Absence Of Neurological Symptoms Research Articles

Recent advances in the molecular genetics of congenital and acquired primary adrenocortical failure.

IntroductionIn recent years there have been many advances in ourunderstanding of the molecular pathogenesis of both congenitaland acquired adrenocortical failure (autoimmune or otherwise).As well as providing some fascinating insights into adrenalgland development and steroid hormone biosynthesis, therecognition of these various distinct disorders, either at aclinical or molecular genetic level, often has implications forthe management of the patient and their immediate family. In thispaper, we review the salient clinical and molecular features of thevarious causes of primary adrenocortical failure (Table 1).Genetics of autoimmune Addison’s diseaseAutoimmune Addison’s disease (AAD) is a chronic disorder ofthe adrenal gland, characterized by insufficiency of adrenocor-tical hormones due to autoimmune destruction of steroidogenicadrenocortical cells (Oelkers, 1996). The cytochrome P450enzymes involved in steroidogenesis, including 21-hydroxylase(Baumann-Antczak et al., 1992; Winqvist et al., 1992), 17-hydroxylase (Krohn et al., 1992) and side chain cleavageenzyme (Winqvist et al., 1993) have been identified as primaryautoantigens in AAD. With the overall decrease in theprevalence of tuberculosis, AAD has emerged as the mostcommon cause of primary adrenal failure in developedcountries (Nerup, 1974; Kong & Jeffcoate, 1994). Nevertheless,AAD is a relatively rare endocrinopathy; recent epidemiologi-cal studies showing an estimated prevalence in the generalEuropean population of about 100 per million (Kong J Laureti et al., 1999).The results of human leucocyte antigen (HLA) typing, takentogether with the clinical heterogeneity of presentation anddifferent modes of inheritance, have suggested distinctpathogenic bases for different forms of AAD. Thus, AADmay occur in isolation, as a manifestation of the autoimmunepolyendocrinopathy type 1 syndrome (APS1), or as part of theautoimmune polyendocrinopathy type 2 (APS2) syndrome(Table 1) (Spinner et al., 1968; Neufeld et al., 1981; Maclaren& Riley, 1986).Autoimmune polyendocrinopathy type 1 syndrome: amonogenic autoimmune disorderIn the autoimmune polyendocrinopathy type 1 (APS1)syndrome, which is also known as the autoimmune poly-endocrinopathy, candidiasis and ectodermal dystrophy(APECED) syndrome, AAD occurs in association withautoimmune hypoparathyroidism, chronic mucocutaneous can-didiasis and other organ-specific autoimmune disorders. Theseinclude type 1 diabetes, primary gonadal failure, perniciousanaemia, chronic active hepatitis and hypothyroidism (Neufeldet al., 1981; Ahonen et al., 1990). The age of onset of AAD inAPS1 is typically between 11 and 15years, although othermanifestations of APS1 (e.g. hypoparathyroidism and candi-diasis) are likely to present at an earlier age. APS1 is amonogenic disorder with autosomal recessive inheritance,affecting both sexes with equal prevalence (Ahonen, 1985),and is rare in most populations. However, because of foundereffects, it is relatively common in the Finnish population andIranian Jews with estimated prevalences of 1/25000 and 1/9000, respectively (Ahonen, 1985; Zlotogora & Shapiro, 1992).Initial genetic studies of APS1 focused on HLA, and noassociation of this disorder with any specific HLA haplotypehas been found (Neufeld et al., 1981; Maclaren & Riley, 1986;Aaltonen et al., 1993; Huang et al., 1996). The gene underlyingAPS1 was subsequently localized on chromosome 21q22 bylinkage analysis (Aaltonen et al., 1994) and identified bypositional cloning (Finnish-German APECED consortium,1997; Nagamine et al., 1997). This gene, designated auto-immune regulator-1 (AIRE-1), encodes a 545 amino acidprotein that has two plant homeodomain (PHD)-type zinc-finger motifs, suggesting a role as a transcription factor(Finnish-German APECED consortium, 1997; Nagamine etal., 1997). AIRE-1 mRNA is expressed in lymphoid tissuesincluding thymus, lymph node and spleen, and possibly also inother tissues including the adrenal cortex (Finnish-GermanAPECED consortium, 1997; Nagamine et al., 1997), whichsuggests that it may have an important role in the developmentof a normal immune response.

Factors affecting induction of neurological disorders in mice by paralysis-inducing Friend-related PVC viruses.

Our previous studies showed that the passage of the Friend virus complex through rats generated variant MuLVs, designated PVC111, PVC211, PVC321 and PVC441, that induced neurological disorders associated with tremor and paralysis. In this study, we tested the pathogenicity of four different PVC viruses in mice. Although histopathological studies revealed spongiform degeneration in the spinal cords of NFS mice infected with each PVC virus, only PVC441 frequently induced tremor and paralysis. After a long latency, all of these viruses induced leukemia associated with severe anemia. Further studies with PVC441 revealed dose- and age-dependence for tremor induction. In contrast to NFS mice, BALB/c, DBA/2 and C57BL/6 mice infected with PVC441 virus showed no neurological symptoms, although the virus could be isolated from the tissues of central nervous system. Despite the absence of neurological symptoms, a high degree of neuronal degeneration in the lumbar spinal cord was found in PVC441-infected BALB/c mice. A low degree of neuronal degeneration was found in PVC441-infected DBA/2 or C57BL/6 mice. Genetic crosses of these resistant mice with susceptible NFS mice indicated that resistance to tremor induction by PVC441 was dominant in all mouse strains and suggested that various host genes may control the susceptibility of mice to tremor induction by PVC441 virus.

Cranial computed tomography as a part of the initial staging procedures for patients with non-small-cell lung cancer.

With the possible exception of chemotherapy for the small-cell type, a complete surgical excision is still the only effective treatment of lung cancer. Routine brain computed tomography (CT) for staging purposes has been both advocated and opposed. In this retrospective study, we aimed to assess the clinical yield of the technique. We saw 184 consecutive patients with a new histologically proven non-small-cell lung cancer. Using as reference criteria clinical judgment supported by a strict follow-up evaluation, we counted 1 false- and 23 true-positive brain CT results, plus 2 false- and 158 true-negative findings. These figures allow for sensitivity, specificity, and accuracy of 92 percent, 99 percent, and 98 percent. The frequency of brain metastases did not correlate with the various histologic types, even though adenocarcinoma was the most common cause of cerebral metastases. The absence of neurologic symptoms did not exclude cerebral involvement: in our experience, 16 of 25 patients with positive brain CT scans were asymptomatic (64 percent). Three of 31 subjects (10 percent) with an otherwise operable carcinoma were found to have metastases after brain CT. We conclude that routine cranial CT is useful in the staging evaluation of the patient with non-small-cell lung cancer (NSCLC) and that it should be performed in any candidate prior to surgical resection.

Central Nervous System Disease Associated with Langerhansʼ Cell Histiocytosis

To study the pathogenesis of central nervous system (CNS) lesions in Langerhans' cell histiocytosis (LCH), discuss their differential diagnosis and suggest guidelines for their management. Central nervous system (CNS) disease with Langerhans' cell histiocytosis (LCH) is a poorly understood disorder. Most commonly, the hypothalamic-pituitary region is involved, leading to diabetes insipidus (DI) or other endocrinopathies. We report four patients in whom lesions in the pons, cerebellum, basal ganglia, cerebral white matter, or optic nerve and tract were demonstrated by magnetic resonance imaging (MRI). Three developed a progressive neurological disorder with cerebellar and pontine symptoms leading to severe disability--in one patient to blindness and death--in spite of various treatment approaches. In the fourth patient, who had MRI examinations to evaluate long-standing DI, CNS lesions were detected in the absence of neurological symptoms. There was no correlation between activity of LCH, severity and course of the CNS disease, or morphology of the lesions on MRI. Brain biopsy was performed in the three symptomatic patients and revealed cerebellar atrophy in one. Normal brain tissue was obtained from two patients. In none of the patients could autoantibodies to nervous system tissue be detected in serum or cerebrospinal fluid. Based on clinical, pathological, and MRI findings in our four patients and on information in the literature, we conclude that the CNS disease associated with LCH, although insufficiently understood, is likely to be a manifestation of histiocytosis in the brain, and we propose guidelines for the management of patients with this disorder.

The Expectant Treatment of “Asymptomatic” Supratentorial Epidural Hematomas

Seventy-four patients with a traumatic epidural hematoma (EDH) and a Glasgow Coma Scale score of more than 12 received expectant treatment; 14 subsequently underwent surgical evacuation of the EDH. A patient with initial brain computed tomograms (CT) showing an EDH volume of more than 30 ml, a thickness of more than 15 mm, and a midline shift beyond 5 mm tended to require surgery within 3 days of the injury when the brain had exhausted its compensatory mechanism and yielded to the expanding EDH. After the 3-day period, in the absence of neurological symptoms, the presence of the EDH may not be an indication for surgical evacuation or hospitalization beyond 7 days. In our patients, the presence of a skull fracture in the temporal bone, the heterogeneous density of the EDH in the CT scan, or the 6-hour period between the CT study and the injury did not significantly increase the failure rate of nonsurgical treatment. Although a zero mortality was achieved in this series, these guidelines may not be applicable to the management of an infratentorial EDH.

Response of latent syphilis or neurosyphilis to ceftriaxone therapy in persons infected with human immunodeficiency virus

objective: To evaluate the effect of ceftriaxone in treating latent syphilis or asymptomatic neurosyphilis in patients infected with the human immunodeficiency virus (HIV).design: Follow-up study of patients treated at two HIV-based clinics during 16 months from 1989 to 1991.patients: Patients were those in whom a clinical diagnosis of latent syphilis or asymptomatic neurosyphilis was made, who received all recommended doses of antimicrobial therapy, and who returned for follow-up visits for 6 or more months.results: Forty-three patients were treated with ceftriaxone, 1 to 2 g daily for 10 to 14 days. Thirteen underwent lumbar puncture before treatment; 7 (58%) had documented neurosyphilis (pleocytosis in 5, elevated protein levels in 6, VDRL reactive in cerebrospinal fluid [CSF] in 7), and 6 had documented latent syphilis (entirely normal CSF). The remaining 30 were said to have presumed latent syphilis. There was no relation between the diagnosis and the selected dosage of ceftriaxone. Response rates were similar in those who had documented neurosyphilis and documented or presumed latent syphilis. Overall, 28 patients (65%) responded to therapy, 5 (12%) were serofast, 9 (21%) had a serologic relapse, and 1 (2%) who experienced progression to symptomatic neurosyphilis was a therapeutic failure. Thirteen patients received benzathine penicillin for presumed latent syphilis; results were similar to those observed after ceftriaxone therapy, with 8 (62%) responders, 1 (8%) serofast, 2 (15%) relapses, and 2 (15%) failures. CD4 cell counts in responders were not different from those who failed to respond.conclusions: Even in the absence of neurologic symptoms, half of the HIV-infected persons who have serologic evidence of syphilis may have neurosyphilis. Although ceftriaxone achieves high serum and CSF levels, 10 to 14 days of treatment with this drug were associated with a 23% failure rate in HIV-infected patients who had latent syphilis or asymptomatic neurosyphilis. Three doses of benzathine penicillin did not have a significantly higher relapse rate and may provide appropriate therapy, at least for documented latent syphilis in persons co-infected with HIV. Studies comparing ceftriaxone with 10 to 14 doses of procaine penicillin are needed to determine the most cost-effective treatment for asymptomatic neurosyphilis or presumed latent syphilis in this group of patients.

Multiple Meningiomas of the Spinal Canal and Posterior Fossa

The majority of multiple meningiomas are associated with von Recklinghausen's disease, and those that are not, i.e., true multiple meningiomas, particularly with simultaneous development in the posterior fossa and spinal canal, are very rare. We recently encountered a case of true multiple meningiomas in which the lesions were found simultaneously in the left posterior fossa and the upper thoracic spinal canal. The spinal meningioma consisted mainly of meningotheliomatous components, and that in the posterior fossa of fibroblastic components. Both tumors were surgically removed. The cause of the multiplicity in cases of true multiple meningiomas is unknown. Incidental multiplicity is a consideration when the number of tumors is relatively small. Spinal meningiomas are often undetected in the absence of neurological symptoms. However, even if von Recklinghausen's disease is not present, and particularly when more than two meningiomas have been discovered, the patient must be carefully examined for other tumors.

AURENOLEUKUDYSTROPHY MAY RESEMBLE FAMILIAL ACTH UNRESPONSIVENESS

Adrenoleukodystrophy (ALD) is a well-described cause of familial primary adrenal insufficiency in which neurological symptoms may be absent for many years. While the spectrum of adrenal insufficiency in ALD is variable, primary impairment of glucocorticoid secretion may resemble familial ACTH unresponsiveness, a different rare form of adrenal insufficiency. To distinguish ALD from other forms of familial adrenal insufficiency, we carried out the following studies in 3 male patients (age 11-16 yr): measurement of plasma saturated very-long-chain fatty acids (C26 and C26/C22 ratio), adrenal antibodies (AAb), plasma renin activity (PRA), and computerized tomography (CT) or magnetic resonance (MR) studies of the CNS. C26 was elevated above control in all three patients, 2.14 ± 1.21 μg/ml, mean ± S.D. (normal 0.33 ± 0.18) as was the C26/C22 ratio, 0.04 ± 0.01 (normal 0.01 ± 0.01), consistent with the diagnosis of ALD. AAb were undetectable in all patients. PRA was normal in one patient and elevated in two. Neurological examinations were unremarkable in all patients, without evidence of leukodystrophy on CT or MR scans. This study illustrates the need to consider ALD in the differential diagnosis of childhood familial primary adrenal insufficiency in the absence of neurological symptoms. Furthermore, it is important to recognize that ALD may present with isolated glucorticoid deficiency and thus may mimic ACTH unresponsiveness, which has separate genetic, prognostic, and therapeutic considerations.

Importance of early radiologic diagnosis of congenital anomalies of the spine

Manifest or occult spinal dysraphism in the absence of neurological symptoms is likely to remain undetected. Therefore, accurate and early diagnosis of such underlying anomalies is of prime importance for early surgical intervention in order to avoid late irreparable damage. During a period of just over 1 year, 17 such cases of spinal congenital anomalies were diagnosed by myelography with metrizamide and computed tomography-myelography. There were 16 cases of tethered cord, six with myelomeningocele, two with diastematomyelia, two with a split spinal cord, three with a lipoma, and the remaining three with vertebral anomalies. Scoliosis was present in 60%, weakness of both legs in 45%, and asymmetry of the feet in 25%. Some of these patients were initially brought to the orthopedic department for corrective surgery before undergoing a complete neurological evaluation; thus the radiologist was acting as the link between patient and neurosurgeon. Clinical experience has shown that surgical treatment can be successful and can thereby obviate further progression of neurological symptoms.

Morquio disease, type B: Activation of G M1-β-galactosidase by G M1-activator protein

Residual G M1-β-galactosidase activity of Morquio B fibroblasts increases from 4 % to at least 20 % of the respective normal value in the presence of partially purified G M1-activator protein. The activator does not lead to a stimulation of keratan sulfate-degrading β-galactosidase. There is no significant difference between normal and Morquio B fibroblasts in the rates of synthesis of pro-β-galactosidase (M r = 85.000) and in conversion to a mature form (M r = 68.000). The absence of neurological symptoms in Morquio B patients may therefore be explained by a specific activation of G M1-β-galactosidase in vivo .

Routine skull films in hospitalized psychiatric patients.

Skull films were taken routinely for a sample consisting of all inpatients at a psychiatric facility over a 5-year period (N = 2,943). The skull series revealed some abnormalities in 17.3% of the patients and significant abnormalities in 2.4%. The author concludes that the results of this trial do not justify routine skull films for psychiatric patients in the absence of neurological symptoms.

Headache in small vessel disease of the brain: a study of patients with systemic lupus erythematosus.

SYNOPSISSeventy‐two records of patient with systemic lupus erythematosus were reviewed retrospectively. Sixty‐one fulfilled the criteria for the disease. Forty‐six percent had clinical evidence of central nervous system involvement. The incidence of headache was compared in those with and without central nervous system lupus. No difference in the frequency of headache in the two groups were found and the incidence of hypertension, renal disease and steroid therapy was equally distributed among those with and without headache. A significantly higher incidence of hypertension was found in patients with central nervous system lupus erythematosus. We conclude that headache in systemic lupus erythematosus in the absence of neurologic symptoms or signs is no indication of central nervous system involvement by the process and that small vessel disease of the brain is not a cause of headache.

Intraspinal dermoid and epidermoid tumors

São relatados dois casos de tumores epidermóides e um de tumor dermóide, todos intrarraquianos. Este último era de localização epidural ao nível da coluna torácica (caso 3); os dois tumores epidermóides situavam-se na coluna tóraco-lombar (caso 1) e lombar (caso 2), respectivamente, sendo o primeiro intramedular e o segundo intradural. Em dois casos (casos 2 e 3) os tumores associavam-se a fístula dérmica congênita. Um paciente (caso 3) foi operado aos dois meses de idade; a descoberta do tumor deveu-se à realização da raquimanometria que revelou bloqueio, apesar do paciente não apresentar qualquer sinal neurológico de compressão medular. Os autores são de opinião que, em presença de fístula dérmica congênita ao nível da coluna vertebral, principalmente quando localizada acima do segmento lombosacro, deve-se sempre suspeitar da possibilidade do tumor epidermóide ou dermóide intrarraquiano, mesmo na ausência de sinais neurológicos. A combinação de sintomas neurológicos de longa duração, a evidência radiológica de erosão e alargamento do canal raquiano e a história de fístula dérmica congênita proporcionaram o diagnóstico pré-operatório correto no caso 2.

DYSPHAGIA CAUSED BY ELONGATION AND TORTUOSITY OF THE COMMON CAROTID ARTERY.

BUCKLING of the major arteries in the neck and mediastinum was described during the last century by Coulson1 (1852) and by Balfour2 (1898), but not until the introduction of contrast angiography did this clinical entity become more widely recognized.3 Ouattlebaum and his associates4 recently indicted elongation and kinking of the internal carotid artery as a cause of transient stroke, although the anatomic abnormality may be found also in the absence of neurologic symptoms. On occasion other vascular malformations in this region, such as arterial aneurysms5 and anomalies of the aortic arch, may give rise to symptoms of dysphagia by externally . . .

Folic Acid Deficiency

MACROCYTIC anamia, associated with a megaloblastic erythropoiesis, glossitis, weight loss, diarrhcra, and an absence of neurological symptoms or signs and of evidence of deficiency of vitamin B12 are usually accepted as the features of deficiency of folic acid or related pteroylglutamate compounds. Such an assumption is based on the clinical and hxematological remission induced by the administration of a synthetic compound, folic acid. The term ' folic acid' also stands for the family of conjugated pterins and pteridines having ' folic' biological activity (Hutner, Nathan and Baker, 1959). The clinical picture occurs in malnutrition, in certain diseases of the small intestine, such as cceliac disease, tropical sprue or jejunitis from various causes, and in pregnancy. Sometimes it follows treatment with anti-folic compounds, such as aminopterin, or with certain anti-convulsant drugs, such as primidone, phenobarbitone, epanutin or mysoline. Because of the variety of conditions in which deficiency of folic acid occurs, it is thought that it is the result of a poor intake, poor absorption, increased demand created by a disordered metabolism, or a combination of these factors.