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Foster Kennedy syndrome and optociliary shunt vessels in a patient with an olfactory groove meningioma.

A 48-year-old woman complained of acute loss of vision in her right eye. Ophthalmoscopically, the right optic disk appeared pale, and abnormally dilated vessels were noted on the disk. The left optic disk was reddish and swollen. Fluorescein angiography revealed abnormal vessels on the right optic disk that might be venous. The patient had right-sided anosmia. Computed tomography and magnetic resonance imaging showed a lesion in the frontal lobe that was deviated to the right and attached to the olfactory groove. A histopathologic study of the excised specimen disclosed a meningioma. We believe that this patient with olfactory groove meningioma represents a rare case of Foster Kennedy syndrome and optociliary shunt vessels.

Ciliary Body↗

Pituitary-testicular responsiveness in male hypogonadotropic hypogonadism.

An isolated deficiency of pituitary gonadotropins was demonstrated in six 46 XY males, 22 to 36 years of age, with and without anosmia. Undetectable or low levels of serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) clearly separated hypogonadotropic from normal adult males. Chronic (8-12 wk) administration of clomiphene citrate caused no increase in serum FSH or LH in gonadotropin-deficient subjects. However, the administration of synthetic luteinizing hormone releasing factor (LRF) resulted in the appearance of serum LH and, to a lesser degree, serum FSH in three subjects tested. While levels of plasma testosterone were significantly lower in gonadotropin-deficient subjects, plasma androstenedione and dehydroepiandrosterone were in a range similar to that of age-matched normal men. Treatment with human chorionic gonadotropin (HCG) increased levels of plasma testosterone to normal adult male values in all gonadotropin-deficient subjects. Cessation of treatment with HCG resulted in the return of plasma testosterone to low, pretreatment levels. That HCG therapy with resultant normal levels of plasma testosterone may somehow stimulate endogenous gonadotropin secretion in gonadotropin-deficient subjects was not evident. The adult male levels of serum FSH and LH after LRF, and plasma testosterone after HCG, confirm pituitary and Leydig cell responsiveness in these subjects.

Adult↗

Olfactory changes at threshold and suprathreshold levels following septoplasty with partial inferior turbinectomy.

Partial inferior turbinectomy with septoplasty is routinely carried out for airway obstruction. However, its effects on the sense of smell have not been systematically evaluated. The aim of this prospective study was to evaluate the influence of septoplasty with partial inferior turbinectomy on threshold and suprathreshold olfactory acuity. The subjects were 30 patients undergoing septoplasty including partial inferior turbinectomy. Olfactory function was determined by the "Sniffin' Sticks," which allow the assessment of odor thresholds, odor discrimination, and odor identification. The patients rated both olfactory function and nasal airflow using visual analog scales. Nasal airflow was measured by anterior rhinomanometry. Multivariate analyses of variance for repeated measures were used to analyze the results before and after surgery (mean interval, 9.1 weeks). After operation, 87% of the patients had increased airflow, 80% had improved olfactory function in terms of odor identification, and in 70% odor discrimination was found to be improved - but only 54% had improved olfactory function in terms of odor thresholds. Surgery increased ratings of nasal airflow in 93%, and those of olfactory function in 77% (p < .001). Similarly, bilateral inspiratory nasal flow increased (p < .001) and olfactory function was improved (p < .001) after surgical treatment. However, this increase was most pronounced for suprathreshold tests, while it was moderate for odor thresholds (interaction "surgery" x "olfactory test," p = .001). The present investigation suggests that septoplasty in combination with inferior turbinectomy has a beneficial effect on olfaction, mainly on suprathreshold olfactory functions. This effect may be partly due to interactions between the increased perception of nasal airflow and cognitive factors involved in olfactory sensitivity. According to the present results and data from the literature, a moderate decrease of olfactory function appears to occur in as many as 20% of patients. However, anosmia seems to be an extremely rare complication of septoplasty and partial turbinectomy.

Adolescent↗

Diagnosis of chronic rhinosinusitis.

Chronic rhinosinusitis is a multifactorial disease defined as inflammation of the nasal cavity and paranasal sinuses with a history of at least 12 weeks in duration. The major symptoms include facial pressure or pain, nasal obstruction, discharge or purulence, and hyposmia or anosmia. The minor symptoms include fever, halitosis, fatigue, and dental pain. Microorganisms play a significant role in the persistence and origination of the inflammatory process, although the exact role of these organisms in the pathogenesis of chronic rhinosinusitis is unclear. The clinical diagnosis relies heavily on the patient history and physical examination, which may include nasal endoscopy and computed tomography. Diagnostic techniques are here reviewed.

Bacterial Infections↗

Correlation between nasosinusal symptoms and topographic diagnosis in chronic rhinosinusitis.

Rhinitis and sinusitis concern roughly a quarter of the population in the Western world. They are associated with a wide range of symptoms: nasal obstruction, anterior and posterior nasal discharge, sneezing episodes, facial pain or congestion, and taste and smell disorders. The aim of this prospective study was to evaluate the clinical significance of these various symptoms as a function of the topographic diagnosis of chronic rhinosinusitis. The study involved 474 patients with signs of chronic perennial and persistent rhinosinusitis. The disorders of the nasal cavities and paranasal sinuses were classified into three main diagnostic categories: chronic rhinitis, localized sinusitis (mainly, anterior sinusitis), and diffuse rhinosinusitis (ie, nasal polyposis). A principal components analysis was performed. The symptom patterns of the three main clinical entities differed greatly. Most of the following clinical signs--nasal obstruction, anterior and posterior nasal discharge, sneezing, and facial congestion--are found in all diagnostic categories and hold no specific clinical significance. By contrast, four symptoms seem to have a substantial differentiating potential: anosmia and complete loss of flavor for diffuse rhinosinusitis, cacosmia for localized anterior sinusitis, and severe facial pain for localized sinusitis. This study proposes a new analysis of the relationship between symptoms of chronic rhinosinusitis and findings on a sinus computed tomography scan.

Adolescent↗

Modifications of the nasal cycle in patients with hypothalamic disorders: Kallmann's syndrome.

The nasal cycle is a phenomenon characterized by cyclic changes in the airflow resistance of each nasal fossa from congestion or constriction of the nasal erectile tissue. This phenomenon is caused by alterations in the influence exerted by the autonomic nervous system and is believed to be regulated by a hypothalamic center. In order to verify this hypothesis on the hypothalamic regulation of the nasal cycle, the authors studied a group of subjects with Kallmann's syndrome. This disorder is characterized by coexisting hypothalamic hypogonadism and hyposmia or anosmia due to hypothalamic and olfactory center hypoplasia. An anomalous nasal cycle was found in all the subjects with Kallmann's syndrome. This disorder might be related to hypothalamus atrophy.

Adolescent↗

Congenital lack of olfactory ability.

Twenty-two patients, all of whom reported never having been able to smell anything, were studied to determine the particular features that distinguish individuals with congenital anosmia. The clinical evaluation on these patients included a thorough medical and chemosensory history, physical examination, nasal endoscopy, chemosensory testing, olfactory biopsies, and imaging studies. There was no evidence to indicate that these patients ever had a sense of smell. The results of olfactory testing suggested that these patients had an inability to detect both olfactory and trigeminal odorants; however, many of the patients in the group seemed to have a slight ability to perceive at least some component of trigeminal odorants. The olfactory epithelium, if it was present at all on biopsy, was abnormal in appearance.

Adolescent↗

Olfactory evoked potentials and contingent negative variation simultaneously recorded for diagnosis of smell disorders.

Objective diagnosis of olfaction can be performed by registration of cortical olfactory evoked potentials (OEP) and of contingent negative variation (CNV). The CNV is a negative voltage developing at the vertex after discrimination of one of two smells while the patient is expecting a second stimulus. By an adequate procedure, including a long time window for averaging (2.56 seconds) with appropriate filters, the two tests can be performed simultaneously in a single session of less than 10 minutes. Anosmia is determinable by both OEP and CNV, although CNV shows less variability. On the other hand, CNV requires attention and some cooperation of the patient. Parosmia is accessible by CNV only; two odor qualities presented in random order have to be distinguished. Hyposmia can also be detected; just above the discrimination threshold, CNV amplitudes tend to be large--even enhanced--whereas OEP amplitudes may still be undetectable.

Contingent Negative Variation↗

Olfactory neuron loss in adult male CD rats following subchronic inhalation exposure to hydrogen sulfide.

Dysosmia and anosmia are reported to occur following human exposure to hydrogen sulfide (H2S) gas. The clinical association between H2S exposure and olfactory dysfunction in humans necessitates evaluation of the nasal cavity and olfactory system in experimental animals used to study H2S toxicity. The purpose of this study was to subchronically expose 10-week-old male CD rats to relatively low concentrations of H2S and to histologically evaluate the nasal cavity for exposure-related lesions. Rats (n = 12/group) were exposed via inhalation to 0, 10, 30, or 80 ppm H2S 6 h/d and 7 d/wk for 10 weeks. Following exposure to 30 and 80 ppm H2S, a significant increase in nasal lesions limited to the olfactory mucosa was observed. The lesions, which consisted of olfactory neuron loss and basal cell hyperplasia, were multifocal, bilaterally symmetrical, and had a characteristic rostrocaudal distribution pattern. Regions of the nasal cavity affected included the dorsal medial meatus and the dorsal and medial portions of the ethmoid recess. The no observed adverse effect level for olfactory lesions in this study was 10 ppm. For perspective, the American Conference of Governmental Industrial Hygienists threshold limit value (TLV) recommendation for H2S is currently 10 ppm (proposed revision: 5 ppm), so the concentrations employed in the present study were 3 and 8 times the TLV. These findings suggest that subchronic inhalation exposure to a relatively low level of H2S (30 ppm) can result in olfactory toxicity in rats. However, because of differences in the breathing style and nasal anatomy of rats and humans, additional research is required to determine the significance of these results for human health risk assessment.

Administration, Inhalation↗

Dementia with Lewy bodies: clinical characteristics and diagnostic criteria.

Dementia with Lewy bodies (DLB) is increasingly recognized as a distinct clinical and pathologic entity. It is a progressive dementia characterized by persistent and well-formed visual hallucinations, marked second-to-second fluctuations in attention, and progressive extrapyramidal signs. The diagnostic value of additional clinical features such as delusions, depression, falls, anosmia, and rapid progression continues to be debated. Despite the growing acceptance of the diagnosis, DLB has not yet been included in either International Classification of Disease (ICD-10) or Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria. However, the existing consensus diagnostic criteria continue to be validated. Most prospective studies to date indicate that their performance is acceptable, with specificity similar to the present diagnostic criteria for Alzheimer's disease. Nevertheless, at least one in five patients with DLB will continue to be misclassified.

Aged↗

A preliminary study of neuroSPECT evaluation of patients with post-traumatic smell impairment.

BACKGROUND: Most olfactory testings are subjective and since they depend upon the patients' response, they are prone to false positive results. The aim of this study was to use quantitative brain perfusion SPECT in order to detect possible areas of brain activation in response to odorant stimulation in patients with post-traumatic impaired smell in comparison to a group of normal subjects. METHODS: Fourteen patients with post-traumatic impaired smell and ten healthy controls were entered in this prospective study. All subjects underwent brain SPECT after intravenous injection of 740-MBq 99mTc-ECD and 48 hours later, the same procedure was repeated following olfactory stimulus (vanilla powder). RESULTS: In most of seven regions of interest (Orbital Frontal Cortex, Inferior Frontal Pole, Superior Frontal Pole, Posterior Superior Frontal Lobe, Parasagittal Area, Occipital Pole, and Cerebellar area) the post-stimulation quantitative values show increased cortical perfusion being more pronounced in normal volunteers than the anosmic patients (except cerebellar areas and the right occipital pole). Maximal activation was observed in orbitofrontal regions (right+ 25.45% and left +25.47%). CONCLUSION: Brain SPECT is a valuable imaging technique in the assessment of post-traumatic anosmia and could be competitive as an alternative to other imaging techniques, especially when functional MRI is unavailable or unsuitable. However, this procedure may benefit from complementary MRI or CT anatomical imaging.

Journal Article↗

Further studies on the substrate spectrum of phytanoyl-CoA hydroxylase: implications for Refsum disease?

Refsum disease is a peroxisomal disorder characterized by adult-onset retinitis pigmentosa, anosmia, sensory neuropathy, ataxia, and an accumulation of phytanic acid in plasma and tissues. Approximately 45% of cases are caused by mutations in phytanoyl-CoA hydroxylase (PAHX), the enzyme catalyzing the second step in the peroxisomal alpha-oxidation of 3-methyl-branched fatty acids. To study the substrate specificity of human PAHX, different 3-alkyl-branched substrates were synthesized and incubated with a recombinant polyhistidine-tagged protein. The enzyme showed activity not only toward racemic phytanoyl-CoA and the isomers of 3-methylhexadecanoyl-CoA, but also toward a variety of other mono-branched 3-methylacyl-CoA esters with a chain length down to seven carbon atoms. Furthermore, PAHX hydroxylated a 3-ethylacyl-CoA quite well, whereas a 3-propylacyl-CoA was a poor substrate. Hydroxylation of neither 2- or 4-methyl-branched acyl-CoA esters, nor long or very long straight-chain acyl-CoA esters could be detected. The results presented in this paper show that the substrate specificity of PAHX, with regard to the length of both the acyl-chain and the branch at position 3, is broader than expected. Hence, Refsum disease might be characterized by an accumulation of not only phytanic acid but also other 3-alkyl-branched fatty acids.

Coenzyme A↗

Medical management of noncognitive sequelae of minor traumatic brain injury.

Mild traumatic brain injury (TBI) encompasses the postconcussion syndrome characterized by symptoms that include a variety of physical symptoms as well as cognitive and behavioral impairments. The focus of this discussion is on the medical management of posttraumatic headaches, posttraumatic seizures, dizziness, auditory impairments, anosmia, tremor, paraspinal pain, and visual symptoms. Adjustment disorders with disturbances of affect and emotion lability also may accompany mild TBI. All of these conditions may be approached with medications or a variety of therapy techniques or both. The approach to concussion in sports-related injuries is also reviewed.

Journal Article↗

X chromosome-linked Kallmann syndrome: clinical heterogeneity in three siblings carrying an intragenic deletion of the KAL-1 gene.

Kallmann syndrome (KS) is characterized by the association of hypogonadotropic hypogonadism and anosmia. The gene underlying the X chromosome-linked form of the disease, KAL-1, consists of 14 coding exons. It encodes a glycoprotein, anosmin-1, which is involved in the embryonic migration of GnRH-synthesizing neurons and the differentiation of the olfactory bulbs. We describe herein the clinical heterogeneity in three affected brothers who carry a large deletion (exons 3-13) in KAL-1. All three had a history of hypogonadotropic hypogonadism with delayed puberty. Although brain magnetic resonance imaging showed hypoplastic olfactory bulbs in the three siblings, variable degrees of anosmia/hyposmia were shown by olfactometry. In addition, these brothers had different phenotypic anomalies, i.e. unilateral renal aplasia (siblings B and C), high-arched palate (sibling A), brachymetacarpia (sibling A), mirror movements (siblings A and B), and abnormal eye movements (sibling C). Last but not least, sibling A suffered from a severe congenital hearing impairment, a feature that had been reported in KS but had not yet been ascribed unambiguously to the X-linked form of the disease. The variable phenotype, both qualitatively and quantitatively, in this family further emphasizes the role of putative modifier genes, and/or epigenetic factors, in the expressivity of the X-linked KS.

Adolescent↗

Clinical assessment and mutation analysis of Kallmann syndrome 1 (KAL1) and fibroblast growth factor receptor 1 (FGFR1, or KAL2) in five families and 18 sporadic patients.

We report on the clinical and molecular findings in 25 males and three females with Kallmann syndrome (KS) aged 10-53 yr. Ten males were from five families, and the remaining 15 males and three females were apparently sporadic cases. Molecular studies were performed for Kallmann syndrome 1 (KAL1) and fibroblast growth factor receptor 1 (FGFR1, also known as KAL2) by sequence analysis for all the coding exons, by PCR-based deletion analysis, and by fluorescence in situ hybridization (FISH) analysis, showing six novel and two recurrent intragenic KAL1 mutations in seven familial and four sporadic male cases and two novel intragenic FGFR1 mutations in two sporadic male cases. In addition, submicroscopic deletions at Xp22.3 involving VCX-A, STS, KAL1, and OA1 were identified in three familial cases and one sporadic male case affected by a contiguous gene syndrome. Clinical assessment in the 15 males with KAL1 mutations showed normal and borderline olfactory function in two males and right-side dominant renal lesion in seven males, in addition to variable degrees of hypogonadotropic hypogonadism (HH) in all the 15 males and olfactory dysfunction in 13 males. The two males with FGFR1 mutations had HH and anosmia and lacked other features. Clinical features in the remaining 11 cases with no demonstrable KAL1 or FGFR1 mutations included right renal aplasia in one female, cleft palate in one male, cleft palate and perceptive deafness in one male, and dental agenesis and perceptive deafness in one male, in addition to a variable extent of HH and olfactory dysfunction. The results suggest the following: 1) KAL1 mutations might be more prevalent in the Japanese patients than previously estimated in the Caucasian patients and can be associated with apparently normal olfactory function; 2) FGFR1 mutations account for approximately 10% of KS patients, as previously reported in the Caucasian patients, and can result in HH and olfactory dysfunction-only phenotype; and 3) renal aplasia, which is characteristic of KAL1 mutations, and cleft palate and dental agenesis, which are characteristic of FGFR1 mutations, can occur in patients without KAL1 and FGFR1 mutations.

Adolescent↗

Events surrounding the initiation of puberty with long term subcutaneous pulsatile gonadotropin-releasing hormone in a female patient with Kallman's syndrome.

An 18-yr-old woman with primary amenorrhea, anosmia, and total lack of secondary sexual development was treated for 230 days using sc pulsatile GnRH. GnRH testing with 100 micrograms, sc, initially revealed a peak FSH to LH ratio greater than 1. After 28 days of treatment, this ratio had reversed. A dosage of 20 micrograms/2 h for 200 days resulted in a LH to FSH ratio greater than 2. Widening the interval to 20 micrograms/3 h significantly lowered LH, but not FSH, levels. Increasing the frequency to 20 micrograms/90 min again increased the LH to FSH ratio. Twenty-four-hour testing revealed a sleep-entrained PRL rise both during and after GnRH therapy, but no sleep-entrained rise in LH. Ultrasound monitoring revealed cyclic changes in ovarian diameter at 30- to 60-day intervals that coincided with cyclic increases in LH and estradiol. The uterine fundus doubled in length between days 50 and 110 of treatment. The patient progressed from Tanner pubic hair and breast stage I to stage II during treatment, which was terminated due to an allergic reaction to GnRH. This study provides the first report of hormonal and ultrasound events surrounding puberty induction with GnRH in the female. We conclude widening the interval of GnRH administration can reduce LH levels while maintaining FSH levels, cyclic changes in ovarian diameter, LH, and estradiol occur before menarche, and although pulsatile GnRH provides a fascinating model for the study of puberty in the female, the chronicity of therapy needed and its potential for allergic reaction make this method of inducing puberty suboptimal.

Adolescent↗

Gonadotropin releasing hormone agonist (nafarelin) test to differentiate gonadotropin deficiency from constitutionally delayed puberty in teen-age boys--a clinical research center study.

The objective of this study was to determine whether the hormonal response to a GnRH agonist (nafarelin) challenge differentiates hypogonadotropinism from delayed puberty as well as the sleep test does. We studied boys ages 13.25-17.6 yr with prepubertal constitutional delay of puberty (CDP, n = 11), prepubertal gonadotropin deficiency (GnD, n = 10), pubertal CDP (PCDP, n = 11) and partial GnD (PGnD, n = 2). These disorders were defined on the basis of the following independent criteria: CDP = isolated delayed puberty with documentation of subsequent pubertal progression; GnD = panhypopituitarism or anosmia with absence of subsequent pubertal progression; PCDP = isolated delayed puberty in an early pubertal child; and PGnD = arrest of puberty in boys with partial hypopituitarism. CDP was compared with GnD and PCDP was compared with PGnD by analysis of variance and two-tailed t tests. Each patient had a nafarelin test with measurement of LH, FSH, and testosterone responses at intervals after nafarelin administration. Most patients had a sleep test with measurement of LH and testosterone levels at intervals overnight. CDP and GnD patients could not be distinguished by pubertal staging criteria. All but 1 patient with CDP had an LH response higher than that of GnD patients 4 h postnafarelin (P = 0.003). An incremental response to nafarelin of LH (delta LH at 4 h) below 4.8 IU/L was the best discriminant; it distinguished GnD from CDP in 95% of the cases and PGnD from PCDP completely. During the sleep test, all patients with CDP and 2 of 8 with GnD exhibited a significant increase in plasma LH. An incremental increase in LH during sleep (mean LH asleep minus mean LH awake) of less than 0.35 IU/L, near the limit of sensitivity of the method, differentiated GnD from CDP similarly to the nafarelin test. We conclude that the LH response to nafarelin distinguished gonadotropin deficiency from constitutional delay of puberty as well as the sleep test did and with certain advantages. The diagnostic reliability of the GnRH agonist test deserves to be determined prospectively in teen-agers with isolated GnD and partial hypopituitarism.

Adolescent↗

Exaggerated free alpha-subunit levels during pulsatile gonadotropin-releasing hormone replacement in women with idiopathic hypogonadotropic hypogonadism.

The goals of this study were to determine whether women with idiopathic hypogonadotropic hypogonadism (IHH) respond to pulsatile GnRH replacement therapy with exaggerated glycoprotein free alpha-subunit (FAS) levels, as reported in GnRH-deficient men, and to determine whether this pattern is unique to congenital GnRH deficiency or is also characteristic of patients with hypogonadotropic hypogonadism caused by other factors. GnRH was administered i.v. at a physiologic frequency and dose (75-100 ng/kg.bolus) to women with IHH (n = 11; n = 6 with anosmia); acquired GnRH deficiency secondary to treatment for cranial tumors (AHH; n = 7); and secondary hypothalamic amenorrhea (HA; n = 8). Results were compared with 24 normal cycling women. Gonadotropins, sex steroids, and FAS levels were measured in samples drawn daily across induced or normal menstrual cycles in patients or normal women, respectively. Samples were drawn at the same time of day and were collected 45 min after a GnRH bolus in patients. All women ovulated in response to pulsatile GnRH. There were no differences in the patterns of LH or gonadal steroid secretion between any of the patient groups (IHH, AHH, and HA). The patterns of LH and FSH secretion in the induced patient cycles were not different from normal women, with the exception of lower midcycle FSH levels in IHH women (P < 0.002). However, the daily dynamic secretion of FAS was exaggerated in IHH (compared with AHH, HA, and normal) women (P < 0.002). The increase in FAS levels in IHH was dependent on cycle stage, with the greatest difference observed during the early (P < 0.005) and midfollicular phase (P < 0.05) and the early luteal phase (P < 0.05). There was no difference in FAS between groups during the late follicular phase, at the midcycle, or in the midluteal and late luteal phase. This exaggerated FAS response to GnRH replacement in IHH was demonstrated in repeat cycles in two patients. Conclusions are: 1) Women with IHH respond to pulsatile GnRH replacement with an exaggerated secretion of FAS, which seems to be modified by gonadal factors; 2) this exaggerated FAS response, which is similar to that seen in GnRH-deficient men, is unique to congenital GnRH deficiency, and it is not observed in patients with acquired or secondary hypogonadotropic hypogonadism, suggesting that IHH patients may be missing a factor, in addition to GnRH, which normally restrains FAS secretion; and 3) the FAS response may prove to be a useful marker to distinguish constitutional delay of puberty from congenital GnRH deficiency.

Adolescent↗