Spinocerebellar ataxia 27B: a frequent and slowly progressive autosomal-dominant cerebellar ataxia-experience from an Italian cohort.

BACKGROUND: Autosomal-dominant spinocerebellar ataxia (ADCA) due to intronic GAA repeat expansion in FGF14 (SCA27B) is a recent, relatively common form of late-onset ataxia. OBJECTIVE: Here, we aimed to: (1) investigate the relative frequency of SCA27B in different clinically defined disease subgroups with late-onset ataxia collected among 16 tertiary Italian centers; (2) characterize phenotype and diagnostic findings of patients with SCA27B; (3) compare the Italian cohort with other cohorts reported in recent studies. METHODS: We screened 396 clinically diagnosed late-onset cerebellar ataxias of unknown cause, subdivided in sporadic cerebellar ataxia, ADCA, and multisystem atrophy cerebellar type. We identified 72 new genetically defined subjects with SCA27B. Then, we analyzed the clinical, neurophysiological, and imaging features of 64 symptomatic cases. RESULTS: In our cohort, the prevalence of SCA27B was 13.4% (53/396) with as high as 38.5% (22/57) in ADCA. The median age of onset of SCA27B patients was 62 years. All symptomatic individuals showed evidence of impaired balance and gait; cerebellar ocular motor signs were also frequent. Episodic manifestations at onset occurred in 31% of patients. Extrapyramidal features (17%) and cognitive impairment (25%) were also reported. Brain magnetic resonance imaging showed cerebellar atrophy in most cases (78%). Pseudo-longitudinal assessments indicated slow progression of ataxia and minimal functional impairment. CONCLUSION: Patients with SCA27B in Italy present as an adult-onset, slowly progressive cerebellar ataxia with predominant axial involvement and frequent cerebellar ocular motor signs. The high consistency of clinical features in SCA27B cohorts in multiple populations paves the way toward large-scale, multicenter studies.

Mood Disorders in Uncontrolled Hypertension Despite Multiple Anti-Hypertensive Medications: Searching for a Link.

INTRODUCTION: Resistant hypertension is a clinical condition in which blood pressure (BP) control is not achieved under a pharmacological therapy including a diuretic and at least two additional antihypertensive drug classes. AIM: To discuss an unusual presentation of uncontrolled hypertension despite multiple anti-hypertensive medications. METHODS AND RESULTS: A 46-year-old woman presented with resistant hypertension (HT) and with a long history of polydipsia, polyuria, weight loss and psychiatric symptoms (sudden onset of personality disorder with free anxiety, negativism and asthenia) unsuccessfully treated with antidepressant drugs. Tests for secondary HT showed a marked increase of serum renin and aldosterone both in clinostatic (342 pg/ml and 907 pmol/l, respectively) and orthostatic posture (351 pg/ml and 2845 pmol/l, respectively), hypokalemia (2.9 mmol/l) and macroalbuminuria (431 mg/day). Diagnostic examinations also revealed a focal stenosis of approximately 70 % of the proximal right renal artery with post-stenotic dilation. After percutaneous balloon angioplasty and stent implantation, BP was normalized with 5 mg/day amlodipine and psychiatric symptoms suddenly disappeared. CONCLUSIONS: Psychopathological symptoms are rare at the onset of hyperaldosteronism, and their aetiology is not well defined. A proper diagnostic and therapeutic process is mandatory in order to get the recommended therapeutic targets in short-midterm improving long-term prognosis. We also suggest not considering depressed or treat with antidepressant agents a young hypertensive subject with uncontrolled hypertension despite multiple anti-hypertensive medications without having ruled out a secondary form of hypertension.

Hyperhomocysteinemia is an independent predictor of sub-clinical carotid vascular damage in subjects with grade-1 hypertension.

Although the role of homocysteinemia (Hcy) as a coronary risk factor (RF) has been scaled down, hyper-Hcy and carotid vascular damage (CVD) are still considered as RFs for cerebrovascular events. In 276 grade-1 hypertensives (160 men and 116 women aged 59.6 ± 15.0 years) without known cardiovascular disease and having hyper-Hcy (≥15 µM/L), subclinical CVD was evaluated by ultrasonographic carotid-wall intima media thickness (IMT). Hcy was divided into quartiles and C667→T polymorphism codifying for methylenetetrahydrofolate reductase (MTHFR) was determined. According to the genotype, subjects were divided into CC (wild), CT (heterozygote) and TT (homozygous mutation). Differences between continuous variables were evaluated by analysis of variance, while gender specific odds ratio (OR) and 95 % confidence intervals (CI) of CVD (IMT >0.9 mm or plaque) were calculated by multivariate logistic regression analysis. Blood pressure (BP) values were not different across the quartiles of Hcy. In 46.4 % of cases, sub-clinical CVD was found, with a prevalence increasingly distributed in the quartiles of Hcy (31.9, 42, 52.2, 59.4 %, p < 0.001). Prevalence of TT allele of the MTHFR genotype was also significantly distributed in the quartiles of Hcy (13.6, 12.3, 23.5 and 50.6 %, p < 0.0001), whereas no relationship was found between genotype and CVD. The last quartile of Hcy predicted CVD (OR 1.32, CI 1.12-2.2, p = 0.02) independent of age (OR 1.23, CI 1.002-1.56, p = 0.0001), systolic BP (OR 1.52, CI 1.24-2.10), diabetes (OR 2.11, CI 1:32-2.88, p = 0.01) and smoking (OR 1.45, CI 1.14-1.98, p = 0.04). Adding gender did not modify the model. In hypertensives, Hcy values >36.5 µM/L independently predict CVD and in those who are also diabetic and smokers, Hcy assessment without MTHFR genotype should be recommended to obtain a better stratification of global cerebrovascular risk.

Anti-hypertensive treatment in pheochromocytoma and paraganglioma: current management and therapeutic features.

Pheochromocytoma (PH) and paraganglioma (PG) are neuroendocrine neoplasms arising from chromaffin cells of the adrenal medulla and the sympathetic ganglia, respectively. Although are unusual cause of hypertension (HT) accounting for at most 0.1-0.2 % of cases, they may lead to severe and potentially lethal hypertensive crisis due to the effects of the released catecholamines. However, both PH and PG may be asymptomatic as ~30 % of subjects are normotensive or have orthostatic hypotension and in these cases the 24 h ambulatory blood pressure (BP) monitoring is an important toll to diagnose and treat HT. HT treatment may be difficult when PH or PG occurs in pregnancy or in the elderly subjects and in these cases a multidisciplinary team is required. When surgical excision is mandatory the perioperative management requires the administration of selective α1-adrenergic blocking agents (i.e., doxazosin, prazosin or terazosin) followed by a ß-adrenergic blockade (i.e., propranolol, atenolol). This latter should never be started first because blockade of vasodilatory peripheral ß-adrenergic receptors with unopposed α-adrenergic receptor stimulation can lead to a further elevation of BP. Although labetalol is traditionally considered the ideal agent due to its α- and ß-adrenergic antagonism, experimental studies do not support its use in this clinical setting. As second regimen, the administration of vasodilators as calcium channel blockers (i.e., nicardipine, nifedipine) may be required to control BP. Oral and sublingual short-acting nifedipine are potentially dangerous in patients with hypertensive emergencies and are not recommend. The latest evidences into the diagnosis and treatment of hypertensive crisis due to PH and PG are reviewed here.

Conversion ratio between Dysport and Botox in clinical practice: an overview of available evidence.

The optimal conversion ratio between Dysport and Botox--the two botulinum neurotoxin type A products (BoNT-As) supported by the larger bulk of evidence-has been extensively debated, because of its broad medical and economic implications. The article discusses the available evidence on the conversion ratio between Dysport and Botox in adults affected by spasticity, cervical dystonia, blepharospasm and hemifacial spasm, with a focus on clinical trials that specifically addressed this issue. In addition, some suggestions on the conversion ratio between Dysport and Xeomin can be extrapolated, since Xeomin has the same efficacy and safety profile as Botox and is exchangeable with Botox with a 1:1 conversion ratio. Taken together, the findings retrieved from this literature research suggest that a conversion ratio of 3:1 (Dysport:Botox)--or even lower--can be considered appropriate for the treatment of the above-mentioned conditions. Higher conversion ratios may lead to an overdosing of Dysport, with a potential increased incidence of adverse events. Therefore, we recommend that physicians using both products consider using a lower conversion factor as a guide, adjusting it upwards as required based on the specific characteristics and response to treatment of each patient.

Arterial hypertension, a tricky side of Parkinson's disease: physiopathology and therapeutic features.

The role of arterial hypertension (HT) as risk factor for Parkinson's disease (PD) is still debated. Case-control and retrospective studies do not support an association between HT and PD and the risk of PD seems to be lower in hypertensive than in normotensive subjects. In addition, the use of calcium-channel blockers (CCBs) and angiotensin-converting enzyme inhibitors seems to have a protective effect on the risk of developing PD. In clinical practice, a crucial finding in subjects with PD is the high supine systolic blood pressure (SBP) coupled with orthostatic hypotension (OH). It is not clear whether this SBP load could be a risk factor for target organ damage as this load can be largely due to the drugs used to treat OH (i.e., fludrocortisone acetate, midodrine) or PD itself (i.e., monoamine oxidase inhibitors, dopamine D2-receptor antagonists). This blood pressure (BP) load is largely independent of medications as the 40 % of subjects with PD have a non-dipping pattern of BP during 24 h ambulatory monitoring (24-h ABPM). In PD, nocturnal HT is usually asymptomatic and 24-h ABPM should be used to track both supine HT and OH. Treatment of HT in PD is difficult because the reduction of supine BP could worsen OH. To avoid this, short-acting dihydropyridine CCBs, clonidine or nitrates are recommended, assuming between meals, in late afternoon or in the evening in avoiding an aggravation in the post-prandial hypotension characteristic of PD.

Recurrent syncope in a hypertensive subject with vascular cognitive impairment and permanent pacemaker.

Syncope following permanent pacemaker (PM) implantation is a nightmare for electrophysiologists. We describe a case of daily recurrent syncope in an 84-year-old man having a dual-chamber pacemaker implanted for complete atrio-ventricular block occurred 4 years before the admission to our department. He had a history of arterial hypertension, parossistic atrial fibrillation, chronic obstructive pulmonary disease, stage-III chronic renal failure, mild vascular cognitive impairment and glaucoma. The initial work-up including electrocardiogram (ECG), repeated PM interrogations, Holter electrocardiogram, blood pressure measurement in orthostatic position, complete blood count, serum glycaemia, electrolytes and thyroid function tests showed normal findings. Syncope occurred in lying position and during 90° left clockwise neck rotation and was associated to pallor, sweating, tonic-clonic seizures and transient self-limited loss of consciousness lasting a few seconds. Electroencephalogram was normal. During continuous ECG monitoring, the right rotation of the head determined a ventricular asystolic pause lasting 9 seconds associated with loss of consciousness. Restoration of sinus rhythm was observed after bringing back the head in axis. The PM interrogation, performed during pacing failure, recorded low impedance of bipolar ventricular lead, suggesting a damage in lead insulation. It is likely that lead movements during clockwise neck rotation produced an intermittent short circuit that prevented sufficient energy delivery to the myocardium with a consequence of sudden loss of capture.

Antihypertensive Treatment in the Elderly and Very Elderly: Always "the Lower, the Better?".

Arterial hypertension (HT) is age dependent and, with the prolongation of life expectancy, affects more and more elderly people. In the elderly, HT is a risk factor for organ damage and cardiovascular (CV) events. Both pharmacologic and nonpharmacologic reduction of blood pressure (BP) is associated with a corresponding decrease in systolic-diastolic or isolated systolic HT. Clinical trials have shown that BP lowering is associated with a decrease in stroke and other CV events. Therefore, BP reduction per se appears more important than a particular class of antihypertensive drugs. The benefit of antihypertensive treatment has been confirmed up to the age of 80 years, remaining unclear in the octogenarians. The benefit in lowering diastolic BP between 80 and 90 mmHg is well established, while that of lowering systolic BP below 140 mmHg requires further confirmations.

Intermittent Broca's aphasia management in an emergency unit: from theory to practice.

Although Broca's aphasia (BA) may mimic different neurological illness, its sudden onset often requires an emergency approach. In this paper, the management of a case of intermittent BA occurred in a young woman without history of neurological, cardiovascular and arrhythmic diseases is discussed. Diffusion-weighted magnetic resonance imaging showed two areas of hypoperfusion in the terminal branches of the left medial cerebral artery not previously diagnosed by computed tomography. Although there were no eligibility criteria for thrombolysis, patient received intravenous treatment with recombinant tissue-type plasminogen activator (rt-PA) over 1 h and at the end of rt-PA infusion aphasia completely disappeared without neurological sequelae. Transesophageal echocardiography revealed a thrombus in the left atrial appendage not previously detected by transthoracic echocardiography. In the month following the cardioembolic stroke, heart rhythm was monitored for 30 days by an external loop recorder and during this test two episodes of silent lone atrial fibrillation were collected.

Primary stroke prevention and hypertension treatment: which is the first-line strategy?

Hypertension (HT) is considered the main classic vascular risk factor for stroke and the importance of lowering blood pressure (BP) is well established. However, not all the benefit of antihypertensive treatment is due to BP reduction per se, as the effect of reducing the risk of stroke differs among classes of antihypertensive agents. Extensive evidences support that angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), dihydropyridine calcium channel blockers (CCB) and thiazide diuretics each reduced risk of stroke compared with placebo or no treatment. Therefore, when combination therapy is required, a combination of these antihypertensive classes represents a logical approach. Despite the efficacy of antihypertensive therapy a large proportion of the population, still has undiagnosed or inadequately treated HT, and remain at high risk of stroke. In primary stroke prevention current guidelines recommend a systolic/diastolic BP goal of <140/<90 mmHg in the general population and <130/80 mmHg in diabetics and in subjects with high cardiovascular risk and renal disease. The recent release in the market of the fixed-dose combination (FDC) of ACEI or ARB and CCB should provide a better control of BP. However to confirm the efficacy of the FDC in primary stroke prevention, clinical intervention trials are needed.

Mechanisms of cramp contractions: peripheral or central generation?

We analysed the cramp threshold (i.e. the minimum frequency of electrical stimulation capable of inducing a cramp) and the behaviour of individual motor units during cramps electrically elicited in the absence (intact condition) and presence (blocked condition) of a peripheral nerve block in eight healthy subjects. The cramp threshold was significantly greater in the blocked than in the intact condition (18 ± 3 Hz vs. 13 ± 3 Hz; P = 0.01). Cramp duration and peak EMG amplitude in the intact condition (55.6 ± 19.2 s and 47.5 ± 24.8 µV, respectively) were significantly greater compared to the blocked condition (2.6 ± 1.3 s and 13.9 ± 8.8 µV; P < 0.01). All motor units identified in the blocked condition (n = 38) had a shorter interval of activity and a greater discharge rate compared to the intact condition (n = 37) (respectively, 1.1 ± 1.0 s vs. 29.5 ± 21.8 s, P < 0.0001; 25.7 ± 11.6 pulses s(-1) vs. 20.0 ± 5.9 pulses s(-1); P < 0.05). The motor unit activity detected during the blocked condition corresponded to spontaneous discharges of the motor nerves, while in the intact condition the motor unit discharge patterns presented the typical characteristics of motor neuron discharges. These results indicate a spinal involvement at the origin of cramps and during their development.

Internal carotid artery fibromuscular dysplasia in arterial hypertension: management in clinical practice.

Fibromuscular dysplasia (FMD) reminds of a rare form of secondary arterial hypertension occurring in young people and involving the renal arteries. FMD may also involve vertebral, subclavian, mesenteric, iliac arteries and carotid arteries. FMD of internal carotid arteries is a rare finding that is frequently incidental and asymptomatic. It usually occurs in middle-aged women and is secondary to media-intima fibrodysplasia. The carotid artery may be elongated or kinked and associated cerebral aneurysms have been reported. Symptoms including transient ischaemic attack or stroke are uncommon and are related to decrease of blood flow or embolization by platelet aggregates. At the onset, differential diagnosis with vasculitis must be placed. Computed tomography or magnetic resonance imaging (MRI) angiography demonstrates bilateral high-grade stenosis with the characteristic "string of beads" pattern. Antiplatelet medication is the accepted therapy for asymptomatic lesions. Graduated endoluminal surgical dilation is an outmoded therapy, no longer used in most medical centres. Current percutaneous angioplasty is the preferred treatment for symptomatic carotid FMD, but no randomized controlled trials comparing this methodology with surgery is available. The management of a case of arterial systemic FMD in a 52-year-old women, diagnosed after a hypertensive crysis, is discussed. Imaging methods disclosed stenoses of carotid arteries, of celiac tripod and of superior mesenteric artery. Because of high risk associated to endovascular surgery, medical therapy was started. In the first year of follow-up, no events have been reported.

Reliability of a novel neurostimulation method to study involuntary muscle phenomena.

Experimental methods involving painful electrical stimulation of a peripheral nerve showed the existence of a minimum stimulation frequency capable of inducing cramp, termed "threshold frequency" (TF). Our aim was to test an alternative method to induce fasciculations and cramps electrically. Two daily sessions of electrical stimulation of the abductor hallucis muscle were performed in 19 volunteers on 3 days: stimulation trains of 150 monophasic square pulses (duration 152 micros) of increasing frequency (current intensity 30% higher than maximal; frequency of the first trial, 4 pps; recovery between trials, 1 min) were delivered to the main muscle motor point until a cramp developed. Once a cramp was induced the protocol was repeated after 30 min. To verify by electromyography that cramp occurred, a surface electrode array was placed between the motor point and the distal tendon. Ambient and skin temperature were kept constant in all sessions. Fasciculations and cramps were elicited in all subjects. We observed the following median (interquartile range) values of TF: day 1 (session 1), 13 (6) pps; day 1 (session 2), 16 (4) pps; day 2 (session 1), 16 (6) pps; day 2 (session 2), 18 (6) pps; day 3 (session 1), 17 (4) pps; day 3 (session 2), 18 (8) pps. TF intersession intraclass correlation coefficients were 0.82, 0.92, and 0.90 for days 1, 2, and 3, respectively. TF interday intraclass correlation coefficient was 0.85. The absence of pain due to the stimulation and the demonstration of TF reliability support the use of our method for the study of involuntary muscle phenomena.

Hemihypoglossal nerve transfer in brachial plexus repair: technique and results.

OBJECTIVE: In multiple avulsions of the brachial plexus, the search for extraplexal donor nerves in the hope of achieving motor neurotization is a major goal. We explored the possibility of using the hypoglossal nerve as a transfer point to reanimate muscles in the upper limb. METHODS: The hypoglossal nerve was used as a donor nerve for neurotization in seven patients with avulsive injuries of the brachial plexus. The surgical technique--an end-to-side microsuture using approximately half of the nerve fascicles--is basically the same as that used in the hypoglossal nerve-facial nerve jump graft, which is a well-known technique in facial nerve reanimation. The recipient nerves were the suprascapular (two patients), the musculocutaneous (one patient), the posterior division of the upper trunk (two patients), and the medial contribution to the median nerve (two patients). RESULTS: In spite of a connection documented by electromyography and selective activation in three of seven patients, the functional results in our patients were extremely disappointing: no patient had an outcome better than M1 in the reinnervated muscles. CONCLUSION: This technique was of no help to the patients and thus has been abandoned at our institution.