Work difficulties in people with multiple sclerosis: The role of anxiety, depression and coping.

Background: Symptoms of anxiety and depression affect the daily life of people with multiple sclerosis (MS). This study examined work difficulties and their relationship with anxiety, depression and coping style in people with MS. Methods: 219 employed people with MS (median age = 43 years, 79% female) completed questionnaires on anxiety, depression, coping style, demographics and work difficulties, and underwent a neurological examination. Two regression analyses were performed with work difficulties as the dependent variable and either anxiety or depression as continuous independent variables. Coping style, age, gender, educational level, MS-related disability and disease duration were added as additional predictors, as well as interaction terms between coping style and either symptoms of depression or anxiety. Results: A significant model was found (F (10,205) = 13.14, p < 0.001, R 2 = 0.39) in which anxiety, emotion- and avoidance-oriented coping and MS-related disability were positively related to work difficulties. The analysis of depression resulted in a significant model (F (10,205) = 14.98, p < 0.001, R 2 = 0.42) in which depression, emotion- and avoidance-oriented coping and MS-related disability were positively related to work difficulties. None of the interaction effects were significant. Conclusions: Work difficulties were positively related to anxiety, depression, emotion- and avoidance-oriented coping and MS-related disability in workers with MS.

Caregiver strain among life partners of persons with mild disability due to relapsing-remitting multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a chronic disorder of the central nervous system with an unpredictable disease course. Life partners often become caregivers, which can be both rewarding and challenging, as the caregiver's physical and mental health is often negatively affected. Previous studies on caregiver strain focused on caregivers of persons with MS with relatively high disability levels, while caregiver strain may already be experienced by life partners living with mildly disabled persons with MS. OBJECTIVE: The current study examines factors associated with caregiver strain in life partners of persons with mild disability due to relapsing-remitting MS. METHODS: We included 173 persons with relapsing-remitting MS (79% female; mean age 42.8 years; 90% employed; median EDSS 2.0) and their life partners. The life partners completed questionnaires on caregiver strain and neuropsychiatric and cognitive functioning of the person with MS. The persons with MS completed questionnaires about demographics, fatigue, personality, physical, cognitive and neuropsychiatric functioning, and underwent neuropsychological and neurological examinations. A linear regression analysis was conducted to examine predictors of caregiver strain. RESULTS: 24% of the life partners experienced above average levels of caregiver strain. A multivariate linear regression analysis revealed that a higher age of the person with MS (ß = 0.16, p = 0.04), more physical disability (ß = 0.17 p = 0.04), more cognitive and neuropsychiatric problems of the person with MS as reported by the life partner (ß = 0.33, p = 0.001) and higher severity of neuropsychiatric symptoms as reported by the life partner (ß = 0.32, p = 0.001) were associated with higher caregiver strain (R2 = 0.49). CONCLUSION: Higher caregiver strain in life partners of persons with mild disability due to relapsing-remitting MS was primarily associated with cognitive and neuropsychiatric problems of the person with MS.

Coping strategies in relation to negative work events and accommodations in employed multiple sclerosis patients.

BACKGROUND: Job loss is common in multiple sclerosis (MS) and is known to exert a negative effect on quality of life. The process leading up to job loss typically includes negative work events, productivity losses and a need for accommodations. By using active coping strategies job loss may be prevented or delayed. OBJECTIVE: Our goal was to examine negative work events and accommodations in relation to coping strategies in employed relapsing-remitting MS patients. METHODS: Ninety-seven MS patients (77% females; 21-59 years old) completed questionnaires concerning the patient's work situation, coping strategies, demographics, physical, psychological and cognitive functioning. Forward binary logistic regression analyses were conducted to examine coping strategies and other (disease) characteristics predictive of reported negative work events and accommodations. RESULTS: Nineteen per cent of the employed MS patients reported one or more negative work events, associated with a higher use of emotion-oriented coping and more absenteeism. Seventy-three per cent reported using one or more work accommodations, associated with a higher educational level and more presenteeism. MS patients reporting physical changes to the workplace employed more emotion-oriented coping, while flexible scheduling was associated with task-oriented coping. CONCLUSION: Emotion-oriented and task-oriented coping strategies are associated with negative work events and the use of accommodations.

Concomitant CNS pathology in a patient with amyotropic lateral sclerosis following poliomyelitis in childhood.

Post-polio syndrome (PPS) develops in approximately 30% of polio survivors several decades after the acute attack of paralytic poliomyelitis. Some of these patients develop post-poliomyelitis muscular atrophy (PPMA) which is characterized by a slowly progressive muscle weakness. Due to its clinicopathological features, investigators have often studied PPS and PPMA in association with amyotrophic lateral sclerosis (ALS), the underlying hypothesis being an increased risk of developing ALS from a prior acute paralytic poliomyelitis. Various studies, however, have indicated that de novo ALS cases in patients with prior acute paralytic poliomyelitis are rare. Herein, we describe a rare case of a 75-year-old woman who at post-mortem examination presented a combination of a PPS with proven histopathological sporadic ALS features. Furthermore, neuropathology of this case also revealed several other histopathological findings reminiscent of a tauopathy, synucleinopathy and amyloid angiopathy and a large pituitary cyst. To our knowledge, this is the first reported case of PPS with clear pathological hallmarks of sporadic ALS, including ubiquitin-, TDP-43, phosphorylated TDP-43- and p62-positive inclusions, with accompanying features compatible with Alzheimer's and Parkinson's disease.

Deadly vasospasm.

A patient with Prinzmetal's variant angina (PVA) developed a cardiac arrest due to coronary vasospasm and subsequent myocardial infarction. After resuscitation postanoxic brain injury was diagnosed. After an initial improvement of consciousness he deteriorated rapidly on the seventh day after admission due to severe brain ischaemia apparently caused by cerebral vasospasm, until ultimately brain death was diagnosed. To our knowledge, the association between PVA and cerebral vasospasm has never been described. The combination suggests that this patient had a generalized vasospastic disorder.

[Diagnostic image (379). A confused man with tetraparesis and haemophilia]. / Diagnose in beeld (379). Een man met verwardheid, tetraparese en hemofilie.

A 77-year-old haemophilic man presented with confusion, somnolence and tetraparesis due to massive bilateral subdural haematomas.

[From gene to disease; X-linked adrenoleukodystrophy]. / Van gen naar ziekte; X-gebonden adrenoleukodystrofie.

X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder, characterized by impaired peroxisomal beta-oxidation, subsequent accumulation of very long-chain fatty acids (> 22 carbon atoms), and mutations in the ABCD1 gene. Clinical manifestations, diagnostic procedures and treatment options are discussed.

ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: role in diagnosis and clinical correlations.

X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene, which encodes a peroxisomal ABC half-transporter (ALDP) involved in the import of very long-chain fatty acids (VLCFA) into the peroxisome. The disease is characterized by a striking and unpredictable variation in phenotypic expression. Phenotypes include the rapidly progressive childhood cerebral form (CCALD), the milder adult form, adrenomyeloneuropathy (AMN), and variants without neurologic involvement. There is no apparent correlation between genotype and phenotype. In males, unambiguous diagnosis can be achieved by demonstration of elevated levels of VLCFA in plasma. In 15 to 20% of obligate heterozygotes, however, test results are false-negative. Therefore, mutation analysis is the only reliable method for the identification of heterozygotes. Since most X-ALD kindreds have a unique mutation, a great number of mutations have been identified in the ABCD1 gene in the last seven years. In order to catalog and facilitate the analysis of these mutations, we have established a mutation database for X-ALD ( http://www.x-ald.nl). In this review we report a detailed analysis of all 406 X-ALD mutations currently included in the database. Also, we present 47 novel mutations. In addition, we review the various X-ALD phenotypes, the different diagnostic tools, and the need for extended family screening for the identification of new patients.

Evolution of phenotypes in adult male patients with X-linked adrenoleukodystrophy.

Our objective was to study the phenotype evolution of X-linked adrenoleukodystrophy (X-ALD) and the relation between axonal degeneration and cerebral demyelination. Although different X-ALD phenotypes are recognized, little is known about their evolution. Neuropathological and electrophysiological studies have shown that X-ALD is a disease with mixed features of axonal degeneration, leading to myeloneuropathy, and a severe inflammatory reaction in the cerebral white matter, resulting in demyelination. Retrospectively, 129 men with X-ALD were studied who were 1) at least 20 years presently or at the time of death, and 2) regularly monitored. Phenotype assignments were made at diagnosis and at present, or at death, using medical history and findings of neurological examination. Handicap was studied with the modified Rankin scale, and cerebral abnormalities with the X-ALD MRI severity (Loes) score. The mean follow-up interval was 10.1 +/- 5.0 years. Among 32 patients neurologically asymptomatic at diagnosis, 16 (50%) developed neurological deficits. Among 68 adrenomyeloneuropathy (AMN) patients initially without clinical brain involvement, 13 (19%) additionally developed cerebral demyelination. In a subset of 60 AMN patients, a moderate handicap evolved over a period of 16.2 +/- 8.9 years. Among 13 AMN patients with additional definite or probable cerebral involvement at diagnosis, eight died and one remained in a vegetative state. Most of the 16 patients with the cerebral phenotypes deteriorated. There is a high risk for adult neurologically asymptomatic patients to develop neurological deficits and for AMN patients to develop cerebral demyelination. Axonal degeneration and cerebral demyelination emerge in X-ALD independently of each other. This may have implications for the phenotype classification, the search for modifying factors, and the development and evaluation of new therapies.

[Carrier state of x-linked adrenoleukodystrophy]. / Draagsterschap van X-gebonden adrenoleukodystrofie.

X-linked adrenoleukodystrophy (X-ALD) is a sex-linked, inherited, metabolic disorder affecting the nervous system and endocrine organs. At least 20 to 50% of female carriers develop neurological deficits. Identification of female carriers is important, among other reasons because unnecessary new cases of this disorder, which is frequently lethal in boys, can be prevented by prenatal diagnosis. Furthermore, affected male offspring can be screened for adrenocortical insufficiency, which is treatable, or for early signs of cerebral involvement in which case bone marrow transplantation may be considered. Whether or not someone is a carrier can be investigated by determining the concentrations of saturated very-long-chain fatty acids in the plasma or cultured skin fibroblasts, by looking for the presence of X-ALD protein in cultured fibroblasts and by carrying out mutation analysis. Spasticity, painful muscular cramps, lumbago and arthralgias can be treated symptomatically with the same agents used for other aetiologies. A clinical geneticist can provide advice on heredity and the possibilities of prenatal diagnosis and pre-implantation techniques.

Presence of diarrhea and absence of tendon xanthomas in patients with cerebrotendinous xanthomatosis.

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive disorder of bile acid synthesis. A diagnosis of CTX should be considered in patients with premature bilateral cataracts, intractable diarrhea, neurological signs and symptoms, and tendon xanthomas, especially in the Achilles tendons. The prevalence of these signs and symptoms increases with age. OBJECTIVES: To investigate signs and symptoms, age at onset, and age at diagnosis in 32 patients with biochemically and genetically confirmed CTX, and to compare this clinical spectrum with reports in the literature. METHODS: Retrospective analysis of records of all patients with CTX at our hospital (27 adults and 5 children). After a MEDLINE search in the English, French, and German literature, 181 patients with CTX (165 adults and 16 children) were identified worldwide. RESULTS: Of our 32 patients with CTX, 31 (97%) had cataracts and neurological signs and symptoms, predominantly pyramidal signs (26 [81%]); 21 (66%) had low intelligence and 18 (56%) had cerebellar signs. Only 13 (41%) had visible or palpable tendon xanthomas at the time of diagnosis. In total, 16 patients (50%) had chronic, intractable diarrhea that started in childhood. These findings were in contrast with the literature, where tendon xanthomas were reported in 89% and diarrhea in only 2 patients. CONCLUSIONS: We believe that CTX is underdiagnosed worldwide. We recommend that the presence of 2 of the 4 clinical hallmarks of CTX prompt thorough metabolic screening, including determination of urine bile alcohol excretion and serum cholestanol level, because CTX is a treatable disease.

Progression of abnormalities in adrenomyeloneuropathy and neurologically asymptomatic X-linked adrenoleukodystrophy despite treatment with "Lorenzo's oil".

OBJECTIVES: X-linked adrenoleukodystrophy (X-ALD) is an inherited disorder of peroxisomal fatty acid oxidation, biochemically characterised by the accumulation of saturated very long chain fatty acids (VLCFAs), particularly hexacosanoic acid (C26:0). Dietary treatment with a 4:1 mixture of glyceroltrioleate and glyceroltrierucate ("Lorenzo's oil") normalises plasma VLCFA concentrations, but neither ameliorates nor arrests the rapid progression of neurological symptoms in the cerebral variants of X-ALD. The efficacy of "Lorenzo's oil" in the milder phenotypes of X-ALD was assessed, as this has been much less investigated. METHODS: Twenty two patients who were treated with "Lorenzo's oil" for at least 12 months for a median period of 2.5 (range 1.0-6.0) years were studied. Two had asymptomatic ALD, four the "Addison only" variant, 13 adrenomyeloneuropathy (AMN), and three were symptomatic female carriers. RESULTS: The plasma C26:0 concentration normalised or near normalised in 19 patients (86%), in the three others it decreased significantly. Nevertheless, disability as measured with the extended disability status scale score increased mildly (0.5 (95% confidence interval (95% CI) 0.25-1.0)) in the 16 patients with neurological symptoms. Furthermore, one "Addison only" patient and one patient with AMN developed cerebral demyelination, and another "Addison only" patient developed AMN. Adrenocortical insufficiency evolved in one patient with AMN, and hypogonadism in one patient with asymptomatic ALD and two patients with AMN. Nerve conduction, evoked potential studies (SEP, BAEP, VEP), and abnormalities on cerebral MRI did not improve. On the other hand, side effects were often noted-namely, mild increases in liver enzymes (55%), thrombocytopenia (55%), gastrointestinal complaints (14%), and gingivitis (14%). We also found a mild decrease in haemoglobin concentration and leucocyte count. CONCLUSIONS: The data suggest that treatment with "Lorenzo's oil" neither improved neurological or endocrine function nor arrested progression of the disease. Furthermore, the oil often induced adverse effects. Therefore, it is advocated that "Lorenzo's oil" should not be prescribed routinely to patients with X-ALD who already have neurological deficits.

Lorenzo's oil and platelet activation in adrenomyeloneuropathy and asymptomatic X-linked adrenoleukodystrophy.

X-linked adrenoleukodystrophy (X-ALD) is an inherited disorder of peroxisomal beta-oxidation, which results in accumulation of very long-chain fatty acids, causing damage to the nervous system, adrenal cortex and testis. The two most frequent phenotypes are childhood cerebral adrenoleukodystrophy (CCALD) and adrenomyeloneuropathy (AMN). Some affected males demonstrate no clinical signs (asymptomatic ALD), whereas female carriers can also be affected. Patients with X-ALD have been treated with Lorenzo's oil, a 4:1 combination of oleic acid and erucic acid, with thrombocytopenia as the main side effect and sometimes leading to a hemorrhagic diathesis. We studied platelet count, size and membrane surface exposure of platelet activation antigens in 17 adult X-ALD patients. Eight patients used the prescribed amount of erucic acid (as glyceroltrierucate) or more (very compliant), five used less(compliant), and four did not use the diet. All eight very compliant patients had highly enlarged platelets and seven manifested thrombocytopenia. An enhanced in vivo platelet activation status was established by increased platelet surface expression of P-selectin (CD62P, PADGEM, GMP-140) in five of the seven thrombocytopenic patients, and of increased fibrinogen receptor exposure (measured with the antibody PAC-1) in three of these five patients. The other nine compliant or untreated patients had normal platelet counts and, generally, normal P-selection and fibrinogen receptor expression. A diet-induced 7- to 27-fold enrichment of erucic acid was observed in the platelets of the four patients studied. We conclude that the thrombocytopenia in AMN patients using Lorenzo'soil is associated with circulating platelets that have an increased erucic acid content, size and activation status. We hypothesize that the erucic acid in some way induces the increased size and thus, directly or indirectly, increased platelet activation or instability in vivo. This then causes the thrombocytopenia, with circulating platelets representing a population that has not yet been sufficiently changed to be removed, but has clear signs of activation.

X linked adrenoleukodystrophy: clinical presentation, diagnosis, and therapy.

X linked adrenoleukodystrophy (X-ALD) is an inherited disorder of peroxisomal metabolism, biochemically characterised by accumulation of saturated very long chain fatty acids. Accumulation of these fatty acids is associated with cerebral demyelination, peripheral nerve abnormalities, and adrenocortical and testicular insufficiency. The lowest estimated birth incidence is one per 100,000. At least six phenotypes can be distinguished, of which the two most frequent are childhood cerebral ALD and adrenomyeloneuropathy. The X-ALD gene has been identified, but thus far no relation between genotype and phenotype has been found. Diagnosis is relatively easy and can be confirmed reliably, and prenatal testing is possible in affected families. Several therapeutic options, some with promising perspectives, are available. Neurologists and other physicians seem not to be familiar with the many facets of X-ALD. In this review, the clinical presentation, the relative frequencies of the different phenotypes, and the diagnostic and therapeutic options are presented.

ALDP expression in fibroblasts of patients with X-linked adrenoleukodystrophy.

The adrenoleukodystrophy gene encodes a peroxisomal integral membrane protein (ALDP) consisting of 745 amino acids with a molecular weight of 75kDa. ALDP expression was studied in fibroblasts from 24 male ALD patients from 17 unrelated ALD kindreds. In four kindreds an identical 2-base-pair deletion was found. We report the absence of ALDP in 12 kindreds carrying nonsense mutations, frame shifts or amino acid substitutions in the carboxy terminus of ALDP, together accounting for 71% of the ALD kindreds. ALDP was present in five kindreds (29%) with amino acid substitutions in the amino terminal half of the protein; in two of these kindreds ALDP was present although at a reduced level. The absence of truncated proteins suggests that the carboxy terminus has a function in the stabilization of ALDP.

Peripheral nerve abnormalities in adrenomyeloneuropathy: a clinical and electrodiagnostic study.

Adrenomyeloneuropathy (AMN) is one of the most frequent phenotypes of X-linked adrenoleukodystrophy. Whether the polyneuropathy in AMN results from primary demyelination or axonal degeneration is uncertain. We examined 23 patients (18 men with AMN and five female carrier with AMN symptomatology), performed electroneurography and EMG, and compared our results with standardized electrodiagnostic criteria for primary demyelination. Both clinically and electrodiagnostically, the lower extremities were most frequently and most severely affected. A longer duration of symptoms was related to more severe pyramidal dysfunction (p < 0.004) and spasticity (p < 0.04), and to a more severe impairment of vibration sense (p < 0.05). There were on correlations between the different electrophysiologic studies and the duration of neurologic symptoms. Only two AMN patients (9%) fulfilled the electrodiagnostic criteria for primary demyelination. However, both had abnormally low compound muscle action potentials, which may have been a reflection of primary axonal degeneration. Six other patients (26%) partially fulfilled the criteria for primary demyelination, of whom five also manifested low compound muscle action potentials. In 15 patients (65%), we found polyneuropathy with predominantly axonal, sensorimotor features. We conclude that the neuropathy in AMN patients is due to primary axonal degeneration.

Spectrum of mutations in the gene encoding the adrenoleukodystrophy protein.

X-linked adrenoleukodystrophy (ALD) has been associated with mutations in a gene encoding an ATP-binding transporter, which is located in the peroxisomal membrane. Deficiency of the gene leads to impaired peroxisomal beta-oxidation. Systematic analysis of the open reading frame of the ALD gene, using reverse transcriptase-PCR, followed by direct sequencing, revealed mutations in all 28 unrelated kindreds analyzed. No entire gene deletions or drastic promoter mutations were detected. In only one kindred did the mutation involve multiple exons. The other mutations were small alterations leading to missense (13 of 28) or nonsense mutations, a single amino acid deletion, frameshifts, or splice acceptor-site defects. Mutations affecting a single amino acid were concentrated in the region between the third and fourth putative transmembrane domains and in the ATP-binding domain. Mutations were detected in all investigated ALD kindreds, suggesting that this gene is the only gene responsible for X-linked ALD. This overview of mutations is useful in the determination of structurally and functionally important regions and provides an efficient screening strategy for identification of mutations in the ALD gene.

Predominance of the adrenomyeloneuropathy phenotype of X-linked adrenoleukodystrophy in The Netherlands: a survey of 30 kindreds.

X-linked adrenoleukodystrophy (X-ALD) is an inherited disorder of peroxisomal beta-oxidation associated with accumulation of saturated very long-chain fatty acids, which results in central and peripheral demyelination and in impaired function of adrenal cortex and testes. The phenotypic expression is highly variable, childhood cerebral ALD (CCALD) and adrenomyeloneuropathy (AMN) being the main variants. We explored the 30 Dutch kindreds well known to the Dutch X-ALD/AMN Study Group and phenotyped 77 male patients: 35 (46%) had AMN and 24 (31%) CCALD or adolescent cerebral ALD (AdolCALD). These percentages differ significantly from previous reports, in which 25 to 28% of the patients developed AMN and 53 to 57% CCALD or AdolCALD. Our findings indicate that--at least in the Netherlands--AMN may be the most frequent phenotype of X-ALD.

Identification of a two base pair deletion in five unrelated families with adrenoleukodystrophy: a possible hot spot for mutations.

The gene for X-linked adrenoleukodystrophy (ALD) was recently identified. Intragenic deletions of several kilobases were found in about 7% of patients. Point mutations, expected to be very heterogeneous, were identified so far in only two patients. We report the identification of a two base pair deletion at position 1801-1802 of the ALD cDNA, located within the fifth exon of the ALD gene, which precedes the two consensus motives for ATP-binding. This microdeletion was found in five out of 40 unrelated ALD kindreds, indicating that this position is a hot spot for mutations. The mutation was observed both in patients with childhood cerebral ALD (CCALD) and in patients with adrenomyeloneuropathy (AMN).