Sara Varanese

Apathy, but Not Depression, Reflects Inefficient Cognitive Strategies in Parkinson's Disease

Background The relationship between apathy, depression and cognitive impairment in Parkinsons disease (PD) is still controversial. The objective of this study is to investigate whether apathy and depression are associated with inefficient cognitive strategies in PD. Methods In this prospective clinical cohort study conducted in a university-based clinical and research movement disorders center we studied 48 PD patients. Based on clinical evaluation, they were classified in two groups: PD with apathy (PD-A group, n = 23) and PD without apathy (PD-NA group, n = 25). Patients received clinical and neuropsychological evaluations. The clinical evaluation included: Apathy Evaluation Scale-patient version, Hamilton Depression Rating Scale-17 items, the Unified Parkinsons Disease Rating Scale and the Hoehn and Yahr staging system; the neuropsychological evaluation explored speed information processing, attention, working memory, executive function, learning abilities and memory, which included several measures of recall (immediate free, short delay free, long delay free and cued, and total recall). Findings PD-A and PD-NA groups did not differ in age, disease duration, treatment, and motor condition, but differed in recall (p<0.001) and executive tasks (p<0.001). Immediate free recall had the highest predictive value for apathy (F =  10.94; p = 0.002). Depression and apathy had a weak correlation (Pearson index  = 0.3; p<0.07), with three items of the depression scale correlating with apathy (Pearson index between .3 and.4; p<0.04). The depressed and non-depressed PD patients within the non-apathetic group did not differ. Conclusion Apathy, but not depression, is associated with deficit in implementing efficient cognitive strategies. As the implementation of efficient strategies relies on the fronto-striatal circuit, we conclude that apathy, unlike depression, is an early expression of executive impairment in PD.

Botulinum Toxin Treatment of Lateral Axial Dystonia in Parkinsonism

Lateral axial dystonia (LAD) has been described in patients with Parkinsons disease (PD), but treatment might be more controversial than treatment of LAD in other neurological conditions. Our study was designed as a blinded cross‐over with botulinum toxin (BTX) and placebo in order to investigate the efficacy of BTX in PD LAD. Nine patients with LAD who failed to experience benefit from oral medications were randomly assigned to 2 groups, 4 patients received BTX and 5 placebo as a first treatment, and were switched‐over to BTX or placebo in the following treatment session, performed 3 months after the first session. Each patient was evaluated at baseline, 2 and 4 weeks after injection and after 3 months follow‐up with the Trunk Dystonia Disability Scale (TDDS), a Visual Analogue Scale (VAS) and a goniometric measurement of the lateral displacement. Patients were videotaped at each visit. None of the patients of the placebo group experienced benefit from treatment. BTX treatment was effective in 6 patients. One patient reported subjective benefit, with improvement of VAS score and mild improvement of TDDS score, but with no improvement of flexion degree. Two patients did not report any benefit. Four patients opted to continue to receive BTX treatment for 2 years after the cross‐over study. Our study shows that BTX could be considered a possible treatment for LAD in parkinsonism.

Treatment of Advanced Parkinson's Disease

Patients at late stage Parkinsons disease (PD) develop several motor and nonmotor complications, which dramatically impair their quality of life. These complications include motor fluctuations, dyskinesia, unpredictable or absent response to medications, falls, dysautonomia, dementia, hallucinations, sleep disorders, depression, and psychosis. The therapeutic management should be driven by the attempt to create a balance between benefit and side effects of the pharmacological treatments available. Supportive care, including physical and rehabilitative interventions, speech therapy, occupational therapy, and nursing care, has a key role in the late stage of disease. In this review we discuss the several complications experienced by advance PD patients and their management. The importance of an integrative approach, including both pharmacological and supportive interventions, is emphasized.

Two novel POLG1 mutations in a patient with progressive external ophthalmoplegia, levodopa-responsive pseudo-orthostatic tremor and parkinsonism

Different mutations, or combinations of mutations, in POLG1, the gene encoding pol gammaA, the catalytic subunit of mitochondrial DNA polymerase, are associated with a spectrum of clinical presentations including autosomal dominant or recessive progressive external ophthalmoplegia (PEO), juvenile-onset ataxia and epilepsy, and Alpers-Huttenlocher syndrome. Parkinsonian features have been reported as a late complication of POLG1-associated dominant PEO. Good response to levodopa or dopamine agonists, reduced dopamine uptake in the corpus striatum and neuronal loss of the Substantia Nigra pars compacta have been documented in a few cases. Here we report two novel mutations in POLG1 in a compound heterozygous patient with autosomal recessive PEO, followed by pseudo-orthostatic tremor evolving into levodopa-responsive parkinsonism. These observations support the hypothesis that mtDNA dysfunction is engaged in the pathogenesis of idiopathic Parkinsons disease.

Behavioural assessment of dysexecutive syndrome in Parkinson's disease without dementia: A comparison with other clinical executive tasks

The Behavioural Assessment of the Dysexecutive Syndrome (BADS) is a neuropsychological battery developed with the intent of measuring a wide range of executive impairments. Although the psychometric characteristics of BADS have previously been investigated in distinct neurological disorders, data on its validity in Parkinsons Disease (PD) without dementia are still lacking. The principal aim of the study was to address this issue. Twenty-five non-demented PD patients and 24 demographically-matched controls were administered BADS and other commonly used executive tools. Comparisons between groups indicated that two of the six BADS subtests (Temporal Judgement and Action Program) did not have sufficient sensitivity to executive impairments. However, when we explored group-predictive capabilities among the tests, the BADS total score was the most sensitive, followed by the Tower of London (TOL). We obtained similar results when we disentangled the sensitivity of the six BADS subtests. The BADS Six Elements task was the best group predictor followed by the TOL. Our findings showed that BADS is more sensitive to executive dysfunction than some of the tools commonly used to assess this construct in PD. However, we also demonstrated that, to assess executive impairments in PD without dementia adequately, this battery should be administered in combination with the TOL.

Acetyl-L-carnitine: from a biological curiosity to a drug for the peripheral nervous system and beyond

Acetyl-L-carnitine (ALC) is a molecule derived from acetylation of carnitine in the mitochondria. Carnitine acetylation enables the function of CoA and facilitates elimination of oxidative products. Beyond this metabolic activity, ALC provides acetyl groups for acetylcholine synthesis, exerts a cholinergic effect and optimizes the balance of energy processes. Acetylcarnitine supplementation induces neuroprotective, neurotrophic and analgesic effects in the peripheral nervous system. In the recent studies, ALC, by acting as a donor of acetyl groups to NF-kb p65/RelA, enhanced the transcription of the GRM2 gene encoding the mGLU2 receptors, inducing long-term upregulation of the mGluR2, evidencing therefore that its long-term analgesic effects are dependent on epigenetic modifications. Several studies, including double-blind, placebo-controlled, parallel group studies and few open studies showed the effect of ALC in diseases characterized by neuropathies and neuropathic pain: the studies included diabetic neuropathy, HIV and antiretroviral therapy–induced neuropathies, neuropathies due to compression and chemotherapeutic agents. Double-blinded studies involved 1773 patients. Statistical evaluations evidenced reduction of pain, improvements of nerve function and trophism. In conclusion, ALC represents a consistent therapeutic option for peripheral neuropathies, and its complex effects, neurotrophic and analgesic, based on epigenetic mechanism, open new pathways in the study of peripheral nerve disease management.

Delayed blink reflex in dementia with Lewy bodies

Blink reflexes (BR) to electric stimuli of the supraorbital nerve were recorded in 26 patients with dementia with Lewy bodies (DLB), 26 patients with multiple system atrophy, 26 patients with Parkinson’s disease, with or without REM sleep behaviour disorder (RBD), and in 20 patients with Alzheimer’s disease and 20 with progressive supranuclear palsy without RBD, and compared with recordings in 30 healthy controls. BR were significantly delayed (p<0.001) only in DLB patients in comparison with controls and with the other groups of patients; 14 (53.8%) patients had BR latency above 2 SD of the control mean, ranging from 36.1 to 46.3 ms. BR latency was not related to the presence of RBD, while a Spearman correlation rho of 0.68 was found for scores assessing the presence of cognitive fluctuations. R2 delay was prominently (71.5%) bilateral.

Fava beans and Parkinson’s disease: useful ‘natural supplement’ or useless risk?

In April 2008, a 54-year-old man of Ashkenazi Jewish/Polish descent developed an acute episode of malaise and severe jaundice. He was diagnosed with Parkinson s disease (PD) in May 2007 and was treated with rasagiline, 1 mg daily, and Co-Enzyme Q10, 1200 mg daily. His past medical history was significant for hepatitis B and Epstein-Barr virus, and Gilbert s disease. He had no family history of anemia or jaundice, although information was limited because most of his relatives perished in the Holocaust. In the fall of 2007, he began ingesting canned, frozen or pre-cooked fava beans as a form of natural L-dopa supplementation, with no adverse effects. In the spring of 2008, he switched to fresh, uncooked fava beans. Shortly thereafter, he experienced mild jaundice and fatigue. He stopped eating fava beans and his symptoms resolved the following week. Laboratory studies at that time were unremarkable. One week later, he again began eating uncooked fresh fava beans. Within 48 h, he developed severe fatigue, marked jaundice, and dark urine discoloration. Laboratory evaluation revealed creatine-phospho-kinase 250 U/l, total bilirubin 30 mg/dl, hematocrit 28%, and blood, not bilirubin, present on urinalysis. All other investigations, including hepatic transaminases and abdominal computerized tomography, were unremarkable. Enzymatic assay for glucose 6-phosphate dehydrogenase (G6PD) revealed very low activity of 0.25 IU/g Hgb (normal range, 4.25–8.25 IU/g Hgb). Genetic analysis determined that he was heterozygous for the C563T Mediterranean G6PD mutation, confirming that this was an episode of favism with hemolysis, and had Gilbert s disease. At 3 months follow-up after discontinuing the ingestion of fava beans, all clinical and laboratory abnormalities had normalized. Glucose 6-phosphate dehydrogenase deficiency is due to various mutations in the X-linked G6PD gene, affecting up to 400 million people of Mediterranean, African, Middle-Eastern and Asian descent, but is extremely rare amongst Ashkenazi Jews [1]. To our knowledge, there is only one other report of adult onset favism in an Ashkenazi Jews [2]. As the authors of that report suggest, reliance on ethnic origin in the diagnosis of inherited red blood cell defects can be misleading. There is no known biological reason to suggest that PD predisposes to favism nor is it likely that rasagiline or Co-Enzyme Q10 contributed to the hemolytic reaction. L-Dopa was first isolated in fava beans by Guggheneim in 1913 [3], long before its pharmacological role in PD was discovered [4]. Ingestion of fava beans as a source of natural L-dopa is popular amongst patients with PD, despite only anecdotal evidence of clinical efficacy [5] and the variable content of L-dopa measured in the beans. There is, however, limited public awareness that fava beans may trigger a severe hemolytic anemia, particularly amongst unsuspecting populations where G6PD deficiency is uncommon and fava beans are rarely eaten. It should be noted that the hemolytic reaction is not related to the L-dopa content of the beans. It is also important to notice that other serious complications have been reported in patients consuming fava beans, including a neuroleptic malignantlike syndrome that developed abruptly in a patient after the beans were discontinued [6]. Our case of favism, the second ever reported in an Ashkenazi Jew, serves as a powerful reminder that natural and seemingly innocuous food supplements can harbor significant health risks. Physicians should be ever mindful and vigilant of their risks and caution patients to avoid potentially catastrophic complications. As G6PD testing is widely available and relatively innocuous, it would seem prudent to screen patients with PD for G6PD deficiency prior to their consuming fava beans.

Modafinil and armodafinil improve attention and global mental status in Lewy bodies disorders: preliminary evidence

Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB) share several disturbances of attention, including cognitive fluctuations (FC), which are known to correlate with worse dementia symptoms (Varanese et al., 2010). Although cholinesterase inhibitors may improve them to some degree, their effect is inconsistent in PDD/DLB. Modafinil (Minzenberg and Carter, 2008) and armodafinil (Lankford, 2008), the racemic form of modafinil, are wake-promoting eugeroic agents that activate the central nervous system through the hypocretin/orexin system. They have been shown to improve attention in different conditions (Minzenberg and Carter, 2008; Lankford, 2008). Improvement of sleepiness is reported for modafinil in PDD and recently for armodafinil in DLB patients, with related improvement of quality of life (Kuntz et al., 2012). There is currently no evidence, however, in respect to attention and global mental status.

Responsiveness of dysphagia to acute l-Dopa challenge in progressive supranuclear palsy

Dysphagia occurs in up to 80 % of patients with progressive supranuclear palsy (PSP) [1], and may result in aspiration pneumonia, which is the leading cause of death in PSP [2]. We report the improvement of dysphagia following L-Dopa challenge in three patients diagnosed with probable PSP [3] and evaluated for enteral nutrition. All patients showed MRI signs suggestive of PSP [4] and had the specific finger tap pattern of ‘‘hypokinesia without decrement’’ [5]. None of them had prior or concomitant history of REM Sleep Behaviour Disorder. Disease severity was rated through the Progressive Supranuclear Palsy Rating Scale and Staging System (PSPRS) [6]. Dysphagia was evaluated by a trained Speech and Language Therapist through the Dysphagia Rating Scale (DRS), a recently developed tool able to predict the risk of complications of dysphagia [7] (Table 1). Case 1: 78-year-old male with PSP history of 5 years, treated with L-Dopa 300 mg/day. He showed complete supranuclear upward and downward gaze palsy, increased latency onset of horizontal saccades, square wave jerks, positive applause sign, moderate dysarthria, moderate rigidity in the upper and lower limbs, mild dystonia and akinesia in the right arm and hand, trunk apraxia and inability to walk unassisted. Mild oral apraxia associated with oromandibular dystonia resulted in prolonged oropharyngeal phase, food accumulation, and coughing. L-Dopa was increased up to 600 mg in 2 days, leading to less frequent episodes of oral apraxia and decreased latency of the oropharyngeal phase, with significant reduction of dysphagia risks. He received logopedic training, and for the following 3 months his condition was stable. Case 2: 66-year-old male diagnosed with PSP at the age of 61 following the onset of gaze abnormalities, tremor, falls, and bradykinesia and treated with low doses of L-Dopa to mild benefit. At the time of L-Dopa challenge he showed complete vertical and partial horizontal supranuclear gaze palsy, positive applause sign, severe dysarthria, neck dystonia, severe axial and limb rigidity, dystonia, and akinesia of the right hand. He was wheelchair-bound and unable to stand unassisted. Prolonged oropharyngeal phase due to oral dystonia and oral apraxia was observed. L-Dopa was increased up to 1,200 mg/day, with improvement of swallowing. He received logopedic training, and at 6 months’ follow-up his condition was stable. Case 3: 69-year-old female with a PSP history of 4 years, treated with L-Dopa 400 mg/day. She came to our observation after progressive worsening of her general conditions such as severe axial and limb rigidity, severe dystonia and akinesia in her left arm and leg, akinetic mutism, complete vertical supranuclear gaze palsy, and severe oral apraxia and oromandibular dystonia that made her almost unable to open her mouth or push food behind. She showed signs of malnutrition and dehydration. L-Dopa was increased to 1,000 mg in 4 days. By the second day, the patient showed a reduction of body stiffness and spontaneous mouth opening at food presentation. After a S. Varanese (&) P. Di Ruscio L. Ben M’ Barek Casa di cura Villa Pini d’Abruzzo, Policlinico Abano Terme, Via dei Frentani 124, 66100 Chieti, Italy e-mail: sara78_96@yahoo.it