hemodynamics in normal individuals and patients with cerebral venous thrombosis.

BACKGROUND AND PURPOSE: Despite ongoing improvements in noninvasive imaging techniques, transcranial color-coded duplex sonography (TCCS) has so far been used only on a limited basis in patients with cerebral venous thrombosis. We evaluated the diagnostic value of both noncontrast and contrast-enhanced TCCS by comparing normal volunteers and patients with acute cerebral venous thrombosis. METHODS: In 75 healthy volunteers (aged 45.8+/-17.4 years), normal values for the deep cerebral veins (DCVs) and the posterior fossa sinuses were established by transtemporal insonation. Eight patients with cerebral venous thrombosis were assessed by TCCS, through which the hemodynamics of the DCVs were measured, and the patients were followed-up over a period of between 33 and 387 days after examination. MR angiography served as the "gold standard" technique for confirming the venous status in all 8 patients. RESULTS: No side differences in flow velocities were detected in the paired venous structures in normal volunteers. As indirect signs of (and diagnostic criteria for) cerebral venous thrombosis, pathologically increased flow velocities or significant side differences in the DCVs were registered in 5 of the 8 patients; the other patients showed nonsignificant increases in flow velocity which decreased over time. During follow-up, the status of the posterior fossa sinuses could be diagnosed correctly in seven patients after contrast enhancement when these results were compared with those of venous MR angiography. In 1 patient, a partial recanalization was mistakenly diagnosed as an occlusion. CONCLUSIONS: TCCS allows a reliable evaluation of the major DCVs and posterior fossa sinuses. The anterior and mid portions of the superior sagittal sinus and cortical veins cannot be assessed. Increased venous blood flow velocity can be used as an indirect criterion for indicating a cerebral venous thrombosis. Clinical recovery coincided with decreases in blood flow velocity in the series of patients investigated in this study.

[Significance of lactate level, lysozyme concentration and phosphohexose isomerase activity in the cerebrospinal fluid in the differential diagnosis of meningitis]. / Die Bedeutung des Laktatspiegels, der Lysozymkonzentration und der Phosphohexose-Isomerase-Aktivität im zerebrospinalen Liquor für die Differentialdiagnose der Meningitis.

The significance of the measurement of lactate, lysozyme and PHI in CSF for differential diagnosis of meningitis was examined in 58 cases of viral, 36 of bacterial and 5 of tuberculous etiology. In the early phase of the illness CSF lactate was found to be the most sensitive parameter for distinction of viral from bacterial or tuberculous meningitis respectively. Except for one case CSF lactate exceeded 3.8 mmol/l in all cases of bacterial etiology, whereas this value was never reached in any case of viral meningitis. While lactate concentration was maximal on the day of admission and declined continuously thereafter, PHI activity reached its maximum on the third day after beginning of the therapy. At this time all patients with a bacterial or tuberculous meningitis had PHI activities about 50 U/l. This value wasn't exceeded in any case of viral meningitis. In a few cases some days after onset of therapy a distinction of bacterial meningitis from viral forms was still possible by PHI determination but not by lactate measurement. Determination of lysozyme also could be helpful in the later phase of the disease.

[Current status of transcranial color duplex ultrasound in the adult]. / Aktueller Stand der transkraniellen Farbduplexsonographie beim Erwachsenen.

Technical improvements accomplished over the last few years allow imaging of intracranial parenchymal structures as well as of basal cerebral arteries by ultrasound. Low frequency probes (2-2.5 MHz) and colour Doppler technology are required for these examinations. Recent experience in clinical practice proves that perfusion patterns in basal cerebral arteries can be depicted more accurately and with better reproducibility compared to conventional transcranial Doppler sonography. Simultaneous B-Mode imaging allows detection of cerebral haemorrhage, brain tumours and ventricular enlargement. Preliminary data on the sensitivity and specificity are promising and encourage further prospective studies.

Early outcome and recurrences after cardiogenic brain embolism.

Functional outcome and recurrence rate were evaluated retrospectively in a series of 566 consecutive patients with a cardioembolic TIA or stroke. Seventy-five patients had a TIA/RIND, 163 a minor stroke, 238 a major deficit, and 90 a fatal event. In a logistic regression analysis the probability of a disabling or fatal outcome was significantly influenced by age (p = 0.0023), a previous stroke (p = 0.0262), concomitant carotid artery disease in Doppler sonography (p = 0.0210), and the underlying heart disease (p = 0.0001). Fatal or major strokes predominated among patients with nonvalvular atrial fibrillation, prosthetic heart valves, acute or chronic myocardial infarction. Kaplan-Meier estimates revealed a cumulative risk of recurrent cerebral embolism of 2.9% within three weeks. In a proportional hazards model only the underlying heart disease was significantly linked with the risk of recurrent embolism (p = 0.021).