[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.

A transgenic rat model of Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy in humans and has been associated with a partial duplication of chromosome 17 (CMT type 1A). We have generated a transgenic rat model of this disease and provide experimental evidence that CMT1A is caused by increased expression of the gene for peripheral myelin protein-22 (PMP22, gas-3). PMP22-transgenic rats develop gait abnormalities caused by a peripheral hypomyelination, Schwann cell hypertrophy (onion bulb formation), and muscle weakness. Reduced nerve conduction velocities closely resemble recordings in human patients with CMT1A. When bred to homozygosity, transgenic animals completely fail to elaborate myelin. We anticipate that the CMT rat model will facilitate the identification of a cellular disease mechanism and serve in the evaluation of potential treatment strategies.

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.

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.

Inclusion body myositis presenting with isolated erector spinae paresis.

We report a 70-year-old patient who presented with a 4-year history of weakness of paravertebral muscles. Electrodiagnostic studies revealed a mixed neurogenic-myopathic pattern. Light microscopic examination revealed atrophic fibers with rimmed vacuoles; electron microscopy demonstrated cytoplasmic and intranuclear filaments measuring about 16 nm in width, consistent with the diagnosis of inclusion body myositis. Therapy with corticosteroids provided only a mild and transient benefit. Ten months after the initial evaluation, clinical and electrodiagnostic examination demonstrated mild progression of the disease.

Proximal myotonic myopathy with MRI white matter abnormalities of the brain.

Proximal myotonic myopathy (PROMM) is an autosomal dominantly inherited multisystemic disorder characterized by myotonia, proximal muscle weakness, and cataracts. This disorder is not linked to the gene locus of myotonic dystrophy (DM). We describe three new families with PROMM. In all patients, CTG repeats of the DM gene in DNA from blood leukocytes were normal. MRI of the brain revealed a consistent pattern of marked white matter hyperintensity on T2-weighted images in four patients; two additional patients had similar but mild to moderate MRI abnormalities. The morphology of these abnormalities is unknown. Clinical symptoms of brain disease were not consistent and included mental changes with hypersomnia, parkinsonian features, stroke-like episodes, and seizures. The causative relationship of these clinical features with the MRI white matter abnormalities remains to be established. Our observations suggest that PROMM may involve the brain.

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.

Vasoactive hormones in children with chronic renal failure.

Plasma renin activity (PRA), aldosterone, vasopressin and catecholamines were measured in 15 children (ages 7.3 to 16.2 years) with chronic renal failure (CRF) before and after one session of hemodialysis and in 15 control children. Basal levels of PRA and aldosterone in children with CRF did not differ significantly from control values, but showed a wider range. Uremic patients with nephronophthisis showed the highest basal PRA and aldosterone levels. In children with CRF, basal vasopressin levels were significantly higher (9.7 +/- [SEM] 2.0 ng/liter) than control values (3.2 +/- 0.8 ng/liter). Plasma noradrenalin and adrenalin concentrations were similar in children with CRF and controls. During hemodialysis, a fall in blood pressure and a rise in heart rate was observed in all children. PRA and catecholamines increased twofold to fivefold during dialysis while aldosterone and vasopressin showed a variable response. In contrast to reports in adults, there is no evidence for an insufficiency of vasoactive hormones or of the sympathetic nervous system in children on hemodialysis.

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.

Neuromuscular complications in the ICU: the spectrum of critical illness-related conditions causing muscular weakness and weaning failure.

Muscular weakness and atrophy in intensive care patients has long been attributed to a combination of immobilization and cataboly. More recently, it has become apparent that specific injuries to the peripheral nerve, the neuromuscular junction and the muscle are more likely causes of weakness in these patients. Clinically, delayed weaning from the ventilator and prolonged neurologic rehabilitation are the most important consequences. Detailed electrodiagnostic examination is necessary for accurate diagnosis. In selected patients, a combined muscle and nerve biopsy is helpful. In this review, I describe the current knowledge of neuromuscular complications in patients with long-term treatment in the intensive care unit.

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.

Progressive cerebellar ataxia, proximal neurogenic weakness and ocular motor disturbances: hexosaminidase A deficiency with late clinical onset in four siblings.

Tay-Sachs disease is a genetically determined neurodegenerative disorder, resulting from mutations of the hexosaminidase (Hex) A gene coding for the alpha-subunit of beta-D-N-acetyl-hexosaminidase. Clinically, there is severe encephalomyelopathy leading to death within the first few years of life. Hex A activity is usually absent in tissue and body fluids of these patients. Juvenile and adult Hex A deficiencies are less severe but rare variants with some residual Hex A activity. All these variants are most prevalent among Ashkenazi Jews. We describe a non-Jewish family in which four adult brothers and sisters had markedly reduced Hex A activities and onset of symptoms in the second decade of life. The phenotypical expression was remarkably homogeneous, consisting in a combination of slowly progressive motor neuron disease, ataxia and ocular motor disturbances. None of the patients were demented at this stage of their illness. Magnetic resonance studies showed severe cerebellar atrophy, but were otherwise normal. Hex A deficiency was established by biochemical measurements in the serum and skin fibroblasts using the fluorogenic substrates 4-MUG and 4-MUGS as well as by gel electrophoresis. Molecular genetic studies revealed that the patients are compound heterozygotes for the 'adult' mutation Gly269 --> Ser and the 'infantile' 4-base insertion in exon 11 of the Hex A gene.

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.

Neurocritical care for acute ischemic stroke.

Therapy for acute ischemic stroke includes general and specific measures. General management such as respiratory and cardiac care, fluid and electrolyte management, blood pressure control, and treatment of increased ICP is the basis of all stroke treatment. Specific treatment is directed to recanalization of the occluded vessel, control of life-threatening brain edema, and protection of neuronal tissue against the toxic effects of ischemia. Although controlled studies are still lacking, application of the proposed general interventions provides a high-quality standard in patients with acute stroke. Among specific therapies, medical thrombolysis has demonstrated instances of significant and sustained neurologic improvement. Several multicenter trials are underway to confirm these preliminary results. In addition to thrombolysis, cell-protecting drugs hold promise for the future. Presumably, a combination of thrombolytic and cell-protecting agents will be the treatment of choice in early stroke in the future.

Critical illness polyneuropathy: a new iatrogenically induced syndrome after cardiac surgery?

OBJECTIVE: Critical illness polyneuropathy (CIP) is a newly described severe complication after open heart surgery leading to tetraplegia for weeks to months. The purpose of the study was to gather further information on critical illness polyneuropathy developing in patients after cardiac surgery and to evaluate the hypothetical risk factors possibly related to the onset of this neurological disorder. METHODS: From July 1994 to October 1995, 7 out of 1511 patients undergoing open heart surgery developed critical illness polyneuropathy, which was diagnosed on the basis of electromyographic and nerve conduction features. The only common clinical finding was an intensive care unit (ICU) stay beyond seven days, therefore a similar group of 37 patients staying longer than seven days in the intensive care unit during the same period of time was evaluated and retrospectively compared to the 7 patients developing critical illness polyneuropathy. Univariate analysis of several traits was performed to evaluate possible risk factors. RESULTS: 4 Out of 7 patients in the CIP group died, all due to multiple organ failure, in contrast to 3/37 patients in the control group, again due to multiple organ failure. Patients developing CIP were staying significantly longer in the ICU (62+/-3 versus 14+/-8 days, P < 0.01) and had a significantly longer time on ventilator support (50+/-28 versus 7+/-13 days, P < 0.01) The incidence of sepsis was significantly higher in the CIP group than in the control group (85.7 versus 10.8%, P < 0.01). Compared to the control group the proportion of patients receiving corticosteroids (100 versus 10.8%, P < 0.01) and increased dosages of epinephrine and norepinephrine was higher in the CIP group (85.7 versus 35.1%, P < 0.05). Furthermore, the proportion of patients requiring chronic venovenous hemodiafiltration was significantly elevated in the CIP group (85.7 versus 5.4%, P < 0.01). CONCLUSIONS: CIP, despite it's benign nature due to it's spontaneous remission in patients who survive, is a disturbing complication following cardiac surgery which is associated with high mortality, a prolonged stay in the ICU, as well as an extended time on ventilator support. Interventions like chronic hemodiafiltration, the application of corticosteroids and the administration of high doses of catecholamines are more frequent in patients with CIP. Whether this indicates a causal relationship remains to be elucidated.

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.

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.

Neurocritical care for acute ischemic stroke.

Treatment strategies for acute ischemic stroke include general and specific measures. The rationale for these strategies is discussed, and the current practice in the acute phase of ischemic stroke is presented. Special attention is given to the patient requiring intensive care.

[Transtracheal monitoring of the recurrent laryngeal nerve. Prototype of a new tube]. / Transtracheales Monitoring des Nervus laryngeus recurrens. Der Prototyp eines neuen Tubus.

A new sensing device for the continuous intraoperative monitoring of the recurrent laryngeal nerve is presented. It is based on a double ballooned endotracheal tube including stimulating and tracing electrodes. The system is characterised by three advantages: 1) it is atraumatic, 2) it is operating completely outside the operating field (extraterritorially), 3) nerve function is being monitored continuously from the time of intubation to the time of extubation. The presented system has been evaluated in piglets. First results in humans will be available shortly.