João Massano

Clinical Approach to Parkinson's Disease: Features, Diagnosis, and Principles of Management

Parkinsons disease (PD) is one of the most common neurodegenerative disorders. The condition causes a heavy burden both on those affected, as well as their families. Accurate diagnosis is critical and remains founded on clinical grounds as no specific diagnostic test is available so far. The clinical picture of PD is typical in many instances; however, features distinguishing it from other disorders should be thoroughly sought. Monogenic forms of PD also have some distinctive characteristics in many cases. This text is a roadmap to accurate diagnosis in PD, as it approaches clinical features, diagnostic methodology, and leading differential diagnoses. Therapeutic issues are also briefly discussed.

A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy

Progressive myoclonus epilepsies (PMEs) are a group of rare, inherited disorders manifesting with action myoclonus, tonic-clonic seizures and ataxia. We sequenced the exomes of 84 unrelated individuals with PME of unknown cause and molecularly solved 26 cases (31%). Remarkably, a recurrent de novo mutation, c.959G>A (p.Arg320His), in KCNC1 was identified as a new major cause for PME. Eleven unrelated exome-sequenced (13%) and two affected individuals in a secondary cohort (7%) had this mutation. KCNC1 encodes KV3.1, a subunit of the KV3 voltage-gated potassium ion channels, which are major determinants of high-frequency neuronal firing. Functional analysis of the Arg320His mutant channel showed a dominant-negative loss-of-function effect. Ten cases had pathogenic mutations in known PME-associated genes (NEU1, NHLRC1, AFG3L2, EPM2A, CLN6 and SERPINI1). Identification of mutations in PRNP, SACS and TBC1D24 expand their phenotypic spectra to PME. These findings provide insights into the molecular genetic basis of PME and show the role of de novo mutations in this disease entity.

Cognitive Impairment and Dementia in Parkinson’s Disease: Clinical Features, Diagnosis, and Management

Parkinson’s disease (PD) is a common, disabling, neurodegenerative disorder. In addition to classical motor symptoms, non-motor features are now widely accepted as part of the clinical picture, and cognitive decline is a very important aspect of the disease, as it brings an additional significant burden for the patient and caregivers. The diagnosis of cognitive decline in PD, namely mild cognitive impairment (MCI) and dementia, can be extremely challenging, remaining largely based on clinical and cognitive assessments. Diagnostic criteria and methods for PD dementia and MCI have been recently issued by expert work groups. This manuscript has synthesized relevant data in order to obtain a pragmatic and updated review regarding cognitive decline in PD, from milder stages to dementia. This text will summarize clinical features, diagnostic methodology, and therapeutic issues of clinical decline in PD. Relevant clinical genetic issues, including recent advances, will also be approached.

Deep brain stimulation and cognitive decline in Parkinson's disease: a clinical review

Parkinson’s disease is a common and often debilitating disorder, with a growing prevalence accompanying global population aging. Current drug therapy is not satisfactory enough for many patients, especially after a few years of symptom progression. This is mainly due to the motor complications that frequently emerge as disease progresses. Deep brain stimulation (DBS) is a useful therapeutic option in carefully selected patients that significantly improves motor symptoms, functional status, and quality of life. However, cognitive impairment may limit patient selection for DBS, as patients need to have sufficient mental capabilities in order to understand the procedure, as well as its benefits and limitations, and cooperate with the medical team throughout the process of selection, surgery, and postsurgical follow-up. On the other hand it has been observed that certain aspects of cognitive performance may decline after DBS, namely when the therapeutic target is the widely used subthalamic nucleus. These are important pieces of information for patients, their families, and health care professionals. This manuscript reviews these aspects and their clinical implications.

An updated review of Parkinson's disease genetics and clinicopathological correlations

Knowledge regarding the pathophysiological basis of Parkinsons disease (PD) has been greatly expanded over the past two decades, with extraordinary contributions from the field of genetics. However, genetic classifications became complex, difficult to follow, and at times misleading, by placing well‐established monogenic forms of the disease along with others associated with risk loci, often ill characterized. The present paper summarizes the genetic, clinical, and neuropathological findings of the currently described monogenic forms of PD and also approaches the progress made in determining genetic risk factors for PD. Furthermore, the text incorporates the data into a recently proposed classification system that will hopefully bring a “user‐friendly” approach to this issue. This paper also highlights a number of inconsistencies regarding classification of PD as a single, unique clinicopathological entity—in fact, in order to achieve the development of truly innovative therapies, PD should probably be regarded clinically as a “Parkinsons disease cluster”, instead of a single disease. In the future, we hope that an in‐depth and groundbreaking understanding of PD will allow the development of truly disease‐modifying therapies that will target the molecular processes responsible for the cascade of pathological events underlying each form of PD.

Physical exercise and Parkinson’s disease: influence on symptoms, disease course and prevention

Abstract Parkinson’s disease (PD) is a common, disabling, neurodegenerative condition, and the disease prevalence is expected to increase worldwide in the next few decades. Symptomatic therapy remains unsatisfactory, and greatly needed neuroprotective therapies have not been successfully developed so far. Physical exercise (PE) has been associated with a lower risk of developing a neurodegenerative disease. The literature has been searched, and results have been systematized and interpreted with regard to the effects of PE in PD. Published data show the following: 1) PE has been associated with a lower risk of developing PD; 2) PE has been shown to improve disease symptoms, mobility, balance, gait and quality of life (in this regard, walking training, tai-chi and tango dancing have demonstrated the highest level of evidence of efficacy); and 3) neuroprotective effects from PE could be expected in PD, although this has been suggested in animal studies only. Further research on this topic should be encouraged. Multidisciplinary cooperation between neurologists, sports physicians and researchers is paramount.

Motion integration deficits are independent of magnocellular impairment in Parkinson’s disease

Motion processing involves multiple hierarchical steps, from the magnocellular pathway, sensitive to high temporal frequency modulations, to subsequent motion integration within the visual cortical dorsal stream. We have tested whether motion integration deficits in mild Parkinson disease (PD) can be explained by visual deficits in earlier processing nodes. Contrast sensitivity deficits in the magnocellular pathway, were compared with speed discrimination of local dots moving in random directions, speed and direction discrimination of moving surfaces and motion integration as measured by 2D coherence thresholds (n=27). We have found that low-level magnocellular impairment in PD does not explain deficits in subsequent steps in motion processing. High-level performance was abnormal in particular for tasks requiring perception of coherently moving surfaces. Motion coherence deficits were predictive of visuomotor impairment, corroborating a previous magnetic stimulation study in normal subjects. We conclude that dorsal stream deficits in PD have a high-level visual cortical basis independent of low-level magnocellular damage.

Stroke and multiple peripheral thrombotic events in an adult with varicella

Sirs, Varicella is typically a benign childhood disease caused by varicella zoster virus (VZV), though serious complications can arise [1,2]. Varicella has been commonly associated with stroke in children [3], but exceptional reports have described afflicted immunocompetent adults, repeatedly relating vasculitis with this condition [4–8]. A 39-year-old right-handed male, smoker (10 cigarettes/day), developed varicella 2 weeks after his 4-year-old daughter showed the characteristic rash. Acute pain and pallor of the left lower limb and absent ipsilateral foot pulses suddenly emerged 1 week later, as well as left hemiplegia, left homonymous hemianopia and hemineglect. Emergent lower limb angiography (Fig. 1a and b) showed one occlusive (left femoral artery) and two sub-occlusive thrombi (left common iliac and right femoral arteries); thromboembolectomy was carried out. Intravenous non-fractionated heparin, acyclovir and methylprednisolone (5-day course, followed by oral prednisone and tapering) were prescribed. Acyclovir and corticosteroids were employed because of suspected VZV-related vasculitis. Central retinal artery occlusion of the right eye, probably the first event according to the patient, was later perceived. Laboratory examinations revealed: increased leucocytes (16.87 · 10/l), C-reactive protein (19.3 mg/l) and erythrocyte sedimentation rate (49 mm/h), low protein S (0.18 U/ml, normal range 0.60–1.40), positive anticardiolipin IgM and antibeta2-glycoprotein-I IgM (25.3 MPL and 45.5 SMU, respectively; normal <15), positive VZV-specific IgM and positive VDRL at 1:8 dilutions (TPHA negative). Other blood tests were normal, including folic acid, vitamin B12, homocysteine, thyroid function tests; microbial cultures; screening for HIV, HBV and HCV; immunological screening; other basic coagulation tests and inherited prothrombotic disorders screening. Cerebrospinal fluid examination disclosed 9 cells/ mm, normal protein and glucose levels; negative VZV DNA, anti-VZV antibodies (IgM, IgG), VDRL, TPHA and cultures. Transesophageal echocardiography and ECG were normal. Carotid and transcranial ultrasound showed eccentric luminal stenosis (40%) of the proximal right internal carotid artery with hypoechoic material; on serial testing, gradual shrinkage (to 20% 20 days later) and distal progression were demonstrated – findings that cannot be attributed to an atherosclerotic plaque. Brain MRI (1.5 T) was conducted 1 week after admission, showing the lesions observed in Fig. 1c. On discharge the patient presented right eye blindness, left hemiparesis and hemianopia; 3 months later he walked autonomously using one crutch. All abnormal laboratory findings returned to normal and so remained. Warfarin was stopped 6 months later; his current medication consists of antiplatelet drug and statin. We believe that these data strongly suggest that the vascular events sustained by this patient were associated with VZV, and occurred in the setting of a transitory prothrombotic condition, which also finds support in the fact that anticardiolipin antibodies and protein S ultimately returned to normal values. Nonetheless, analysing all data, we find ourselves unable to further theorize on the pathophysiology of the processes leading to intravascular thrombi formation in this patient. To the best of our knowledge, this case is unique, as previous reports mention VZV-related stroke, without concomitant extracerebral vascular events.

Successful pallidal deep brain stimulation in 15-year-old with Tourette syndrome: 2-year follow-up

Dear Sirs,Tourette syndrome (TS) is a potentially disabling chronictic disorder often associated with neuropsychiatric comor-bidities and typical onset during childhood [1]. Medicationfrequently causes bothersome adverse effects and deepbrain stimulation (DBS) has been tried in severe refractorycases [2].A 14-year-old boy with several motor and phonic tics(including coprolalia) since the age of 8 years was referredto surgery due to symptom refractoriness. Pregnancy andbirth were uneventful, and developmental milestones werenormally achieved. Family history was unremarkable,except for one maternal uncle with simple motor tics.Investigations, including uric acid, copper, ceruloplasmin,and brain MRI were normal. Medication was haloperidol8 mg/day and pimozide 8 mg/day. Previously, risperidoneand quetiapine had been tried, as well as habit reversaltherapy and psychoeducational interventions. At this pointseveral motor tics were seen almost continuously, one ofthem causing significant physical injury (see Supplemen-tary online video, captured and published with consentfrom the patient and his mother). Comorbidities includedtroublesome obsessions (e.g. intense fear that he might losecontrol and stab his mother; obsessive concern with con-tagious diseases), compulsions (e.g. compulsive checkingof locks; compulsive re-writing), anxiety and depression. Inthe classroom he found it very difficult to concentrate, andwould get very anxious; constant conflicts with his class-mates occurred, and he was a victim of bullying. Eventu-ally, the patient became unable to attend school or socializenormally, due to embarrassment. Therapeutic optimizationwas tried with clonidine 0.3 mg/day, aripiprazole 20 mg/day, tetrabenazine 50 mg/day, clonazepam 6 mg/day, ser-traline 100 mg/day, and fluvoxamine 200 mg/day, withoutsignificant benefit; higher doses were not tolerated.After careful review of evidence of efficacy and safetywith the multidisciplinary team, bilateral anteromedialinternal pallidal (AM-GPi) DBS was performed at the ageof 15 years. The procedure was approved by the institu-tional ethics committee. Significant benefits were notedimmediately after surgery, with functional and quality oflife (QOL) improvements and no adverse events occurred.There was also significant psychopathological improve-ment, including mood. The patient reported subjectivelylower anxiety levels, and feeling more confident. Table 1details serial assessments, as well as drug therapy andstimulation parameters at each time point (see also Sup-plementary material online). Symptomatic deteriorationwas noted around 1 year after surgery, namely with regardto tics, depression, and QOL. Despite thorough investiga-tion and questioning no life-events or contextual factorscould be related to the worsening. Drug therapy and

Progranulin Peripheral Levels as a Screening Tool for the Identification of Subjects with Progranulin Mutations in a Portuguese Cohort

Background: Progranulin (PGRN) mutations are associated with different clinical phenotypes, including frontotemporal lobar degeneration (FTLD), corticobasal syndrome (CBS) and Alzheimers disease (AD). As all pathogenic PGRN mutations identified so far cause disease through haploinsufficiency, determination of PGRN levels has been proposed as a reliable method to identify mutation carriers. Objective: To evaluate the accuracy of peripheral PGRN levels in the identification of the PGRN mutation carriers detected thus far in our Portuguese cohort. Methods: Serum PGRN levels were measured in 244 subjects (124 patients in the spectrum of FTLD, 2 asymptomatic descendants of a FTLD patient, 56 AD patients and 64 controls) by a novel commercial ELISA kit. Results: Low PGRN levels were detected in 7 individuals (5 behavioral variant frontotemporal dementia, 1 CBS, and 1 still clinically unaffected) that constituted the group of the null PGRN mutation carriers previously identified in our molecular diagnostic laboratory. The pathogenic mutations found consisted of 4 insertion-deletions, causing frameshifts resulting in premature stop codons, 3 of which were novel. In addition, a normal PGRN level was found in a patient harboring a novel missense variant. For this novel ELISA kit, we established a PGRN cut-off level that identified with 100% accuracy the pathogenic mutation carriers. Conclusion: This study supports the use of a novel assay for the determination of PGRN levels as a screening procedure to identify patients harboring null PGRN mutations. This approach would significantly decrease the required PGRN mutation analysis workload and should be extended to other clinical phenotypes than behavioral variant frontotemporal dementia and to apparently sporadic cases.