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.

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.

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.

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.

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.

[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)

[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.

[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.

Transcranial color-coded duplex sonography of intracerebral hematomas in adults.

BACKGROUND AND PURPOSE: It is well established from pediatric experience and animal experiments that intracerebral blood can be demonstrated by B-mode real-time duplex scanning. This has recently become feasible in adults as well. The present study investigated the changes in the sonographic appearance of intracerebral hematomas over the course of time. METHODS: Starting in May 1991, 23 consecutive patients with intracerebral hematoma confirmed by computed tomography (21 spontaneous and 2 traumatic hematomas) were investigated within 1 year. They were monitored by repeated ultrasound scanning via the transtemporal approach. The sonographic appearance of the hematomas on B-mode scans and the angle-corrected blood flow velocity in the basal cerebral arteries were assessed. RESULTS: There was unequivocal localization of the hematoma in 18 patients (78%). In 3 cases (13%), an adequate acoustic window could not be found. One small intracerebral hemorrhage was overlooked, and one extensive hemorrhage in the basal ganglia was misdiagnosed as a lobar hematoma. There was an alteration of the appearance of the hematoma with time. This was divided into three sonographic stages (initial stage, days 1 to 5; intermediate stage, days 6 to 10; and capsular stage, from day 10). In 14 of the 20 patients with an appropriate acoustic bony echo window, the blood flow velocity in the middle cerebral artery could be measured; in 1 of these patients, the signs of increasing intracranial pressure were apparent from Doppler frequency spectrum. In 5 patients, the intracerebral hematoma could be imaged but not the ipsilateral middle cerebral artery. One female patient showed cerebral circulatory arrest at the time of examination, which took place within 24 hours after the onset of clinical symptoms. CONCLUSIONS: Most intracerebral hematomas in adults can be imaged in B-mode. Their sonographic appearance changes over the course of the disease. The advantages of this noninvasive method are its easy bedside operation and its suitability for follow-up; it is also less stressful than other imaging procedures. It yields a combination of structural and functional diagnostic information. In approximately 13% of the cases, the investigation was not feasible because of inadequate ultrasonic penetration of the intact skull.

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).

[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.

[The treatment of transitory ischemic attacks with acetylsalicylic acid: results of a double-blind-study (author's transl)]. / Behandlung transitorisch-ischämischer Attacken mit Azetylsalizylsäure Ergebnisse einer Doppelblindstudie.

In a randomised double-blind longterm study the value of acetylsalicylic acid in prophylaxis against relapse was investigated against placebo in 58 patients with transitory ischemic attacks of prolonged reversible insults. During the 24 months of observation, significantly fewer relapses of cerebral ischemia occurred in patients with carotid transient ischemia attacks under acetylsalicyclic acid than in the control group. The recurrences usually took the form of transitory ischemic attacks. Of the 5 cerebral infarcts, 4 occurred in the control group, 3 patients died. Patients with vertebrobasilar insufficiency showed no response. On account of the relatively small number of patients the result of the study is to be regarded rather as a confirmation of the results of a larger series of investigations in the USA and Canada than solely a proof of the efficacy of acetylsalicylic acid.