Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms

Leukodystrophies are genetically determined disorders characterized by the selective involvement of the central nervous system white matter. Onset may be at any age, from prenatal life to senescence. Many leukodystrophies are degenerative in nature, but some only impair white matter function. The clinical course is mostly progressive, but may also be static or even improving with time. Progressive leukodystrophies are often fatal, and no curative treatment is known. The last decade has witnessed a tremendous increase in the number of defined leukodystrophies also owing to a diagnostic approach combining magnetic resonance imaging pattern recognition and next generation sequencing. Knowledge on white matter physiology and pathology has also dramatically built up. This led to the recognition that only few leukodystrophies are due to mutations in myelin- or oligodendrocyte-specific genes, and many are rather caused by defects in other white matter structural components, including astrocytes, microglia, axons and blood vessels. We here propose a novel classification of leukodystrophies that takes into account the primary involvement of any white matter component. Categories in this classification are the myelin disorders due to a primary defect in oligodendrocytes or myelin (hypomyelinating and demyelinating leukodystrophies, leukodystrophies with myelin vacuolization); astrocytopathies; leuko-axonopathies; microgliopathies; and leuko-vasculopathies. Following this classification, we illustrate the neuropathology and disease mechanisms of some leukodystrophies taken as example for each category. Some leukodystrophies fall into more than one category. Given the complex molecular and cellular interplay underlying white matter pathology, recognition of the cellular pathology behind a disease becomes crucial in addressing possible treatment strategies

Mild to moderate hidradenitis suppurativa treated with local excision and primary closure

Background Hidradenitis suppurativa (HS) is a chronic skin disease with a great impact on quality of life. Treatment with antibiotics or anti-inflammatory drugs, such as prednisone or TNF-alpha-inhibitors usually achieves only temporary improvement. Surgical intervention is considered as the only curative treatment for recurrent lesions. Objective To determine the efficacy and patient satisfaction of local excision followed by primary closure. Methods Between 2005 and 2010, 92 local excisions with primary closure were performed in 57 patients with mild to moderate HS. All patients were treated on an outpatient basis, under local anaesthesia. Local excision was defined as complete excision of the affected tissue, beyond the borders of activity, leaving clear margins. The medical records were reviewed retrospectively in 2010. The final outcome of the procedure, cosmetic appearance and patient satisfaction was measured using a questionnaire. Results Successful treatment, without recurrence, was accomplished in 66% of the cases. The intervention was generally well tolerated: 84% of the patients stated that they would undergo the same surgical procedure again if necessary, and 89% would recommend the procedure to other patients. Conclusion Local excision followed by primary closure is a valuable treatment for patients with mild to moderate HS (Hurly stage I & II), with low morbidity and a high patient satisfaction rat

New-onset polyarthritis during successful treatment of hidradenitis suppurativa with infliximab

Hidradenitis suppurativa (HS) can be associated with several forms of arthritis, usually considered as reactive arthritis. A new observation is that some patients with HS develop arthritis after treatment with infliximab (antitumour necrosis factor-α). A retrospective study was performed to establish the frequency and clinical presentation of new-onset arthritis during infliximab treatment. Between 2005 and 2009, 27 individuals with severe HS were treated with infliximab and followed up closely. Laboratory parameters and side-effects were recorded. The frequency of arthritis was compared with control groups consisting of 227 patients with HS not treated with any biological, 22 patients with HS treated with adalimumab and 28 patients with psoriasis treated with infliximab, in the same period at the same clinic. Five of the 27 patients with HS (18%) treated with infliximab developed an acute and painful polyarthritis during treatment. The arthritis occurred on average after 12 months of treatment, was not clearly associated with anti-infliximab antibodies and resolved on average after 4 months. Interestingly, none of the patients had suffered from arthritis before despite the long duration of HS and all showed a good skin response to infliximab. Moreover, arthritis was not observed in any of the control groups. Compared with the adalimumab group and the psoriasis group, odds ratios of 7·241 [95% confidence interval (CI) 1·15-45·6] and 9·025 (95% CI 1·45-55·82) were calculated. The five cases described in this article suggest that infliximab treatment in HS can induce a transient but severe polyarthritis. The underlying mechanisms remain to be investigated furthe

DOMINO, doxycycline 40 mg vs. minocycline 100 mg in the treatment of rosacea: a randomized, single-blinded, noninferiority trial, comparing efficacy and safety

Background There is a lack of evidence for minocycline in the treatment of rosacea. Objectives To compare the efficacy and safety of doxycycline 40 mg vs. minocycline 100 mg in papulopustular rosacea. Methods In this randomized, single-centre, 1 : 1 allocation, assessor-blinded, noninferiority trial, patients with mild-to-severe papulopustular rosacea were randomly allocated to either oral doxycycline 40 mg or minocycline 100 mg for a 16-week period with 12 weeks of follow-up. Our primary outcomes were the change in lesion count and change in patient's health-related quality of life (using RosaQoL). Intention-to-treat and per protocol analyses were performed. Results Of the 80 patients randomized (40 minocycline, 40 doxycycline), 71 were treated for 16 weeks. Sixty-eight patients completed the study. At week 16, the median change in lesion count was comparable in both groups: doxycycline vs. minocycline, respectively 13 vs. 14 fewer lesions. The RosaQoL scores were decreased for both doxycycline and minocycline, respectively by 0.62 and 0.86. Secondary outcomes were comparable except for Investigator's Global Assessment success, which was seen significantly more often in the minocycline group than in the doxycycline group (60% vs. 18%, P <0.001). At week 28, outcomes were comparable, except for RosaQoL scores and PaGA, which were significantly different in favour of minocycline (P = 0.005 and P = 0.043, respectively), and fewer relapses were recorded in the minocycline group than in the doxycycline group (7% and 48%, respectively; P <0.001). No serious adverse reactions were reported. Conclusions Minocycline 100 mg is noninferior to doxycycline 40 mg in efficacy over a 16-week treatment period. At follow-up, RosaQoL and PaGA were statistically significantly more improved in the minocycline group than in the doxycycline group, and minocycline 100 mg gives longer remission. In this study there was no significant difference in safety between these treatments; however, based on previous literature minocycline has a lower risk-to-benefit ratio than doxycycline. Minocycline 100 mg may be a good alternative treatment for those patients who, for any reason, are unable or unwilling to take doxycycline 40 m

Peripheral neuropathy in metachromatic leukodystrophy: current status and future perspective

Metachromatic leukodystrophy (MLD) is an autosomal recessively inherited metabolic disease characterized by deficient activity of the lysosomal enzyme arylsulfatase A. Its deficiency results in accumulation of sulfatides in neural and visceral tissues, and causes demyelination of the central and peripheral nervous system. This leads to a broad range of neurological symptoms and eventually premature death. In asymptomatic patients with juvenile and adult MLD, treatment with allogeneic hematopoietic stem cell transplantation (HCT) provides a symptomatic and survival benefit. However, this treatment mainly impacts brain white matter, whereas the peripheral neuropathy shows no or only limited response. Data about the impact of peripheral neuropathy in MLD patients are currently lacking, although in our experience peripheral neuropathy causes significant morbidity due to neuropathic pain, foot deformities and neurogenic bladder disturbances. Besides, the reasons for residual and often progressive peripheral neuropathy after HCT are not fully understood. Preliminary studies suggest that peripheral neuropathy might respond better to gene therapy due to higher enzyme levels achieved than with HCT. However, histopathological and clinical findings also suggest a role of neuroinflammation in the pathology of peripheral neuropathy in MLD. In this literature review, we discuss clinical aspects, pathological findings, distribution of mutations, and treatment approaches in MLD with particular emphasis on peripheral neuropathy. We believe that future therapies need more emphasis on the management of peripheral neuropathy, and additional research is needed to optimize care strategies