Jukka Lyytinen

A novel α-synuclein mutation A53E associated with atypical multiple system atrophy and Parkinson's disease-type pathology

We describe the clinical, neuropathological, and genetic features of a Finnish patient with a novel α-synuclein (SNCA) mutation A53E. The patient was clinically diagnosed with atypical Parkinsons disease (PD) with age of onset at 36 years. In the neuropathological analysis performed at the age of 60 years, highly abundant SNCA pathology was observed throughout the brain and spinal cord showing features of multiple system atrophy and PD. Neuronal and glial (including oligodendroglial) SNCA inclusions and neurites were found to be particularly prominent in the putamen, caudatus, amygdala, temporal and insular cortices, gyrus cinguli, and hippocampus CA2-3 region. These areas as well as the substantia nigra and locus coeruleus showed neuronal loss and gliosis. We also found TDP-43 positive but mostly SNCA negative perinuclear inclusions in the dentate fascia of the hippocampus. The A53E mutation was found in 2 other relatives who had parkinsonism. Our results suggest that the novel SNCA A53E substitution is a causative mutation resulting clinically in parkinsonism and pathologically in severe multiple system atrophy- and PD-type phenotype.

Persistent organochlorine pesticides in serum and risk of Parkinson disease

Background: Pesticides have been implicated as likely environmental risk factors for Parkinson disease (PD), but assessment of past exposure to pesticides can be difficult. No prior studies of pesticide exposure and PD used biomarkers of exposure collected before the onset of PD. Our investigation examined the association between prospective serum biomarkers of organochlorine pesticides and PD. Methods: We conducted a nested case-control study within the Finnish Mobile Clinic Health Examination Survey, with serum samples collected during 1968–1972, and analyzed in 2005–2007 for organochlorine pesticides. Incident PD cases were identified through the Social Insurance Institutions nationwide registry and were confirmed by review of medical records (n = 101). Controls (n = 349) were matched for age, sex, municipality, and vital status. Adjusted odds ratios (ORs) of PD were estimated using logistic regression. Results: Little association emerged with a summary score of the 5 organochlorine pesticides found at high levels, and only increasing dieldrin concentrations trended toward a higher risk of PD (OR per interquartile range [IQR] 1.28, 95% confidence interval [CI] 0.97–1.69, p = 0.08). Because of possible strong confounding by cigarette smoking among smokers, we ran additional analyses restricted to never smokers (n = 68 cases, 183 controls). In these analyses, increasing dieldrin concentrations were associated with increased odds of PD (OR per IQR 1.95, 95% CI 1.26–3.02, p = 0.003). None of the other organochlorine pesticides were associated with PD in these analyses. Conclusions: These results provide some support for an increased risk of Parkinson disease with exposure to dieldrin, but chance or exposure correlation with other less persistent pesticides could contribute to our findings.

The effect of catechol-O-methyltransferase inhibition with entacapone on cardiovascular autonomic responses in L-Dopa-treated patients with Parkinson's disease

We have compared the effects of entacapone, a peripherally acting catechol-O-methyltransferase (COMT) inhibitor, and placebo on cardiovascular autonomic responses in L-Dopa/dopa decarboxylase inhibitor–treated patients with Parkinsons disease (PD). In a double-blind, randomized, crossover study with two consecutive 1-week treatment periods, a battery of cardiovascular reflex tests (orthostatic, Valsalva, deep breathing, and isometric hand grip tests) was performed in a group of 15 patients with idiopathic PD. The first set of tests was performed after withholding L-Dopa overnight (control, “off” stage). The second and third sets of tests were performed in “on” stage after 1-week treatment with either entacapone 200 mg or placebo administered with each dose of L-Dopa/dopa decarboxylase (DDC) inhibitor. Valsalva, deep breathing, and orthostatic tests demonstrated no statistically significant differences in the ratio of the longest and shortest electrocardiographic R-to-R wave (R-R) intervals between entacapone and placebo or between study treatments and control. Blood pressure responses to both orthostatic challenge and prolonged isometric work (hand grip test) were similar between treatments. Systolic orthostatic hypotension was observed in only one patient during the control test, but it occurred more frequently after L-Dopa/DDC inhibitor, regardless of concomitant administration of either entacapone (n = 3) or placebo (n = 4). Peripheral COMT inhibition with entacapone does not significantly alter cardiovascular autonomic responses in L-Dopa-treated patients with PD.

Progressive Stroke-Like Symptoms in a Patient with Sporadic Creutzfeldt-Jakob Disease

Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare neurodegenerative disorder in which accumulation of a pathogenic isoform of prion protein (PrPSc) induces neuronal damage with distinct pathologic features. The prognosis of sCJD is devastating: rapid clinical decline is followed by death generally within months after onset of symptoms. The classic clinical manifestations of sCJD are rapidly progressing dementia, myoclonus, and ataxia. However, the spectrum of clinical features can vary considerably. We describe a definite, neuropathologically verified sCJD in a 67-year-old woman who initially presented with progressive stroke-like symptoms: left-sided hemiparesis and ataxia within a few days. The initial brain magnetic resonance imaging (MRI) showed bilateral cortical hyperintensity on diffusion-weighted sequences (DWI) resembling multiple ischemic lesions. Despite anticoagulation with low-molecular-weight heparin, the patient deteriorated rapidly, became dysphagic and bedridden with myoclonic jerks on her left side extremities correlating with intermittent high-amplitude epileptiform discharges on electroencephalography (EEG). Basal ganglia hyperintense signal changes in addition to cortical ribboning were seen in DWI images of a follow-up MRI. Repeated EEG recordings showed an evolution to periodic sharp wave complexes. Protein 14-3-3 was positive in her cerebrospinal fluid specimen, in addition to an abnormally high total tau level. In the terminal stage the patient was in an akinetic, mutistic state with deteriorating consciousness. She died 19 days after admission to the hospital. Neuropathologic investigation corroborated the clinical diagnosis of sCJD with spongiform degeneration and immunohistochemical demonstration of the deposition of pathologic PrPSc.

Polychlorinated biphenyls in prospectively collected serum and Parkinson's disease risk†‡§

Evidence suggests possible Parkinsons disease (PD)–relevant neural effects of exposure to polychlorinated biphenyls. Limited epidemiological evidence suggests that polychlorinated biphenyl exposure may increase PD risk, but no studies have involved biomarkers of polychlorinated biphenyl exposure before PD onset. We examined the prospective association between serum polychlorinated biphenyls and PD. We conducted a nested case–control study within the Finnish Mobile Clinic Health Examination Survey with serum samples collected during 1968–1972 and analyzed in 2005–2007 for polychlorinated biphenyls. Incident PD cases were identified through the Social Insurance Institutions registry and were confirmed by medical record review (n = 101). Controls (n = 349) were matched on age, sex, municipality, and vital status. We used logistic regression to estimate adjusted odds ratios. There was no evidence of increasing risk of PD with increasing polychlorinated biphenyl exposure in adjusted analyses. Instead, there was a trend toward lower odds of PD with increasing serum polychlorinated biphenyl concentrations, which was most pronounced for the sum of all measured polychlorinated biphenyl congeners and the sum of dioxin‐like congeners. Compared with that of those in the lowest quintile, the odds ratio of PD among those in the highest quintile of total polychlorinated biphenyls was 0.29 (95% confidence interval, 0.12–0.70; P trend = .02) and for dioxin‐like congeners was 0.34 (95% confidence interval, 0.13–0.90; P trend = .05). These results do not support an increased risk of PD from polychlorinated biphenyl exposure and instead suggest a possible protective effect of polychlorinated biphenyl exposure.

Churg-strauss syndrome as an unusual aetiology of stroke with haemorrhagic transformation in a patient with no cardiovascular risk factors.

Background: We present here a case of haemorrhagic brain infarction in a middle-aged and physically active male, who had never smoked. This case report aims to remind the internist and neurologist to bear in mind unusual aetiologies of brain infarcts in patients without classical cardiovascular risk factors. Case Description: A 49-year-old male with pulmonary asthma and a prior history of nasal polyps had a wake-up stroke with left-sided symptoms and speech disturbance. A head MRI and MR angiography revealed a recent haemorrhagic infarct in the right putamen and corona radiata. The left hemiparesis progressed to sensory-motor hemiplegia on the 4th day. In the head CT, it was shown that the haemorrhagic infarct had progressed to a large haematoma. A pansinusitis was also diagnosed. The aetiological investigations revealed a minor atrial septal defect (ASD) with shunting and a heterozygotic clotting factor V R506Q mutation. A remarkable blood eosinophilia of 9.80 E9/l (42%) together with fever, sinusitis, wide-spread bilateral nodular pulmonary infiltrates that did not respond to wide-spectrum antimicrobial treatment, positive anti-neutrophilic cytoplasmic antibodies, a high myeloperoxidase antibody level and slightly positive anti-proteinase 3 antibodies suggested the diagnosis of Churg-Strauss syndrome. These inflammatory symptoms and findings promptly responded to treatment with corticosteroids and cyclophosphamide. Conclusions: Even after the concomitant findings of the low risk factors, i.e. small ASD and heterozygotic clotting factor mutation, continued search for the final aetiology of stroke revealed Churg-Strauss syndrome, which was the key to the treatment.

Problems related to levodopa-carbidopa intestinal gel treatment in advanced Parkinson's disease

Continuous levodopa‐carbidopa intestinal gel (LCIG) diminishes daily “off” time and dyskinesia in patients with advanced Parkinson′s disease (PD). Complications are common with percutaneous endoscopic gastrostomy with a jejunal extension tube (PEG‐J).

Bilateral hippocampal infarction as etiology of sudden and prolonged memory loss.

Sudden memory loss, with prolonged cognitive deterioration, clinically initially resembling a transitory global amnesia (TGA)-like episode, might be caused by ischemic stroke in the hippocampal regions. We report a patient with TGA-type sudden anterograde amnesia and normal head CT. Examinations revealed that the patient had several vascular risk factors and 3 tesla (T) head MRI showed ischemic lesions in diffusion-weighted images (DWI) in both hippocampi. Neuropsychological assessment revealed sustained moderate verbal memory deterioration and abnormal executive functions. We suggest that small ischemic strokes in hippocampal regions might remain unrecognized and underdiagnosed if follow-up of TGA-type episodes is not adequate and if head CT remains the only method of brain imaging.

Magnetoencephalographic Abnormalities in Creutzfeldt-Jakob Disease: A Case Report.

Creutzfeldt-Jakob disease (CJD) is a rare neurodegenerative disease with no effective therapy available. We recorded spontaneous magnetoencephalography and auditory evoked fields (AEFs) from a male patient with a rapidly progressive memory disorder, ataxia and myoclonus. Post-mortem examination confirmed sporadic CJD. Sources of the abnormal slow wave activity were localized with a beamformer software. Sources of sharp transients and AEFs were modeled with equivalent current dipoles. The estimated sources of spontaneous activity abnormalities were more dominant in the left hemisphere, in line with left-dominant abnormalities in diffusion-weighted MRI. Sources of AEFs were found in both temporal lobes. Magnetoencephalography measurements on CJD patients are feasible, and provide efficient means for localizing abnormal cortical activity in CJD.

MEG Abnormalities in Creutzfeldt-Jakob Disease, a Case Report

Creutzfeldt-Jakob Disease (CJD) is a rare neurodegenerative disease, which belongs to a group of spongiform encephalopathies termed prion diseases.