This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Parkinsonâs disease (PD) is one of the neurodegenerative diseases of which we can by certainty identify its pathology; however, this confidence disappears when we talk about the cause and clinical complications of the disease. Dopamine deficiency, caused by the degeneration of nigrostriatal dopaminergic neurons, is the cause of the major clinical motor symptoms of PD and these symptoms can be treated successfully with a range of drugs that include levodopa, inhibitors of the enzymatic breakdown of levodopa and dopamine agonists. However, PD involves degeneration of non-dopaminergic neurons and result in broad spectrum of clinical manifestations, extending beyond movement disorders. These include cardiovascular, olfactory, gastrointestinal, sleep, autonomic, sensory, cognitive dysfunction, as well as psychiatric manifestations. Thus treatment of the resulting predominantly non-motor features remains a multifacteted challenge for the physicians. Clinical complications mentioned in this review deserve a special address and attention by the research community as well as by the clinicians as they may help to understand the complexity of disorder as well as may serve to diagnose and manage PD.
INTRODUCTIONParkinsonâs disease (PD) is the second most common neurodegenerative disease and its prevalence is increasing such that over the next 25 years the number of individuals over 50 years of age with PD can be expected to double in the worldâs 10 most populous nations [1]. Parkinsonâs disease was first described in 1817 by the physician James Parkinson [2] even prior to this, accounts of the symptoms were remarkably scarce, which led many researchers to theorize whether this disease may have been a product of the beginning of the early 19th century and the industrial revolution in England[3].Earlier than James Parkinson, many physicians have picked up some of the features of Parkinsonâs disease and described them in their writings, for example, Franciscus de le Boe (1614â1672) who described tremors and Francois Boissier de Sauvages de la Croix (1706â1767) who described patients with ârunning disturbances of the limbsâ[4].Even though its incidence is higher in individuals of 50 to 70 years of age, with a peak at the age of 60, the onset of PD can also occur, before the age of 40 (early-onset Parkinson) or 20 (juvenile Parkinson) [5,6].The term âParkinsonâs diseaseâ refers to a neurodegenerative disease that affects several regions of the brain, including the pigmented nuclei in midbrain and brainstem, the olfactory tubercle, the cerebral cortex, and elements of the peripheral nervous system [7]. Parkinsonâs disease (PD) is the most common disease of motor system [3] and takes a heavy toll in mental anguish, lost productivity, and health care expenditures. Parkinsonâs disease is now recognized to be a widespread degenerative illness that affects not just the central nervous system, but also the peripheral and enteric systems [8].PD is marked by the degeneration of the dopaminergic neurons of the substantia nigra, thyrosine hydroxylase deficiency and the presence of intracytoplasmatic inclusions rich in α-synuclein, named Lewyâs bodies [9]. In this disease, the dopaminergic areas of the central nervous system are not equally affected. Initially, neuronal loss tends to occur mainly in the ventrolateral layer of the substantia nigra (estimated at 60% to 70%), progressing towards the medial ventral and dorsal layers. An extensive loss of neurons is also observed in the brain stem, in the hypothalamus, in the cortex and in Meynertâs basal nucleus [10].Dopaminergic cell loss in Substantia niagra (SN) directly leads to dopaminergic deficiency in the substantia nigra pars compacta (SNpc) [11]. Formerly the disease was typecast as motor system degeneration, yet sensory fields, association areas, and premotor fields become damaged throughout the brain. The limbic, autonomic, and neurosecretory control fields (hypothalamus) all show micro-anatomic damage [6].The variable presentations of PD often cause diagnostic confusion and a delay in treatment. In the early stages, Parkinsonian symptoms are often mistaken for simple arthritis or bursitis, depression, normal aging, Alzheimerâs disease, or stroke [12]. A prodromal phase 4â6 years characterized before the main manifestation in PD patients. During this period, PD patients, compared with normal controls, had a higher frequency of mood disorder, âfibromyalgia,â and shoulder pain [4]. Parkinsonâs disease (PD) may involve skeletal abnormalities including extreme neck flexion (âdropped headâ) and truncal flexion (camptocormia) [13].Pathology of PD can be associated with a very broad spectrum of clinical manifestations, extending beyond movement disorders. These include olfactory, gastrointestinal, sleep, sensory, and cognitive dysfunction, as well as psychiatric manifestations such as depression and anxiety. Many of these features predate the development of the classic motor disorder, and thus may serve as early markers of the disease, but are also common in the general population. It may be possible to identify individuals in the earliest stages of neurodegeneration using these early premotor features of PD in combination with other novel biomarkers [14, 15].
TREMORS Resting tremor is a characteristic of Parkinsonism and in fact, begins on one side of the body, most commonly in the hand and then spreads, over months and years, to the other side of the body [16]. Classic Parkinsonian tremor is a rest tremor of 4-5 Hz affecting the limbs, asymmetric or unilateral in the early stages of the disease. The combination of postural deformity and tremor can produce the unique tremor which Charcot described as follows: âThe patient closes the fingers on the thumb as though in the act of spinning woolâ or âcrumbing breadâ. In the limbs it is distal. Arms are affected more commonly than legs. Less commonly it is present in lips, chin and tongue. Tremor is abolished during sleep [17]. The tremor of Idiopathic PD can affect the eyelids (blepharoclonus), jaw, and legs, while essential tremor targets the head, voice, and upper limbs. Parkinsonian tremor is increased by anxiety, and abolished by sleep. Limb activity attenuates rest but increases postural tremor. Around 50% of rest tremors respond well to dopaminergic and anticholinergic agents [18].RIGIDITY Rigidity is of the extrapyramidal âplasticâ or âlead-pipeâ type, i.e. not dependent on the velocity of passive muscle stretch. Many patients, particularly those with tremor have cog-wheeling but anyone with tremor (e.g. a patient with severe essential tremor) may have cog-wheeling [17]. The rigidity initially targets limbs but later spreads axially. A predominant involvement of limb and trunk flexors leads to characteristic âdystonicâ posturing with trunk, neck, and arm flexion, and foot inversion. The rigidity is abolished by sleep and in 80% of cases responds well to dopaminergic agents [18].SLOWNESSFifty per cent of IPD patients complain of slowing up at presentation. Writing becomes progressively smaller (micrographia). Difficulty in chewing and swallowing are common. [19]. Later on they develop difficulty washing, feeding, dressing, and turning in bed, but reveals slowing [18].VOICE CHANGES AND SIALORRHEAThis initially becomes quiet and speech loses its natural cadence and prosody. Later lingual and labial bradykinesia leads to problems with articulation and speech becomes indistinct. Pallilalia is a feature of end stage disease.Sometimes sialorrhea appears when saliva is not swallowed as fast as it is produced, although increased saliva production may also occur as an autonomic symptom of Parkinsonism.DYSTONIADystonia is characterized by slow or sustained involuntary muscle contractions, frequently causing twisting and repetitive movements or abnormal postures [20, 21]. The muscles involved are usually localized in the head (mouth and eyes), neck, trunk and limbs. When dystonia becomes irreversible (which is often the case in tardive dystonia), it is one of the most disabling and untreatable adverse events in psychiatry [22].Younger onset IPD cases (including genetic Parkinsonâs disease associated with parkin mutations) are particularly prone to exhibit limb dystonia. This can be early morning or wearing off dystonia with a predilection for painful foot inversion, but can also manifest as a variety of segmental syndromes. Levodopa and dopamine agonists may worsen rather than improve dystonia in some of these young onset IPD cases and anticholinergic treatment or amantadine can be helpful [4, 17, 18].BRADYKINESIABradykinesia(Slowed movement), hypokinesia (reduced movement), and akinesia (loss of movement) may be seen in a progressive decrement in the speed and amplitude of rapid succession movements e.g. finger tapping or fist opening and closing. These are the most common and disabling features of Parkinsonism. It also manifests in other ways. Reduction of arm swing during walking and micrographia are other examples. Ulnar deviation of the hands, extension of the interphalangeal joints and flexion of the metacarpophalangeal joints may stimulate the changes of rheumatoid arthritis. Many patients find this to be the most frustrating aspect of their disease. It results in a loss of independence as it progresses, due to difficulties performing everyday functions, such as getting dressed, using utensils, and rising from chairs or bed.CAMPTOCORMIACamptocormia is a relatively common sign in PD and present therapeutic regimens, including drug therapy, surgical therapy and rehabilitation, have limited effect on camptocormia[23]. Camptocormia in PD is defined by marked anteroflexion of the trunk, which abates in the recumbent position, with no or minimal response to levodopa [13, 24, 25]. The condition is exacerbated by walking and is relieved by sitting, lying in the supine position or by volitionally extending the trunk when the patient leans against a wall or a table. Although early reports often attributed camptocormia to a conversion disorder, it is now accepted as an axial feature of Parkinsonâs disease [26, 27, 28]COGNITIVE DEFICITS AND DEMENTIANowadays Parkinsonism is not only recognised as a movement disorder but a multisystem disease affecting cognitive functions even in the earlier stages of disease [29].The prevalence rate of dementia in PD patients can range from 17-43 % [29] and increases up to 83% after 20 years follow up [30].Patients with Parkinsonâs disease are impaired in cognitive tasks. A likely source of these deficits is depleted levels of the neuromodulator dopamine in the basal ganglia of Parkinsonâs patients [31] because dopamine plays a key role in reinforcement learning processes in animals. Dementia commonly accompanies late-stage Parkinsonâs disease can be associated with nocturnal confusional episodes and vocalizations and awakenings [32].INSOMNIABased on the National Center for Sleep Disorders Research Classification [33] insomnia symptoms can be defined as subjective complaints of difficulty falling asleep, difficulty maintaining sleep, early awakening and non refreshing sleep despite an adequate opportunity to sleep.Sleep disturbances tend to increase with age and is particularly common in Parkinsonâs disease. Difficulty falling asleep and difficulty remaining asleep are the most common complaints. Loss of dopaminergic neurons of the substantia nigra is responsible for most of the daytime features of Parkinsonâs disease. Other neurochemical changes affecting cholinergic, serotonergic and noradrenergic systems are also involved and have been implicated in the sleep-wake disturbances in Parkinsonâs disease. The precise role of these neurotransmitters in the disruption of the sleep-wake cycle is as yet unclear. Depression and anxiety may be the prime reasons for early awakening and difficulty in falling asleep. The on-off phenomena and presence of hallucinations can result in severe sleep disruption [32]. Sleep disorders are common in patients with Parkinsonâs disease. They consist of insomnia, excessive daytime sleepiness, parasomnias, sleep breathing disorders and abnormal movements during sleep [34].BLADDER DISORDERIn Parkinsonism beside several clinical disabilities, complaints of bladder and bowel dysfunction may add considerably to the patientsâ disabilities. In some patients, urinary symptoms were the sole presenting complaints and these included difficulties in voiding, nocturnal urinary frequency of more than twice, sensation of urgency, urge incontinence, daytime frequency of more than eight times, nocturnal enuresis and urinary retention[35,36,37]. Urinary dysfunction in PD may reflect pathology of the disease. Detrusor hyperreflexia has been found cause of filling disorder [37].The responsible sites for the detrusor hyperreflexia seem to be the nigrostriatal lesions in PD. Experimental studies showed that electrical stimulation of the basal ganglia inhibits micturition reflex in the cat [38] probably by activating striatal GABAergic neurons which descend to the locus ceruleus (PMC). Bladder hyperreflexia occurs in MPTP (1-methyl-4-phenyl- 1, 2, 3, 6-tetrahydropyridine)-induced Parkinsonian animals. There is experimental evidence that D1 receptors have an inhibitory and D2 a facilitatory effect on the micturition reflex [39]. Therefore, it seems likely that bladder hyperactivity in PD is associated with a reduction in the central dopamine D1 receptors.BOWEL DISORDERPatientsâ symptoms of anorectal dysfunction are common with PD, and constipation appears to be increasingly common with advancing disease [40]. Constipation occurs in 29-77% of PD patients compared to 10-13% of age-matched controls. Difficulty in defecation occurs in 67-94% of PD compared to 28% of a control group [41].Megacolon in PD patients has severe fecal impaction (intestinal pseudo-obstruction) and rectal transit times were also prolonged, indicating reduction of rectal contractility. Immunostaining of biopsied colonic musculature and the submucosa showed a reduction of dopamine containing neurons and there has also been a report showing Lewy bodies in the myenteric plexus of the colon [42]. These findings suggest that not only central, but also peripheral dopamine dysfunction in the colon account for the prolonged transit time and constipation in PD.Rectoanal manometry has shown reduced resting and defecating pressures [35,40]. These probably reflect dysfunction of the internal anal sphincter innervated by lumbosacral sympathetic nerve. Other possible causes include over extension injury of the myenteric plexus due to severe fecal impaction, and an adverse effect of anticholinergic agents in PD. Defecography and anal sphincter EMG showed paradoxical contraction of the puborectal muscle in PD as a cause of rectal constipation [43].SEXUAL DYSFUNCTIONEstimates of the prevalence of erectile dysfunction (ED) in patients with PD show that it is a significant problem, affecting 60% of a group of men compared with an age-matched healthy group without PD in whom the prevalence was 37%. ED and premature ejaculation was a complaint in a significant proportion. In general terms, however, sexual dysfunction appeared to be multifactorial with no simple single cause identified [44].PSYCHOSIS IN PARKINSONâS DISEASEPatients with Parkinsonâs disease (PD), particularly those exposed to dopamimetic agents such as levodopa, have a high incidence of psychiatric symptoms. Common symptoms are hallucinations [45,46] delusions[46,47,48], depression, euphoria (48,49} agitated confusion, sleep disturbances, and delirium [50].Visual hallucinations are the most common psychotic symptom exhibited by PD patients. Typical hallucinations have been described as nocturnal, nonthreatening images of people or animals, which the patient recognizes, or comes to recognize, as imaginary [46]. Delusions are less common in PD patients than hallucinations. Both hallucinations and delusions are serious complications of PD [51].Risk factors for psychosis in PD patients include advancing age [52], increased dosage of levodopa [53, 54] long-term treatment with levodopa [55] anticholinergic therapy, multiple drug therapy [45] dementia [47], cerebral atrophy [53] and pre-existing psychiatric conditions [54].EPILEPSYIn literature, there is brief information about the presence of epileptic seizures in patients with Parkinsonâs disease but epileptic seizures are not very rare in patients with Parkinsonâs disease. In their etiopathologenesis probably are included common pathophysiological mechanisms. These epileptic seizures are symptomatic, maybe a consequence of degenerative brain process and respond well to antiepileptic therapy [56].CANCERItâs hard to imagine two diseases more different than Parkinsonâs and cancer but Parkin as a tumor suppressor gene was the latest-discovered link between the two diseases. Parkin mutations cause up to half of early-onset hereditary cases of Parkinsonâs disease. Another early onset Parkinsonâs gene, DJ-1, has been implicated in cancer, and a third gene, LRRK2, has features that strongly hint at cancer like effects. In the 1980s researchers reported that Parkinsonâs patients had an overall decreased incidence of cancer, with some important exceptions, mainly melanoma. People with Parkinsonâs disease had a twofold increased risk of melanoma and also of breast cancer and there is a huge body of epidemiological data to support these conclusions [57].OTHERSPatients have impaired sense of smell [19].Increased sweating âseborrhoeaâ and facial flushing are late disease features (18,58). Further, A group of neurobehavioral abnormalities can be found in PD such as apathy, fearfulness, emotional liability, social withdrawal, increasing dependency, depression,, bradyphrenia, a type of anomia termed the âtip-of-the-tongue phenomenon,â visual-spatial impairment and other psychiatric problems [14].Hypomimia (masked facies), Speech disturbance (hypokinetic dysarthria), Hypophonia, Dysphagia, Respiratory difficulties, Loss of associated movements, Shuffling, short-step gait, Festination, Difficulty turning in bed, Slowness in activities of daily living, Stooped posture, kyphosis, scoliosis, orofacial dyskinesia and decreased blink rate are also experienced by the patients depending on the status and progress of disease [59]. Myersonâs sign is the inability to resist blinking when the glabella (area above the nose and between eyebrows) is tapped with finger; it can be seen early in PD [60].Other autonomic abnormalities include cardiovascular disorders and gastrointestinal dysfunction [19].
Variety of motor and non motor complications signifies the involvement of several neurotransmitters and signaling pathways involved in the neurobiology of Parkinsonism. Thus a multicentered and multitargeted approach must be applied by research community to understand the molecular mechanisms involved in pathogenesis of disease so that we can have a drug that can stop the progression of disease rather than provide symptomatic relief only.
Authors would like to thank Late Prof. Manjeet Singh (Ex. Director (academics), ISF College of Pharmacy, Moga), Satyanarayna SV Padi (Ex. Asst. Prof. ISF College of Pharmacy, Moga) and Mr. Rahul Deshmukh (Asst. Prof. ISF College of Pharmacy, Moga) for their blessings.
1. Dorsey ER, Constantinescu R, Thompson JP et al. Projected number of people with Parkinson disease in the most populous nations 2005 through 2030. Neurology 2007; 68:384â386.2. Perlmutter D. BrainRecovery.com: Powerful therapy for Challenging Brain Disorders. Naples, FL: The Perlmutter Health Center (www.brainrecovery.com); 2000.3. Saunders CD. Parkinsonâs disease: A New Hope. Boston, MA: Harvard Health Publications; 2000.4. Elhak GAS, Aziz AA, Ghaffar HA, Sahar E, Dakroury, Mohamed M. Parkinsonâs Disease: Is It a Toxic Syndrome? Neurology Research International 2010; Article ID 103094.5. Meneses MS, Teive HAG. Doença de Parkinson: a spectos clÃnicos e cirúrgicos. Rio de Janeiro. Guanabara Koogan1996.6. Kidd PM. Parkinsonâs disease as Multifactorial Oxidative Neurodegeneration: Implications for Integrative Management. Alternative Medicine Review2000; 5(6).7. Galvan A and Wichmann T. Pathophysiology of Parkinsonism. Clinical Neurophysiology2008; 119(7)1459â 1474.8. Braak H, Braak E. Pathoanatomy of Parkinsonâs disease. J Neurol 2000;247(2)3-10.9. Lotharius J, Brundin P. Pathogenesis of Parkinsonâs disease: dopamine, vesicles and alpha-synuclein. Nat Rev Neurosci 2002; 3(12):932-42.10. Fearnely JM, Lees AJ. Ageing and Parkinsonâs disease: substancia nigra regional selectivity. Brain1991; 114(5):2283-2301.11. Savitt JM, Dawson VL, Dawson TM. Diagnosis and treatment of Parkinson disease: molecules to medicine. J Clin Invest 2006;116(7):1744-54.12. Gonera EG, Hof VM, Berger HJC, Van Weel M,and M. W. I. M. Horstink. Symptoms and duration of the prodromal phase in Parkinsonâs disease. Movement Disorders1997; 12(6) 871â876.13. Ashour R and Jankovic J. Joint and skeletal deformities in Parkinsonâs disease, multiple system atrophy, and progressive supranuclear palsy. Movement Disorders2006; 21(11)1856â1863.14. Jankovic J and Lang AE. Movement disorders: diagnosis and assessment,â in Neurology in Clinical Practice, W. G.Bradley, R. B. Daroff, G. M. Fenichel, and J. Jankovic, Eds.,chapter 24, pp. 293â322, Butterworth-Heinemann (Elsevier), Philadelphia, Pa, USA, 4th edition, 2004.15. Marras C and Lang A. Changing concepts in Parkinson disease: Moving beyond the Decade of the Brain. Neurology2008; 70:1996â2003.16. Krishna De A. Therapy in Parkinsonâs disease: Some Recent Developments. Resonance1999; 1:1-11.17. Thyagarajan D. Parkinsonâs disease and related movement disorders. Middle east journal of ageing 2005; 3: 1-14.18. Brooks DJ. Diagnosis and management of atypical parkinsonian Syndromes. J neurol neurosurg psychiatry 2002; 72(suppl i):10â16.19. Khan NL, Thomas B. Parkinsonâs disease clinical features, pathophysiology and genetics. Hospiotal Pharmacist 2004;11;:9-15.20. Cardoso F and Jankovic J. Dystonia and dyskinesia. Psychiatr Clin North Am1997; 20, 821-838.21. Harten VPN and Kahn RS (1999). Tardive dystonia. Schizophr Bull1999; 25: 741-748.22. Gerlach J. The continuing problem of extrapyramidal symptoms: strategies for avoidance and effective treatment. J Clin Psychiatry1999; 60 Suppl 23: 20-24.23. Abe K, Uchida Y, Notani M. Camptocormia in Parkinsonâs Disease. Parkinsonâs Disease 2010; Article ID 2676405.24. Parkinson J. An Essay of the Shaking Palsy. Whittingham and Rowland, London, UK, 1817.25. Brodie BC. Pathological and surgical observations of the disease of the joints in Longman, R. Hurst and B. Orme, Eds.,p. 376, London, UK, 1818;1822.26. Souques A and Rosanoff-Saloff M. La camptocormie; incurvation du tronc, consecutive aux traumatismes du dos et des lombes; consid´erations morphologiques. Revista de Neurologia1914; 28:937â939.27. Djaldetti R, Mosberg-Galili R, Sroka H, Merims D and Melamed E. Camptocormia (bent spine) in patients with Parkinsonâs diseaseâcharacterization and possible pathogenesis of an unusual phenomenon. Movement Disorders1999;14(3)443â447.28. Djaldetti R and Melamed E. Camptocormia in Parkinsonâs disease: new insights. Journal of Neurology, Neurosurgery and Psychiatry2006; 77(11) 1205-09.29. Aarsland D, Bronnick K, Larsen JP, Tysnes OB, Alves G. Cognitive impairment in incident untreated Parkinsonâs disease; Norwegian Parkwest study. Neurology; 72(13); 1121-1126.30. Hely MA, Reid WG, Adena MA, Haliday GM and Morris JG. The Sydney multicenter study of Parkinsonâs disease: the inevitability of dementia at 20 years; Mov Disord2008;23(6):837-844.31. Kish S, Shannak K, HornykiewiczO. N. Engl. J. Med. 318, 876 (1988).5. R. A. Wise, P.-P. Rompre, Annu. Rev. Psychol. 40, 191(1989).32. Ariff KM and Ariff KK. Insomnia: case studies in family practice. Malaysian Family Physician 2006;1(1):11-14.33. National Heart, Lung, and Blood Institute Working Group on Insomnia. Insomnia: assessment and management in primary care. Am Fam Physician. 1999;59(11):3029-38.34. Billiard M, Dauvillierss Y. Neurodegenerative diseases and sleep disorders; c h w e i z e r a r c h i v f ü r n e u r o l o g i e u n d p s y c h i a t r i e2003; 384 :1 5 4.35. Stocchi F, Carbone A, Inghilleri M, Monge A, Ruggieri S, Berardelli A et al. Urodynamic and neurophysiological evaluation in Parkinsonâs disease and multiple system atrophy. J Neurol Neurosurg Psychiatry 1997; 62:507-11.36. Terao Y, Takeda K, Sakuta M, Nemoto T, Takemura T, Kawai M. Pure progressive autonomic failure; a clinicopathological study. Eur Neurol 1993; 33:409-15.37. Hattori T, Yasuda K, Kita K, Hirayama K. Voiding dysfunction in Parkinsonâs disease. Jpn J Psychiatry Neurol1992; 46:181-6.38. Lewin RJ, Dillard GV, Porter RW. Extrapyramidal inhibition of the urinary bladder. Brain Res 1967; 4:301-7.39. Yoshimura N, Mizuta E, Yoshida O, Kuno S. Therapeutic effects of dopamine D1/D2 receptor agonists on detrusor hyperreflexia in 1-methyl-4-phenyl-1,2,3,5-tetrhydropyridine lesioned parkinsonian cynomolgus monkeys. J Pharmacol Exp Ther 1998; 286:228-33.40. Stocchi F, Badiali D, Vacca L, DâAlba L, Bracci F, Ruggieri S, Torti M, Berardelli A, Corazziari E. Anorectal function in multiple system atrophy and Parkinsonâs disease. Mov Disord 2000; 15:71-6.41. Edwards LL, Quigley EMM, Pfeiffer RF. Gastrointestinal dysfunction in Parkinsonâs disease frequency and pathophysiology. Neurology 1992; 42:726-32.42. Singaram C, Ashraf W, Gaumnitz E et al. Dopaminergic defect of enteric nervous system in Parkinsonâs disease patients with chronic constipation. Lancet 2005; 346:86.43. Mathers S, Kempster P, Swash M, Lees A. Constipation and paradoxical puborectalis contractions in anismus and Parkinsonâs disease: a dystonic phenomenon? J Neurol Neurosurg Psychiatry 1988; 51:1503-7.44. Brown RG, Jahanshahi M, Quinn N, Marsden CD. Sexual function in patients with Parkinsonâs disease and their partners. J Neurol Neurosurg Psychiatry 1990; 53(6):480-6.45. Tanner CM, Vogel C, Goetz C, et al. Hallucinations in Parkinsonâs disease: a population study. Ann Neurol 1983; 14:136.46. Moskovitz C, Moses H, Klawans H. Levodopa induced psychosis: a kindling phenomenon. Am J Psychiatry 1978; 135:669â675.47. Sacks OW, Kohl MS, Messeloff CR, et al: Effects of levodopa in parkinsonian patients with dementia. Neurology 1972; 22:516â 519.48. Celesia GG, Barr AN. Psychosis and other psychiatric manifestations of levodopa therapy. Arch Neurol 1970; 23:193â20049. Mayberg HS, Solomon DH. Depression in Parkinsonâs disease: a biochemical and organic viewpoint. Adv Neurol 1995; 65:49â60.50. Dama´sio AR, Lobo-Antunes J, Macedo C. Psychiatric aspects in parkinsonism treated with L-dopa. J Neurol Neurosurg Psychiatry1971; 34:502â507.51. David MR, John MD, Rogers MD, Jessica H, Robinson Todd, Feinberg M.D. Delusional Misidentification in Association With Parkinsonism. Spring1998; 10 (2), 194-198.52. Pederzoli M, Girotti F, Scigliano G, et al. L-dopa long-term treatment in Parkinsonâs disease: age related side effects. Neurology 1983; 33:1518â1522.53. Doraiswamy M, Martin W, Metz A, et al. Psychosis in Parkinsonâs disease: diagnosis and treatment. Prog Neuropsychopharmacol Biol Psychiatry 1995; 19:835â846.54. Damasio AR, Lobo-Antunes J, Macedo C. Psychiatric aspects in Parkinsonism treated with L-dopa. J Neurol Neurosurg Psychiatry 1971; 34:502â507.55. Moskovitz C, Moses H, Klawans H. Levodopa induced psychosis: a kindling phenomenon. Am J Psychiatry 1978; 135:669â675.56. Petrov I.Association of patients with parkinsonism and epilepsy with EEG changes; Contribution, Sec. Biol. Med. Sci2006;27(1) 107â112.57. Garber K. Parkinsonâs disease and Cancer: The Unexplored Connection. JNCI News2010; 102(6)371-374.58. Barar FSK. Essentials of pharmacotherapeutics.6th edition,6, S Chand & Company LTD. Ram Nagar, New Delhi,2006,164-169.59. Jankovic J."Pathophysiology and clinical assessment,â in Hand Book of Parkinsonâs Disease, R. Pahwa and K. Lyons,Eds., pp. 49â67, InformaHealthcare, New York,NY, USA, 4th edition, 2007.60. Conley SC, Kirchner JT. Parkinson's diseaseâthe shaking palsy. Underlying factors, diagnostic considerations, and clinical course. Postgrad Med 1999;106(1):39-42,