[Hereditary transthyretin amyloidosis]. / Hereditäre Transthyretin-Amyloidosen.

Hereditary amyloidosis is an autosomal dominant fatal multisystem disease caused by extracellular deposition of misfolded proteins and, therefore represents a hereditary protein folding or deposition disease that leads to progressive organ damage and eventually death. In most instances mutations within the transthyretin gene are the underlying cause. The main manifestation is a rapidly progressing axonal sensorimotor and autonomic polyneuropathy (familial amyloid polyneuropathy, FAP). Cardiac involvement is frequent in FAP and additional manifestations include the gastrointestinal tract and the eyes. A second manifestation type is cardiomyopathy with little or no polyneuropathy (familial amyloid cardiomyopathy, FAC). For therapy, orthotopic liver transplantation has been established for 25 years. Recently, the oral agent tafamidis, a transthyretin stabilizer, was licensed for treatment of stage 1 polyneuropathy. Additional treatment options are currently being studied.

[Critical illness myopathy in intensive care patients. Pathogenetic concepts and clinical management]. / "Critical illness myopathy" bei Intensivpatienten. Pathogenetische Konzepte und klinisches Management.

Intensive care patients are at increased risk of developing sepsis with multi-organ failure during treatment (severe sepsis) possibly leading to complications of the central and peripheral nervous system. Among these, septic encephalopathy, critical illness polyneuropathy (CIP) and critical illness myopathy (CIM) are the most important. Neuromuscular complications in particular are difficult to diagnose as they mostly become apparent only when sedation has ceased and the awakening patient experiences difficulties in weaning from the respirator and reduced voluntary strength. CIP and CIM are generally self-limiting, however, they greatly prolong ICU stay and rehabilitation, thus nowadays also imposing a real budget threat. The diagnostics, especially the differentiation between CIM and CIP is difficult and a multi-disciplinary approach involving ICU physicians, anesthetists and neurologists is needed. Our knowledge of the causes of the primary ICU myopathy, although rapidly evolving during recent years, is still in its infancy and specific treatment of CIM is not yet available. The present overview summarizes insights into clinical and new diagnostic strategies for early detection of neuromuscular dysfunction in ICU patients. This article focuses on current concepts and results revealing the pathomechanism(s) of CIM and some simple therapeutic or preventive measures have been deduced which are summarized and discussed.

[Interdisciplinary guidelines on diagnosis and treatment for extracerebral amyloidoses--published by the German Society of Amyloid Diseases (www.amyloid.de)]. / Interdisziplinäre Leitlinien zur Diagnostik und Therapie der extrazerebralen Amyloidosen--Herausgegeben von der Deutschen Gesellschaft für Amyloid-Krankheiten e.V (www.amyloid.de).

Within the past 10 years, a new range of knowledge has been achieved in the field of amyloidosis, especially with regard to pathogenesis, diagnosis and therapy. Amyloidosis leads to variable and distinct symptoms and is caused by different underlying conditions. Some amyloidoses are acquired secondary to a chronic condition; others are caused by genetic mutations. Amyloid and amyloidosis occur more frequently than they are perceived. Among the frequent localized forms are the cerebral amyloidosis linked to Alzheimer disease (AD) and the pancreatic amyloidosis linked to diabetes mellitus. Among the most frequent systemic (extracerebral) forms is AL amyloidosis, which often has a poor prognosis and if untreated can rapidly lead to death. Systemic amyloidosis that happen at infancy are mainly AA amyloidosis that can progress to death already at early or at middle adulthood. Amyloidosis can be treated but therapeutic success significantly depends upon early diagnosis and proper classification of the amyloid type. It is mandatory that differential diagnosis demonstrate the presence of amyloid and clearly identify the type of the disease. Development of methods and techniques have contributed to improvements in the diagnosis and treatment. Early diagnosis and proper classification of amyloid is decisive for therapeutic options and upon them depend quality of life and mortality. The therapeutic spectrum is various and includes organ transplantation, chemotherapy, and anti-inflammatory strategies. Gene therapy and biological active substances have to be considered in the near future.

[Niemann-Pick disease type C--a neurometabolic disease through disturbed intracellular lipid transport]. / Morbus Niemann-Pick Typ C. Eine neurometabolische Erkrankung durch Störung des intrazellulären Lipidtransports.

Niemann-Pick disease type C (NPC) is a rare, neurovisceral lipid storage disorder caused by genetic defects in lipid transporting proteins. It is distinct from Niemann-Pick types A and B (sphingomyelin lipidoses) and displays genetic (mutations in the NPC1 or NPC2[=HE1] gene), biochemical, and clinical heterogeneity. Late infantile to juvenile forms of NPC predominate and are characterised by atypical behaviour, ataxia, dysarthria, dysphagia, dystonia, cataplexy, vertical gaze palsy, splenomegaly, and dementia. In adult variants, psychosis and dementia are common, and dysarthria, ataxia, splenomegaly, and vertical gaze palsy are further facultative signs. Routine laboratory results including serum cholesterol are normal. In bone marrow smears, sea-blue histiocytes are often demonstrated and foam cells sometimes seen. The diagnosis is confirmed by detecting free cholesterol accumulation in perinuclear granules (lysosomes) and reduced cholesterol esterification after challenge with exogenous low-density lipoprotein in fibroblasts. Alternatively or additionally, mutational analysis can be performed. Treatment is restricted to symptomatic measures, since there is no specific therapy.

[Neurologic sequelae of chronic alcoholism]. / Neurologische Folgen des chronischen Alkoholmissbrauchs.

Chronic alcohol abuse causes several distinct diseases of the central and peripheral nervous system. Widely known are the alcohol withdrawal syndrome, alcohol-induced epileptic seizures, alcoholic polyneuropathy and myopathy, and Wernicke's encephalopathy. Beside these complications, less common syndromes have been identified, including Marchiafava-Bignami syndrome, subacute encephalopathy with seizure activity (SESA syndrome), and tobacco alcohol amblyopia. These syndromes can be diagnosed by their characteristic features in cranial MRI or in EEG. Moreover, certain disorders in which alcohol abuse is only indirectly involved in the pathogenesis are more frequent in alcoholics than in nonalcoholics. In daily practice, it is important to differentiate these disorders when encountering patients with chronic alcohol abuse.

[Hereditary amyloidoses associated with transthyretin mutations]. / Transthyretinassoziierte hereditäre Amyloidosen.

Hereditary amyloidoses form a clinically and genetically heterogeneous group of autosomal-dominantly inherited diseases characterized by the ubiquitous extracellular deposit of fibrillary aggregated proteins. Main components of these unsolvable deposits are physiologic proteins that became amyloidogenic through genetically determined conformation changes resulting in an increase in beta-sheet structures. In the vast majority of cases, the offending protein is variant transthyretin (TTR), of which over 80 mutations are known. Among these, substitution of valine by methionine in position 30 (TTR-Met30) is the most commonly encountered. In typical cases, TTR amyloidoses present with polyneuropathy, carpal tunnel syndrome, autonomic insufficiency, cardiomyopathy, and gastrointestinal features, occasionally accompanied by vitreous opacities and renal insufficiency. Rarely, involvement of the leptomeningeal or meningovascular structures dominates the clinical picture. The clinical expression is highly variable, with many atypical manifestations. Asymptomatic mutations have recently been identified. The age of onset varies greatly between early adulthood and old age. Late-onset atypical manifestations and occurrence of asymptomatic carriers render identification of affected family members difficult despite autosomal-dominant inheritance. Orthotopic liver transplantation (OLT) is the only effective therapy available today. This OLT stops progression of the disease, which is otherwise invariably fatal, by removal of the main production site of the amyloidogenic protein. However, cardiac involvement may progress after OLT for unknown reasons. The indication for OLT and its success depend on the grade of cardiovascular and autonomic dysfunction at the time of surgery, age, comorbidity, and type of mutation. Alternative treatment modalities with drugs stabilizing the native tetrameric conformation of TTR, inhibiting fibril formation or breaking beta-sheet structures, are currently being intensively studied.

Critical illness polyneuropathy.

Critical illness polyneuropathy is a self-limited acute axonal neuropathy that develops during treatment of severely ill patients and remits spontaneously once the critical condition is under control. Clinical manifestations include muscle weakness and atrophy, delayed weaning from the respirator, and prolongation of the mobilization phase. The pathogenesis is not understood in detail but most authors assume that the inflammatory cascade that mediates the systemic inflammatory response and multiple organ failure play a pivotal role. This review summarizes current knowledge of this common neuropathic complication during intensive care treatment.

Proper receptor signalling in a mutant catfish gonadotropin-releasing hormone receptor lacking the highly conserved Asp(90) residue.

The negatively charged side chain of an Asp residue in transmembrane domain 2 is likely to play an important role in receptor signalling since it is highly conserved in the whole family of G protein-coupled receptors, except in mammalian gonadotropin-releasing hormone (GnRH) receptors. In this paper we show that the conserved Asp(90) of the catfish GnRH receptor can be substituted by a neutral Asn(90) without abolishing receptor signalling if another negatively charged Glu(93) is introduced in a proximal region of the receptor interior, thereby mimicking the Glu(90)-Lys(121) salt bridge of mammalian GnRH receptors.

Critical illness polyneuropathy: clinical findings and cell culture assay of neurotoxicity assessed by a prospective study.

OBJECTIVE: First, to evaluate the role of typical intensive care-related conditions like sepsis, prolonged ventilation, drug effects and metabolic disorders in the pathogenesis of critical illness polyneuropathy (CIP); second, to investigate the possible significance of patient serum neurotoxicity assessed by an in vitro cytotoxicity assay with respect to CIP development. DESIGN: Prospective study. SETTING: Neurological intensive care unit. PATIENTS AND PARTICIPANTS: Twenty-eight patients who were on mechanical respiratory support for at least 4 days during a 21-month study period. RESULTS: Diagnosis of CIP was established by clinical and electrophysiological examination in 16 (57%) of 28 patients. Patients were investigated on days 4, 8 and 14 of mechanical ventilation. Two of 16 CIP patients had clinical signs of polyneuropathy at initial examination. Factors that correlated significantly with the development of CIP were: the multiple organ failure score on day 8 of ventilation, the total duration of respiratory support, the presence of weaning problems and the manifestation of complicating sepsis and/or lung failure. The in vitro toxicity assay showed serum neurotoxicity in 12 of 16 CIP patients. Electrophysiological investigations yielded false positive results of the toxicity assay in six patients (not developing CIP) and false negative results in four patients (developing clinical and electrophysiological signs of CIP). Statistical analysis did not reveal a significant correlation between the diagnosis of CIP and the finding serum neurotoxicity. CONCLUSION: The results support the hypothesis of a multi-factorial aetiopathogenesis of CIP. We observed serum neurotoxicity in the majority of CIP patients, indicating the possible involvement of a so far unknown, low-molecular-weight neurotoxic agent in CIP pathogenesis.

Transthyretin-associated neuropathic amyloidosis. Pathogenesis and treatment.

Hereditary amyloidoses form a clinically and genetically heterogeneous group of autosomal dominantly inherited diseases characterized by the deposit of insoluble protein fibrils in the extracellular matrix. They typically present with polyneuropathy, carpal tunnel syndrome, autonomic insufficiency, and cardiomyopathy and gastrointestinal features, occasionally accompanied by vitreous opacities and renal insufficiency. Other phenotypes are characterized by nephropathy, gastric ulcers, cranial nerve dysfunction, and corneal lattice dystrophy. Rarely, involvement of the leptomeningeal or cerebral structures dominates the clinical picture. The age at onset is as early as 17 and as late as 78 years. The basic constituents of amyloid fibers are physiologic proteins that have become amyloidogenic through genetically determined conformation changes. Mutated transthyretin (TTR), formerly termed prealbumin, is the most frequent offender in hereditary amyloidosis. Orthotopic liver transplantation (OLT) stops the progression of the disease, which is otherwise invariably fatal, by removing the main production site of amyloidogenic protein. The indications for OLT and its success depend on the grade of cardiovascular and autonomic dysfunction at the time of surgery, age, comorbidity, and type of mutation. Alternative treatment modalities with drugs stabilizing the native tetrameric conformation of TTR and inhibiting fibril formation are currently being studied.

Masking of vertebral artery dissection by severe trauma to the cervical spine.

STUDY DESIGN: A prospective case study was performed. OBJECTIVES: To illustrate the association of cervical trauma with vertebral artery dissection, and to propose a diagnostic and therapeutic algorithm for suspected traumatic vertebral artery dissection. SUMMARY OF BACKGROUND DATA: Vertebral artery dissection is a recognized but underdiagnosed complication of trauma to the cervical spine. Symptoms of spinal cord injury, however, may obscure those of vertebral artery dissection, presumably causing gross underdiagnosis of this complication. METHODS: All patients with vertebral artery dissection admitted to the authors' facility between 1992 and 1997 were screened for cervical trauma. RESULTS: This article presents four patients with severe trauma to the cervical spine, defined as luxation, subluxation, or fracture, in whom symptoms of vertebral artery dissection developed after a delay ranging from several hours to weeks. The traumatic vertebral artery dissection typically was located at the site of vertebral injury or cranial to it. One patient with fracture of the odontoid process survived symptom free without ischemic brain infarctions. Another patient survived with traumatic quadriplegia in addition to large cerebellar and posterior cerebral artery infarctions. Two patients died as a result of fulminant vertebrobasilar infarctions, both with only moderate impairment from the primary spinal cord injury. CONCLUSIONS: Early signs of vertebral artery dissection include head and neck pain, often localized to the site of intimal disruption, which may be disguised by the signs of the spinal injury. Early Doppler ultrasound and duplex sonography as a noninvasive screening method should be performed for patients with severe trauma to the cervical spine. In cases of vertebral artery dissection, immediate anticoagulation should be initiated. Traumatologists should be aware of this complication in evaluating patients with severe trauma of the cervical spine, and also for a variety of forensic reasons.

Neurological complications of sepsis: critical illness polyneuropathy and myopathy.

Sepsis may cause not only failure of parenchymal organs but can also cause damage to peripheral nerves and skeletal muscles. It is now recognized that sepsis-mediated disorders of the peripheral nerves and the muscle, called critical illness polyneuropathy (CIP) and critical illness myopathy, are responsible for weakness and muscle atrophy occurring de novo in intensively treated patients. CIP represents an acute axonal neuropathy that develops during treatment of severely ill patients and remits spontaneously, once the critical condition is under control. The course is monophasic and self-limiting. Among the critical illness myopathies, three main types have been identified: a non-necrotizing "cachectic" myopathy (critical illness myopathy in the strict sense), a myopathy with selective loss of myosin filaments ("thick filament myopathy") and an acute necrotizing myopathy of intensive care. Clinical manifestations of both critical illness myopathies and CIP include delayed weaning from the respirator, muscle weakness, and prolonging of the mobilization phase. The pathogenesis of these neuromuscular complications of sepsis is not understood in detail but most authors assume that the inflammatory factors that mediate systemic inflammatory response and multiple organ failure are closely involved. In thick filament myopathy and acute necrotizing myopathy, administration of steroids and neuromuscular blocking agents may act as triggers. Specific therapies have not been discovered. Stabilization of the underlying critical condition and elimination of sepsis appear to be of major importance. Steroids and muscle relaxants should be avoided or administered at the lowest dose possible.

Sepsis and catecholamine support are the major risk factors for critical illness polyneuropathy after open heart surgery'.

BACKGROUND: Critical illness polyneuropathy (CIP) remains a problem after open heart surgery. Recently, we reported about a retrospectively performed study pointing out that sepsis, the application of higher amounts of catecholamines and intervention such as chronic venovenous hemodiafiltration may be involved in the onset of CIP. A prospectively performed study is presented in order to evaluate the significance of risk factors initially after open heart surgery. METHODS: From June 1997 until September 1998, patients undergoing open heart surgery and being ventilated beyond 3 days were prospectively enrolled in the study and underwent a standard protocol of electromyographic investigation in order to determine CIP. Several items were recorded: amount of catecholamines, serum levels of urea, creatinine, albumin, and glucose. The duration of sepsis and chronic venovenous hemodiafiltration were reevaluated. Additionally the age, the left ventricular end-diastolic pressure prior to the operation, the time of ICU stay and the time of ventilatory support were compared. RESULTS: Within the observation period, 37 adult patients could be enrolled in the study, whereas 12 patients did develop CIP and 7 patients did not. Patients developing CIP required significantly different amounts of epinephrine (0.17 +/- 0.02 vs. 0.09 +/- 0.01 mg/kg/day, p < 0.05, t-test) higher amounts of norepinephrine (0.06 +/- 0.02 vs. 0.02 +/- 0.01 mg/kg/day, p<0.05, t-test), and lesser dosages of dobutamine (2.2 +/- 0.5 vs. 4.9 +/- 0.7, p<0.05, t-test). After cardiac surgery, the plasma levels of urea was initially significantly elevated in patients developing CIP (127.4 +/- 10.5 vs 97.3 +/- 18.5, p<0.05, t-test) Patients suffering from CIP stayed significantly longer in the ICU (40.3 +/- 11.7 vs. 19.6 +/- 11.3 days, p < 0.05 t-test) with an extended time of ventilator support. (769.6 +/- 05.0 vs 295.0 +/- 134.0 hours, p<0.05, t-test). Patients of the CIP group were suffering significant longer from sepsis than patients without CIP. CONCLUSIONS: Sepsis and catecholamine support and an increased level of urea were associated with the development of CIP. The prevention of sepsis and a modulation of the catecholamine support in order to improve microcirculatory flow may reduce the onset of CIP in patients undergoing open heart surgery.

Robustness testing of a reversed-phase high-performance liquid chromatographic assay: comparison of fractional and asymmetrical factorial designs.

Robustness tests were performed on a reversed-phase HPLC assay for triadimenol. Different experimental designs were compared. Two-level fractional factorial designs with different resolutions were used to study the influence of procedure-related factors. The factors chromatographic column manufacturer at four levels and instrument at three levels were stepwise included in the study using asymmetrical factorial designs. The significance of the factor effects was determined statistically, using two types of error estimates in the calculation of critical effects, and graphically, by means of half-normal plots. The asymmetrical designs turned out to be an efficient and economic method to examine the influence of factors at different numbers of levels in the robustness testing of analytical methods.

Treatment of cerebral Langerhans cell histiocytosis.

Cerebral Langerhans cell histiocytosis (LCH) is a rare granulomatous disorder which may be primary or secondary or solitary or multiple. Brain structures outside the hypothalamic-pituitary axis are only scarcely involved, even in multisystem varieties. Since there are neither controlled therapeutic trials nor systematic analyses of hitherto reported cases, optimal treatment strategies are not known. To evaluate the effect of different treatment modalities, we analyzed previous reports of extrahypothalamic LCH back to 1980 in which the diagnosis was made on the basis of examination of cerebral tissues. Thirty-five histologically examined cases were identified, including 10 patients presenting with multiple cerebral lesions. Adding one own case followed up for 10 years, 16 patients had cerebral involvement secondary to multisystem LCH, while another 20 patients had primary cerebral LCH. The peak incidence was far beyond the pediatric range for both primary and secondary cerebral LCH. Localized lesions can be treated successfully by surgery or radiation following biopsy. Chemotherapy may be an additional option. Multiple lesions can tentatively be controlled by chemotherapy and, possibly, radiation. The ultimate outcome is determined by whether or not recurrencies or de-novo lesions will appear and the course of the systemic disease. Studies addressing the effects of therapy in cerebral LCH are urgently needed.

Myopathy in critically ill patients.

OBJECTIVE: To review myopathic changes occurring during intensive care treatment in the light of recent information about manifestation, clinical settings, pathophysiology, and histomorphologic changes. DATA SOURCES: The computerized MEDLINE database, bibliography of pertinent articles, and the author's personal files. STUDY SELECTION: Studies were selected according to their relevance to myopathic complications in critically ill patients. DATA EXTRACTION: All applicable data were extracted. DATA SYNTHESIS: Myopathic changes occur frequently in patients treated in the intensive care unit (ICU). Three main types have been identified: critical illness myopathy, myopathy with selective loss of myosin filaments, and acute necrotizing myopathy of intensive care. These histologic types probably represent variable expressions of a toxic effect not yet identified. Candidates for such myotoxic effects are the mediators of the systemic response in sepsis and high-dose administration of corticosteroids and muscle relaxants. The influence of these latter agents appears to be particularly important in the pathogenesis of myosin loss and myonecrosis. Experimental studies suggest that axonal damage attributable to critical illness neuropathy can be an additional factor triggering myopathies in the ICU. Muscle membrane inexcitability was recently identified as an alternative mechanism of severe weakness in ICU patients. CONCLUSIONS: Myopathic changes are surprisingly frequent in critically ill patients. The clinical importance of this finding is still unknown, but it is likely that weakness caused by myopathy prolongs ICU stay and rehabilitation. Because corticosteroids and muscle relaxants appear to trigger some types of ICU myopathy, they should be avoided or administered at the lowest doses possible. Sepsis, denervation, and muscle membrane inexcitability may be additional factors. Studies addressing the pathophysiology of myopathy in critically ill patients are urgently needed.

[Critical polyneuropathy]. / Intensivpolyneuropathie.

Contrary to earlier belief, muscle weakness and atrophy in critically ill patients is not due to inactivity or disuse but rather caused by neuromuscular disorders arising de novo during the stay in the ICU. Clinical manifestations include delayed weaning from the respirator and prolongation of the rehabilitation phase. The available data indicate that critical illness polyneuropathy is the most frequent cause of such secondary neuromuscular problems. For differential diagnosis prolonged neuromuscular blockade and several myopathies have to be taken into consideration. The pathogenesis of critical illness polyneuropathy is unknown. It has been suggested that the factors mediating the systemic inflammatory response are also responsible for axonal damage in critical illness polyneuropathy. We recently described a neurotoxic activity present in the sera of affected patients, which can be reversed completely by NMDA antagonists. The critical illness per se is unrelated to the development of neuropathy. By contrast, occurrence of myopathies may be triggered by exogenous factors such as high-dose glucosteroids and non-depolarizing muscle blocking agents. Detailed electrodiagnostic studies are desirable in patients with long-lasting ICU stays, whenever possible as weekly monitoring. In doubtful cases, muscle biopsy might be necessary for proper diagnosis and management.

Evaluation of the H-point standard additions method (HPSAM) and the generalized H-point standard additions method (GHPSAM) for the UV-analysis of two-component mixtures.

The H-point standard additions method (HPSAM) and two versions of the generalized H-point standard additions method (GHPSAM) are evaluated for the UV-analysis of two-component mixtures. Synthetic mixtures of anhydrous caffeine and phenazone as well as of atovaquone and proguanil hydrochloride were used. Furthermore, the method was applied to pharmaceutical formulations that contain these compounds as active drug substances. This paper shows both the difficulties that are related to the methods and the conditions by which acceptable results can be obtained.