The yield of diagnostic work-up of patients presenting with myalgia, exercise intolerance, or fatigue: A prospective observational study.

Myalgia, fatigue, and exercise intolerance are cause for referral to a neurologist. However, the diagnostic value of history, neurological examination, and ancillary investigations in patients with these symptoms is unknown. This study provides a sound footing for deciding which ancillary investigations should be conducted. A prospective observational study of the diagnostic approach in 187 patients with myalgia, exercise intolerance, or fatigue as their predominant symptom was performed. The primary outcomes were independent contribution of referral letter, history, examination, and ancillary investigations to a myopathy diagnosis. The secondary outcome was diagnostic value of combined ancillary investigations. 27% of patients had a myopathy. Positive family history (OR 3.2), progressive symptoms (OR 2.2), atrophy (OR 9.7), weakness (OR 10.9), and hyporeflexia (OR 4.4) were associated with a myopathy. Positive predictive values for myopathy were calculated for CK (0.32), EMG (0.66), ultrasound (0.47), and muscle biopsy (0.78). All contributed significantly in predicting myopathy. Multivariate analysis yielded a diagnostic algorithm facilitating a more efficient work-up in future patients. CK levels, EMG, ultrasound, and muscle biopsy independently contribute to predicting a myopathy. The diagnostic algorithm shows which combination of ancillary investigations should be employed in different subgroups and when to omit invasive techniques. This algorithm may drastically improve diagnostic efficiency.

Sleep disturbances in chronic progressive external ophthalmoplegia.

BACKGROUND: Chronic progressive external ophthalmoplegia (CPEO) is a relatively common mitochondrial disorder. In addition to extraocular muscle weakness, various other organs can typically be affected, including laryngeal and limb muscles, cerebrum, cerebellum, and peripheral nerves. Given this multi-organ involvement, patients are likely to be prone to sleep disturbances. Here, we determined the nature, prevalence, and determinants of sleep disturbances in CPEO. METHODS: We used validated questionnaires for various sleep disorders and possible determinants such as mood and anxiety, and we performed ambulant polysomnography (PSG) in 20 patients with genetically confirmed CPEO. RESULTS: Three quarters of patients reported nocturnal sleep dysfunction. Thirty-five percent of patients fulfilled the criteria for restless legs syndrome, 30% excessive daytime sleepiness, and 70% significant periodic limb movements. PSG recordings revealed several indicators of a disrupted sleep architecture. Obstructive sleep disordered breathing was present in only one patient. However, four patients had an increased central sleep apnea index, all of whom had a polymerase gamma-1 mutation and a SANDO phenotype (sensoric atactic neuropathy, dysarthria, ophthalmoplegia). Physical examination and questionnaire outcomes were poor predictors of PSG results. CONCLUSION: Several specific sleep disturbances are part of the phenotype of CPEO. Given that the disease is otherwise incurable, symptomatic treatment of sleep disturbances may be an important tool to improve quality of life. Therefore, patients with CPEO should be actively screened for sleep disorders, with a low threshold to perform PSG.

Cerebellar ataxia with elevated cerebrospinal free sialic acid (CAFSA).

In order to identify new metabolic abnormalities in patients with complex neurodegenerative disorders of unknown aetiology, we performed high resolution in vitro proton nuclear magnetic resonance spectroscopy on patient cerebrospinal fluid (CSF) samples. We identified five adult patients, including two sisters, with significantly elevated free sialic acid in the CSF compared to both the cohort of patients with diseases of unknown aetiology (n = 144; P < 0.001) and a control group of patients with well-defined diseases (n = 91; P < 0.001). All five patients displayed cerebellar ataxia, with peripheral neuropathy and cognitive decline or noteworthy behavioural changes. Cerebral MRI showed mild to moderate cerebellar atrophy (5/5) as well as white matter abnormalities in the cerebellum including the peridentate region (4/5), and at the periventricular level (3/5). Two-dimensional gel analyses revealed significant hyposialylation of transferrin in CSF of all patients compared to age-matched controls (P < 0.001)--a finding not present in the CSF of patients with Salla disease, the most common free sialic acid storage disorder. Free sialic acid content was normal in patients' urine and cultured fibroblasts as were plasma glycosylation patterns of transferrin. Analysis of the ganglioside profile in peripheral nerve biopsies of two out of five patients was also normal. Sequencing of four candidate genes in the free sialic acid biosynthetic pathway did not reveal any mutation. We therefore identified a new free sialic acid syndrome in which cerebellar ataxia is the leading symptom. The term CAFSA is suggested (cerebellar ataxia with free sialic acid).

[Mitochondrial diseases; thinking beyond organ specialism necessary]. / Mitochondriale ziekten; orgaanspecialisme-overstijgend denken gevraagd.

Mitochondrial disorders are caused by a defect in intracellular energy production. In general, these are multi-system disorders, predominantly affecting organs with high energy requirements. Due to the fact that mitochondrial disorders are not as rare as is generally assumed, and due to the diversity of symptoms, many different medical specialists will at some time be confronted with these patients. Early recognition ofa mitochondrial disorder reduces patient anxiety and avoids unnecessary ancillary investigations and potentially hazardous treatments. A mitochondrial disease should be considered in the event of dysfunction of more than 2 organ systems or processes with high energy requirements, certainly if there is a positive maternal family history. If fatigue includes exercise-induced muscle pain or muscle weakness, and if muscle pain predominantly occurs during exertion, a mitochondrial disease should be considered. The combination ofdiabetes mellitus and deafness is also a strong indicator of mitochondrial disease. An extensive family history should always be taken. In adults, the most frequently occurring mitochondrial syndromes are chronic progressive external ophthalmoplegia (CPEO), maternally inherited diabetes and deafness syndrome (MIDDS) and Leber's hereditary optic neuropathy. Since much research effort is currently being invested in the development of causal medical treatments, the importance of an early diagnosis is likely to become of increasing importance in the future.

Hypogammaglobulinaemia: cumulative experience in 49 patients in a tertiary care institution.

In this paper, clinical data of 49 adult patients with agammaglobulinaemia (syn. hypogammaglobulinaemia), 15 cases of X-linked agammaglobulinaemia (XLA) and 34 of common variable immunodeficiency (CVID) are reviewed. Although immunoglobulin substitution largely abolished life-threatening respiratory tract infections, considerable infectious and non-infectious morbidity was still encountered in these patients. Almost all patients suffered from chronic or recurrent upper and lower airway infections, mainly caused by Haemophilus influenzae and pneumococci. The lower respiratory tract infections led to cumulative damage to the respiratory tract, especially in XLA patients. Also the incidence of infections outside the respiratory tract (giardiasis, Campylobacter jejuni infections) was more common in XLA patients than in CVID patients. Nodular lymphoid hyperplasia was only found in CVID. A variety of other non-infectious complications were seen especially in CVID. Neoplastic complications occurred in nine patients (two cases of thymoma, two colorectal cancer, one gastric carcinoma, two haematological malignancies, two cases of skin cancer). Six patients died (five XLA patients and one CVID patient, from infectious and non-infectious causes).