Franz Reisecker

Minocycline for Huntington’s disease: An open label study

Despite advances in understanding the pathogenesis of Huntington’s disease (HD), there is no effective treatment. In the HD transgenic mouse, expression of a dominant-negative caspase-1 mutant extended survival and delayed the onset of symptoms, suggesting that caspase-1 is crucial in HD pathogenesis.1 In fact, the caspase inhibitor minocycline delayed disease progression and extended survival by 14% in the HD mouse model.2 Minocycline is a second-generation tetracycline commonly used for a prolonged period to treat acne. Minocycline crosses the blood–brain barrier and inhibits caspase-1 in acute stroke and decreases infarct size in a mouse stroke model.2 Minocycline protects neurons in mixed spinal cord cultures …

Serum dehydroepiandrosterone and cortisol measurements in Huntington's chorea

Serum levels of dehydroepiandrosterone sulfate (DHEAS), known to antagonize metabolic effects of glucocorticoids in animals, and cortisol (CRT), already shown to be related to cognitive dysfunction in man and animals, were measured in 11 drug-free male subjects with definite Huntingtons chorea (HC) and in 25 age-matched male normal controls. Statistical difference was found between DHEAS serum levels (p < 0.05), CRT levels (p < 0.05) and the DHEAS/CRT ratio (p < 0.01) of HC subjects and normal individuals. These findings may indicate a dysfunction of the hypothalamic-pituitary-adrenal axis (HPAA) and possibly suggest a role of DHEAS as an antiglucocorticoid in HC.

Prevalence of autoimmune thyroiditis and non-immune thyroid disease in multiple sclerosis.

Abstract. Since multiple sclerosis (MS) and autoimmune thyroiditis (AIT) are presumed to be of autoimmune origin the correlation of these two diseases is of special interest. The aim of this study was to determine whether there are differences in the prevalence of thyroid disease with special emphasis on AIT compared with MS and normal subjects and whether the presence of thyroid disease correlates with disability, disease course, age, and disease duration. 353 consecutive patients with clinically definite MS, without interferon-beta treatment and 308 patients with low back pain or headache were extensively examined for the presence of non-immune or autoimmune thyroid disease. We found a significantly higher prevalence of AIT in male MS patients (9.4 %) than in male controls (1.9 %; p = 0.03). The prevalence of AIT in female MS patients (8.7 %) did not differ from female controls (9.2 %). Hypothyroidism, caused by AIT in almost all cases, showed a tendency to be more severe and more often present in patients with MS. There was no association between relapsing-remitting and secondary progressive disease course of MS and the prevalence of AIT. MS patients with AIT were significantly older but did not differ in disease duration and expanded disability status scale (EDSS). Further studies are warranted, to see if there is a difference in sex-hormone levels between MS patients with and without AIT and healthy controls. Longitudinal studies comparing MS patients with or without AIT could show whether there is an influence of AIT on the disease course or progression.

Age and sex differences of dehydroepiandrosterone sulfate (DHEAS) and cortisol (CRT) plasma levels in normal controls and Alzheimer's disease (AD)

In 50 healthy subjects (23 female, 27 male, aged 18–81) and 24 patients with Alzheimers disease (AD) (11 female, 13 male, aged 58–88) DHEAS and CRT plasma levels were studied. In normal subjects there was a clear negative correlation of DHEAS to age, while no significant age correlated decrease of CRT plasma levels was found. There was a significant decrease in the DHEAS/CRT ratio in elderly controls (aged>60) as compared to young individuals (aged<45). Overall there was a trend to lower DHEAS/CRT ratios in AD patients compared to age matched controls out of the total group of normals (P<0.1), there was a significant decrease of this ratio in female AD patients (P<0.05), compared to age matched female controls, but there was none in male Alzheimers; furthermore there was a significant difference in CRT plasma levels between female AD patients and age matched female controls (P<0.01) and between female and male AD patients (P<0.05). Considering the antiglucocorticoid effects of DHEAS, this ratio may account for its protective effect against hippocampal degeneration caused by glucocorticoids and possibly for the higher rate of AD in females.

Ziprasidone in Huntington’s Disease: The First Case Reports

Huntington’s disease (HD) is a relentlessly progressive neuropsychiatric disorder with an underlying autosomal dominantly inherited genetic defect. Classical antipsychotics (i.e. phenothiazines or butyrophenones) are the most used medication to reduce the (probably dopamine-born) choreiform hyperkinesias. Ziprasidone is the latest of a new class of atypical antipsychotics; it has not been studied so far in this indication. We report three genetically confirmed HD patients who improved significantly in several categories of the motor scale of the Unified HD Rating Scale.

Dehydroepiandrosterone-sulfate (DHEAS) serum levels in normal aging and Alzheimer’s disease (AD)

Sixty healthy subjects were studied and a strong negative correlation between age and serum DHEAS levels could be seen: r = −0,79 for females and r = −0,73 for males.In addition, 18 drug-free patients with AD and 16 age-and sex-matched controls were studied. No difference in serum DHEAS levels was found between these two groups, doubting whether there is a specific role of DHEAS in AD.

Zolpidem in progressive supranuclear palsy

often well tolerated, whereas high doses are rarely helpful and may impair motor function, such as swallowing, and cognitive function (Calabrese, 1973; Login et al., 1982). No enduring therapeutic benefit has been reported so far, but recently anectotical reports on the atypical neuroleptic olanzapine give reason to hope in HDassociated psychosis and slight choreatic conditions (Dipple, 1999; Grove et al., 2000). In our view, it also seems to be useful in grave chorea. Moreover, we suggest to add a neuroprotection as is performed in other neurodegenerative disorders like Alzheimer’s disease or Parkinson’s disease. Riluzole is a neuroprotective agent (Urbani & Belluzzi, 2000), which seems to have a proper ameliorative effect on activities of daily living and total functional capacity in HD for some months (Rosas et al., 1999; Seppi et al., 2001). We present two patients: the first, a 59-year-old woman with genetically confirmed HD of 12 years duration was hospitalized because of continuous worsening of her motor abilities. She was not able to walk or eat without help, she could not dress or undress without help. The motor scale of the Unified HD rating scale (UHDRSm) (Huntington Study Group, 1996) revealed 78 of 124 points. The patient was treated with olanzapine (20 mg daily) and her motor function improved significantly, especially the subscores of the fine motor tasks and the chorea (UHDRSm 41 points). After 2 weeks of treatment with olanzapine, riluzole (50 mg/twice a day) was added for neuroprotection and a further slight improvement was seen in the next 2 weeks without additional side-effects (UHDRSm 34 points). The second patient, a 28-year-old man with genetically confirmed HD of 3 years duration presented with an UHDRSm of 43/124 points (mainly oculomotoric function, fine motor tasks, chorea). We treated with 5 mg olanzapine daily and the patient showed a clear improvement (UHDRSm 23 points). After 2 weeks of treatment with olanzapine, riluzole (50 mg/twice a day) was added and a further slight improvement (especially in the fine motor tasks) was seen in the next 2 weeks without additional side-effects (19 points). The patient did not complain of any adverse effects. In summary, severe chorea in HD may be treated effectively and without significant side-effects with a combination of high dose olanzapine and riluzole. In the future, minocycline may be an alternative option for neuroprotection (Chen et al., 2000).

Early diagnosis in Duchenne muscular dystrophy

1 de Lorgeril M, Salen P, Paillard F, Lacan P, Richard G. Lipid-lowering drugs and homocysteine. L a n c e t 1999; 353: 2 0 9 – 1 0 . 2 Townend J, O’Sullivan J, Wilde JT. Hyperhomocysteinaemia and vascular disease. Blood Rev 1998; 12: 2 3 – 2 4 . 3 Bostom A, Brosnan JT, Hall B, Nadeau M R , Selhub J. Net uptake of plasma homocysteine by the rat kidney in vivo. Atherosclerosis 1 9 9 5 ; 116: 5 9 – 6 2 . 4 Wollesen F, Brattstrom L, Refsum H, et al. Plasma total homocysteine and cysteine in relation to glomerular filtration rate in diabetes mellitus. Kidney Int 1999; 5 5 : 1 0 2 8 – 5 5 . 5 Martin SC, Tsakas-Ampatzis I, Bartlett W A , Jones AF. Measurement of plasma total homocysteine by HPLC with coulometric detection. Clin Chem 1999; 45: 1 5 0 – 5 2 .

Single photon emission computed tomography in subjects at risk for Huntington's chorea.

ders [1]. Decreased carnitine levels in muscle have been repor ted in advanced Duchenne and Becker dystrophies, where not lipid droplets in muscle fibres were seen [1]. The efficacy and toxic effects of ipecac depend upon its content of alkaloids, the principal one being emet ine [7]. The mechan i sm by which emet ine causes cardiac and skeletal muscular toxicity has been the subject of many investigations and is still controversial [7, 8]. Because emet ine has a powerful general ized effect on protein synthesis and mi tochondr ia l oxidative phosphoryla t ion , it is difficult to identify a specific effect that may lead to muscular dysfunct ion [4, 8]. Previous reports analysing the h u m a n muscle metabol ism of such a toxic myopa thy are rare [7, 8]: emet ine disrupts mi tochondr ia l oxidative phosphory la t ion [7], and anaerobic glycolysis of muscle f rom two pat ients showed no specific deficit at any level [s]. The mechanisms of carnitine deplet ion in our case are not clear, but may theoret ical ly arise f rom a combinat ion of the following: (1) a dietary deficiency of carnitine, (2) a defect in carnitine biosynthesis, (3) an abnormal renal handl ing of carnit ine, (4) an abnormal release of carnit ine f rom cells or tissues, and (5) a defect in carnit ine t ranspor t of carnit ine by cells or tissues [1]. Points (2) and (3) could not be substant ia ted in our case and seem to be improbable because there was no convincing evidence o f renal or hepat ic dysfunction. In relation to the structural changes observed in patients with emet ineinduced myopa thy , i.e. decreased number or loss of mi tochondr ia and occasional necrot ic fibres, emetine may accelerate the release of carnitine esters f rom muscle mi tochondr ia and interfere with the carnitine t ranspor t by muscle cells. Bo th hypotheses , as well as the possible role of dietary deficiency in our anorexic patient, may cause a significant reduct ion in muscle carnitine content . Those clinical symptoms specifically caused by the carnitine deficiency syndrome could not be distinguished and fur ther studies are needed in order to establish the role of carnitine metabolism in emetine and related druginduced myopathies .

Cerebral vasculitis associated with Reiter's syndrome.

Sirs: Cerebral vasculitis is a rare syndrome, which presents considerable difficulties in recognition and diagnosis in the absence of systemic involvement. It can appear with a variety of clinical signs and symptoms such as headache, encephalitis, seizures and progressive focal deficits. Primary vasculitides include Takayasu’s arteritis, giant cell (temporal) arteritis, polyarteritis nodosa, Churg-Strauss syndrome, Wegener’s granulomatosis, and isolated angiitis of the CNS [7]. Secondary vasculitides may occur with rheumatological disorders, malignancy, drugs, or infections [3]. Reiter’s syndrome, as a seronegative spondyloarthropathy, usually presents with a triad of arthritis, urethritis, and uveitis [5]. It is predominantly a disease of males and patients have a high prevalence of HLA-B27 positivity [5]. Enteric infection with Salmonella, among others, has been implicated as a trigger of this syndrome [5]. We could not find neurological complications of Reiter’s syndrome in the literature although other seronegative spondyloarthropathies such as ankylosing spondylitis for example, where radiculopathy, myelopathy, cauda equina syndrome, vertebrobasilar insufficiency, mostly due to fragile spine, and peripheral neuropathy have been reported [6]. We report a 44-year old non smoking man with Reiter’s syndrome following an infection with salmonellae-D in October 1999. On his first admission to another hospital he had diarrhea and high temperature with massive swelling of his ankles. Iritis of the right eye and balanoposthitis were diagnosed. Routine laboratory tests were normal except for an elevated C-reactive protein (CRP) of 810 mg/l (81 mg/dl; normal range < 6 mg/l) and a moderately elevated white blood cell count. The patient was positive for HLA-B27. A treatment with oral corticosteroids was initiated. On next admission in January 2000 he noticed rapidly evolving paresis and dysesthesia of his right arm. Brain MRI was normal, CRP was still elevated, to 357 mg/l (35,7 mg/dl) and his ankles were swollen. Spinal MRI was not done. Corticosteroids were continued, acetylsalicylic acid was started and the symptoms resolved after three months. In February 2000 therapy with methotrexate 15 mg i. m. once a week was started because as well as his swollen ankles the distal interphallangeal joints of all fingers were affected at this time. On admission to our hospital in April 2000 he had left central facial paresis. Blood leukocyte count was 12,9x109/l (12.900/μl), erythrocyte sedimentation rate was 21 mm/h. Antibody titers against HIV, pANCA, c-ANCA, ANA and cardiolipin were negative. Despite a normal cell count and normal values for protein and glucose, cerebrospinal fluid contained plasma cells. Oligoclonal IgG could not be detected by isoelectric focusing and silver staining. Brain MRI disclosed a round gadolinium enhancing lesion without edema in the right fronto-parietal hemisphere, 2 cm in diameter (figure). MR-angiography (MRA) was normal. Echocardiography and transesophageal echocardiography showed a patent foramen ovale (PFO) with a diameter of 3,5 mm and a right to left shunt. Phlebography of the legs was normal. No abnormal levels were found of factor V Leyden, protein C, protein S or antithrombin III. Stereotactic brain biopsy showed ischemic necrosis and astrocyte proliferation, while all layers of vessel walls and perivascular spaces were infiltrated with leucocytes, mainly lymphocytes and plasma cells, typical for vasculitis (figure). If there had been ischemic stroke, the infiltrating cells should have been granulocytes and macrophages. The symptoms decreased after increasing the corticosteroid dosage. Methotrexate was continued and clopidogrel was started. A follow-up brain MRI in March 2001 only showed the residuum of the biopsy, the patient’s clinical status was normal; he was receiving methotrexate and clopidogrel at this time. In summary our patient suffered from Reiter’s syndrome initiated by a salmonella infection. Three months later a reversible neurological deficit occurred followed by a central facial paresis after another four months under corticosteroid and methotrexate therapy. The finding of a patent foramen ovale could have led to the supposition that paradox embolisation was the reason for the reversible neurological deficits. Patent foramen ovale is present in 20 to 35 % of the normal population [4] and there is an association with cryptogenic stroke in younger persons [2]. LETTER TO THE EDITORS