Abstracts
During the past decade the view of Parkinson’s disease (PD) as a motor disorder has changed significantly and currently it is recognized as a multisystem process with diverse non-motor signs (NMS). In addition to been extremely common, these NMS play a major role in undermining functionality and quality of life. On the other hand, NMS are under recognized by physicians and neglected by patients. Here, we review the most common NMS in PD, including cognitive, psychiatric, sleep, metabolic, and sensory disturbances, discuss the current knowledge from biological, epidemiological, clinical, and prognostic standpoints, highlighting the need for early recognition and management.
Parkinson’s disease; non-motor signs; dementia; hyposmia; psychosis
No decorrer da última década, a visão da doença de Parkinson (DP) como um distúrbio de movimento puro mudou significativamente, sendo atualmente reconhecida como um processo multisistêmico com diversos sinais não motores (SNM). Além de serem extremamente comuns, estes SNM têm um impacto muito significativo na limitacão funcional e da qualidade de vida na DP. Por outro lado, os SNM são mal reconhecidos pelos clínicos e negligenciados pelos pacientes. Nessa revisão os SNM mais comuns na DP foram detalhados, incluindo distúrbios cognitivos, psiquiátricos, do sono, metabólicos, e sensitivos; e discutindo o conhecimento atual sob o ponto de vista biológico, epidemiólogico, clínico e prognóstico, destacando a necessidade de reconhecimento e abordagem terapêutica precoces.
doença de Parkinson; sinais não-motores; demência; hiposmia; psicose
The traditional pathological description of PD as a pre-synaptic degenerative process affecting dopaminergic neurons in the substantia nigra pars compacta (SNc) of the midbrain with formation of Lewy bodies (LB) has changed dramatically in the last decade since functional and neuropathological studies showed the occurrence of extensive extranigral involvement11 Rajput AH, Rozdilsky B, Rajput A. Accuracy of clinical diagnosis in parkinsonism: a prospective study. Can J Neurol Sci. 1991;18(3):275-8.. Among these investigations, the seminal study of Braak et al.22 Braak H, Del Tredici K, Rüb U, Vos RA, Steur ENJ, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging. 2003;24(2):197-211. suggested that the degenerative process in the PD starts in the caudal regions of the brainstem and the olfactory bulb, progressing in the caudal-rostral direction. The involvement of the SNc occurs, according to this hypothesis, on the third of a six-stage process that begins in the dorsal motor nuclei of the glossopharyngeal and vagus nerves and the olfactory bulb. Although it demonstrates the occurrence of this peculiar pathological distribution, the study fails to make the clinical correlation between any of these changes and motor or non-motor manifestations. On the other hand, even considering this caveat, it was one of the studies that formed the basis and motivated the dissemination of the concept of the existence of non-motor signs (NMS), especially dysautonomia, olfaction and sleep disorders, as part of the disease, sometimes even preceding the classic motor symptoms of PD.
The motor aspects of PD typically have a slow progression and direct correlation with the
presence of neuronal degeneration in the SNc, but they do not represent the actual
beginning of the degenerative process. This process is, in fact, in full progression,
despite been apparently silent when one seeks only for motor signs33 Jellinger KA. A critical evaluation of current staging of
alpha-synuclein pathology in Lewy body disorders. Biochim Biophys Acta.
2009;1792:730-40.
http://dx.doi.org/10.1016/S0197-4580(02)00065-9
https://doi.org/10.1016/S0197-4580(02)00...
.
EXTRANIGRAL DEGENERATION
The notion of PD as a multisystemic disease, not restricted to the nigrostriatal tract is not new, however the cited study of Braak et al.22 Braak H, Del Tredici K, Rüb U, Vos RA, Steur ENJ, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging. 2003;24(2):197-211. not only showed that the degenerative process begins in non-dopaminergic structures of the brain stem, or even in the peripheral autonomic system, but also influenced the way in which we interpret apparently nonspecific signs that can be detected in the course of the disease. Another innovative aspect of this hypothesis is that the disease process advances in a sequential and predictable manner. Thus, when the process affects the SNc, components of other brainstem structures are already heavily affected. Also, from the moment when the motor signs appear, other brainstem nuclei will also degenerate, until finally the degenerative process reaches the anteromedial temporal cortex and then the neo cortex, starting with associative and pre frontal, until finally sensory, motor and pre motor areas are affected.
This concept, however, does not escape criticism and between 6% and 43% of the cases
described in other pathological studies published since then do not fit perfectly
with this model, especially the sequential aspect44 Burke RE, Dauer WT, Vonsattel JP. A critical evaluation of the Braak
staging scheme for Parkinson’s disease. Ann Neurol. 2008;64(5):485-91.
http://dx.doi.org/10.1002/ana.21541
https://doi.org/10.1002/ana.21541...
. For example, a study that evaluated pathologically confirmed cases of PD
with the intention of testing the Braak’s model, showed that the distribution of the
pathological markers is consistent with this pattern, but also showed that the
pathologic density in the brainstem was different from the cortex, indicating that
the accumulation of degeneration occurs in these two regions independently. Another
important point was the lack of an adequate correlation between the clinical and
pathological findings in terms of duration and severity of motor and NMS and between
neuronal loss density and these same clinical variables55 Kingsbury AE, Bandopadhyay R, Silveira-Moriyama L, Ayling H, Kallis
C, Sterlacci W et al. Brain stem pathology in Parkinson’s disease: an evaluation
of the Braak staging model. Mov Disord. 2010;25(15):2508-15.
http://dx.doi.org/10.1002/mds.23305
https://doi.org/10.1002/mds.23305...
. Finally, almost 10% of cases from other pathological series feature the
degenerative process markers in the midbrain and cortex, but not in the most caudal
areas of the brainstem, contrary to the model of an upward progression from the
medulla.
Regardless of the lack of consonance of pathological studies in PD, especially in terms of its dynamic distribution during the course of the disease, the literature is unanimous in regards to its progressive and diffuse distribution, advancing in either phase of the disease to cortical and subcortical areas, not restricted to the motor system.
PREVALENCE AND IMPACT OF NON-MOTOR SIGNS OF PARKINSON’S DISEASE
Most, if not all, patients with PD present NMS. A survey that included 1,072 patients
with PD using a structured questionnaire conducted in Italy showed that 98.6% of
patients had at least one of the SNM studied, including more commonly psychiatric,
sensory and sleep-related symptoms. On average, in this study, each patient had
about eight symptoms, a figure that increased
according to the duration of the disease and its severity66 Barone P, Antonini A, Colosimo C, Marconi R, Morgante L, Avarello TP
et al. The PRIAMO study: a multicenter assessment of nonmotor symptoms and their
impact on quality of life in Parkinson’s disease. Mov Disord.
2009;249(11):1641-9. http://dx.doi.org/10.1002/mds.22643
http://dx.doi.org/10.1002/mds.22643...
. These NMS can occur at any time in the course of the disease, however some
are generally described in the early stages, such as REM sleep behavior disorder
(RBD), olfactory disorders and constipation. Others tend to occur in the later
stages, such as psychosis and cognitive deficits. A third group of these symptoms do
not have a clear relationship with stages of the disease, including depression and
forms of dysautonomia77 Chaudhuri KR, Odin P, Antonini A, Martinez-Martin P. Parkinson’s
disease: the non-motor issues. Parkinsonism Relat Disord. 2011;17(10):717-23.
http://dx.doi.org/10.1016/j.parkreldis.2011.02.018
http://dx.doi.org/10.1016/j.parkreldis.2...
.
The functional and the quality of life (QoL) related impact of NMS is very
significant, equaling or even surpassing those imposed by common motor symptoms of
PD. A comprehensive review of the literature assessing the main determinants of QoL
in PD showed that this parameter tends to deteriorate in the later stages; however
it does not correlate closely with disease duration and clinical assessment scores.
On the other hand, the presence and severity of symptoms of depression, cognitive
impairment and sleep problems have a strong correlation with QoL scores. This review
also showed that in half of the studies, the main limitation of QoL was a NMS,
similar to the motor signs classically considered refractory and disabling such as
postural instability and gait disorders88 Schrag A. Quality of life and depression in Parkinson’s disease. J
Neurol Sci. 2006;248(1-2):151-7.
http://dx.doi.org/10.1016/j.jns.2006.05.030
http://dx.doi.org/10.1016/j.jns.2006.05....
. From a different perspective, a study that evaluated the main limiting
factors of activities of daily living (ADL) in patients undergoing stereotactic
surgery with deep brain stimulation for the treatment of PD, showed that after nine
years since the intervention, non-axial signs, including tremor, rigidity and
bradykinesia, remained relatively stable. However, axial signs (postural instability
and gait disorder) and NMS began to exert a growing negative effect, reflecting
levels of functionality that were similar or worse than those observed before
surgery99 Zibetti M, Merola A, Rizzi L, Ricchi V, Angrisano S, Azzaro C et al.
Beyond nine years of continuous subthalamic nucleus deep brain stimulation in
Parkinson’s disease. Mov Disord. 2011;26(13):2327-34.
http://dx.doi.org/10.1002/mds.23903
http://dx.doi.org/10.1002/mds.23903...
.
NMS represent some of the leading causes of disability and impairment in QoL in PD,
therefore, the recognition of these aspects of the disease is essential to provide
care that can potentially induce a decisive and comprehensive impact in these
cases1010 Chaudhuri KR, Healy D, Schapira AHV. Non-motor symptoms of
Parkinson’s disease: diagnosis and management. Lancet Neurol.
2006;5(3):235-45.
http://dx.doi.org/10.1016/S1474-4422(06)70373-8
http://dx.doi.org/10.1016/S1474-4422(06)...
. Despite its importance and frequency, NMS are not adequately recognized in
clinical practice. The impact and the ability to detect NMS in specialized
consultations were the focus of the study by Gallagher et al.1111 Gallagher DA, Lees AJ, Schrag A. What are the most important
nonmotor symptoms in patients with Parkinson’s disease and are we missing them?
Mov Disord. 2010;25(15):2493-500.
http://dx.doi.org/10.1002/mds.23394
http://dx.doi.org/10.1002/mds.23394...
that evaluated cases divided into those with advanced disease and another
group with a confirmed diagnosis of PD for less than least five years, which was
considered “recent diagnosis”. In both situations the NMS were common and associated
with limitations in QoL that surpassed those caused by motor dysfunction.
Interestingly, the NMS with the greatest impact were the same in both groups:
autonomic dysfunction and fatigue, added by depression for the group with more
recent diagnosis. The ability to detect NMS is not uniform. In part this is due to
the perception that certain NMS are not directly related to the DP, such as apathy
and sphincter dysfunctions, so patients do not spontaneously report and the
complaints can be missed during routine clinical investigations. Depression and
hallucinations appear to be routinely investigated in some studies but not in
others1111 Gallagher DA, Lees AJ, Schrag A. What are the most important
nonmotor symptoms in patients with Parkinson’s disease and are we missing them?
Mov Disord. 2010;25(15):2493-500.
http://dx.doi.org/10.1002/mds.23394
http://dx.doi.org/10.1002/mds.23394...
. Most studies evaluating the ability to detect NMS compare the clinical
documentation of consultations with results of specific questionnaires that were not
designed and validated instruments to be used by the clinician on a daily basis.
Thus, other explanations for these differences are the presence of false-positive
responses to the questionnaires, lack of hope for the resolution of problems in
spite of motor symptoms that are considered “legitimate” neurological, and
insufficient time for consultation.
Another study analyzed the results of a series of scales and NMS-related
questionnaires compared to the chance of identifying these same signs by the
neurologist who treated the patient with PD. This study showed that depression,
anxiety, fatigue, and sleep disturbances are not identified in almost 50% of
visits1212 Shulman LM, Taback RL, Rabinstein AA, Weiner WJ. Non-recognition of
depression and other non-motor symptoms in Parkinson’s disease.
Parkinsonism Relat Disord.
2002;8(3):193-7.
http://dx.doi.org/10.1016/S1353-8020(01)00015-3
http://dx.doi.org/10.1016/S1353-8020(01)...
. A study with similar methodology assessed which were the NMS observed in PD
patients among the ones listed in a specific questionnaire compared to those cited
by the same patients during a specialized routine medical consultation. Almost 43%
of NMS noted in the questionnaire had not been mentioned in the consultation,
including hallucinations, sleep disorders (insomnia and RBD), drooling and restless
legs syndrome. The authors highlight that from the list of non-declared NMS, most
were potentially treatable. This study also found more NMS among patients with the
rigid akinetic form of PD1313 Chaudhuri KR, Prieto-Jurcynska C, Naidu Y, Mitra T, Frades-Payo B,
Tluk S et al. The nondeclaration of nonmotor symptoms of Parkinson’s disease to
health care professionals: an international study using the nonmotor symptoms
questionnaire. Mov Disord. 2010;25(6):704-9.
http://dx.doi.org/10.1002/mds.22868
http://dx.doi.org/10.1002/mds.22868...
. A study involving cases with pathological confirmation of PD
retrospectively seeking the first signs of the disease, showed that nearly a quarter
of the patients had NMS in the early stages and that the presence of such symptoms
led to a greater chance of demand for orthopedic surgeons and rheumatologists than
neurologists1414 O’Sullivan SS, Williams DR, Gallagher DA, Massey LA,
Silveira-Moriyama L, Lees AJ. Non motor symptoms as presenting complaints in
Parkinson’s disease: a clinicopathological study. Mov Disord.
2008;23(1):101-6.
http://dx.doi.org/10.1002/mds.21813
http://dx.doi.org/10.1002/mds.21813...
.
CLINICAL CHARACTERIZATION OF NON-MOTOR SIGNS IN PARKINSON’S DISEASE
We discuss below a few key points about each individual NMS. Autonomic dysfunction also comprehends an important and broad group of NMS that is not included in this review (except for constipation) due to length restrictions and also because we believe this particular topic deserves a review on its own.
A summary of prevalence, its correlation with disease progression, level of functional disability and potential role as premotor signs of PD is presented in Table 1 and Figure.
Olfactory deficit
The first description of olfactory deficits in PD was made almost 40 years
ago1515 Ansari KA, Johnson A. Olfactory function in patients with
Parkinson’s disease. J Chronic Dis. 1975;28(9):493-7.
http://dx.doi.org/10.1016/0021-9681(75)90058-2
http://dx.doi.org/10.1016/0021-9681(75)9...
and five years later this signal was described as an early feature and a
“precursor of motor signs”1616 Korten JJ, Meulstee J. Olfactory disturbances in Parkinsonism. Clin
Neurol Neurosurg. 1980;82(2):113-8.
http://dx.doi.org/10.1016/0303-8467(80)90005-0
http://dx.doi.org/10.1016/0303-8467(80)9...
. During the 80s, studies have shown that discrimination, detection
threshold, and identification of odors are abnormal in PD1717 Ward CD, Hess WA, Calne DB. Olfactory impairment in Parkinson’s
disease. Neurology. 1983;33(7):943-6.
http://dx.doi.org/10.1212/WNL.33.7.943
http://dx.doi.org/10.1212/WNL.33.7.943...
,
1818 Quinn NP, Rossor MN, Marsden CD. Olfactory threshold in Parkinson’s
disease. J Neurol Neurosurg Psychiatry. 1987;50(1):88-9.. In addition, sequential studies have shown that olfactory deficits in
these cases do not depend on odor subtype, age of onset, duration and severity
of the disease, motor laterality and phenotype, treatment, and presence of
cognitive impairment1919 Doty RL, Deems DA, Stellar S. Olfactory dysfunction in parkinsonism:
a general deficit unrelated to neurologic signs, disease stage, or disease
duration. Neurology. 1988;38(8):1237-44.
,
2020 Doty RL, Stern MB, Pfeiffer C, Gollomp SM, Hurtig HI. Bilateral
olfactory dysfunction in early stage treated and untreated idiopathic
Parkinson’s disease. J Neurol Neurosurg Psychiatry. 1992;55(2):138-42.
http://dx.doi.org/10.1136/jnnp.55.2.138
http://dx.doi.org/10.1136/jnnp.55.2.138...
. Finally, a more recent study showed that hyposmia does not fluctuate
during periods on and off2121 Saifee T, Lees AJ, Silveira-Moriyama L. Olfactory function in
Parkinson’s disease in ON versus OFF states. J Neurol Neurosurg Psychiatry.
2010;81(11):1293-95. http://dx.doi.org/10.1136/jnnp.2009.182022
http://dx.doi.org/10.1136/jnnp.2009.1820...
. The combination of these data indicates that this dysfunction is not
directly related to the dopaminergic dysfunction or with the degenerative
process responsible for motor signals of PD. In fact, a study that evaluated
cholinergic and dopaminergic innervation concluded that the cholinergic deficit,
especially located in the limbic cortex, represents a more robust determinant to
olfactory deficits in PD than nigrostriatal dopaminergic denervation2222 Bohnen NI, Muller ML, Kotagal V, et al. Olfactory dysfunction,
central cholinergic integrity and cognitive impairment in Parkinson’s disease.
Brain. 2010;133(6):1747-54.
http://dx.doi.org/10.1093/brain/awq079
http://dx.doi.org/10.1093/brain/awq079...
.
From a pathophysiological point of view, the presence of LB in the olfactory bulb
seems to be a constant finding in patients with symptomatic PD, occurring in
100% of cases examined post-mortem. Congruent with the hypothesis described by
Braak et al.22 Braak H, Del Tredici K, Rüb U, Vos RA, Steur ENJ, Braak E. Staging
of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging.
2003;24(2):197-211. cited previously, which proposes that the degenerative process in PD
also begins in the olfactory bulb and anterior olfactory nuclei, loss of
olfactory sensitivity occurs in 70%-90% of patients with PD, including newly
diagnosed cases who did not yet receive any form of treatment2323 Hoyles K, Sharma JC. Olfactory loss as a supporting feature in the
diagnosis of Parkinson’s disease: a pragmatic approach. J Neurol.
2013;260(12):2951-8.
http://dx.doi.org/10.1007/s00415-013-6848-8
http://dx.doi.org/10.1007/s00415-013-684...
. Besides being an inherent part of the established disease, several
evidences suggested and consolidated the hypothesis that hyposmia is an early
sign of pre-motor DP, starting with the fact that the presence of LB in the SNc
invariably accompanied these pathological markers in the olfactory structures.
The opposite, however, is not always true, i.e., many cases have LB in the
olfactory bulb with intact SNc. The length of time between the expression of
hyposmia and the appearance of motor signs is still unknown and may be of
several years2424 Noyce AJ, Bestwock JP, Silveira-Moriyama L, Hawkes CH, Giovannoni G,
Lees AJ et al. Meta-analysis of early nonmotor features and risk factors for
Parkinson disease. Ann Neurol. 2012;72(6):893-901.
http://dx.doi.org/10.1002/ana.23687
http://dx.doi.org/10.1002/ana.23687...
.
Since the early 1990s, it was demonstrated that olfactory deficits could
distinguish sporadic PD from essential tremor, dystonic tremor and progressive
supranuclear palsy (PSP)2525 Busenbark KL, Huber SJ, Greer G, Pahwa R, Koller WC. Olfactory
function in essential tremor. Neurology. 1992;42(8):1631-2.. Later, this same conclusion was determined with respect to multiple
system atrophy (MSA), cortico basal degeneration and monogenic parkinsonism
related to mutations in the PINK1 and PARK2 genes2626 Kertelge L, Bruggemann N, Schmidt A, Tadic V. Wisse C, Dankert S et
al. Impaired sense of smell and color discrimination in monogenic and idiopathic
Parkinson’s disease. Mov Disord. 2010;25(15):2665-9.
http://dx.doi.org/10.1002/mds.23272
http://dx.doi.org/10.1002/mds.23272...
,
2727 Alcalay RN, Siderowf A, Ottman R et al. Olfaction in Parkin
heterozygotes and compound heterozygotes: the CORE-PD study. Neurology.
2011;76(4):319-26.
http://dx.doi.org/10.1212/WNL.0b013e31820882aa
http://dx.doi.org/10.1212/WNL.0b013e3182...
while cases with mutations in the LRRK2 gene have intermediate
results2828 Silveira-Moriyama L, Munhoz RP, Carvalho MJ, Raskin S, Rogaeva E,
Aguiar PC et al. Olfactory heterogeneity in LRRK2 related Parkinsonism. Mov
Disord. 2010;25:2879-83. http://dx.doi.org/10.1002/mds.23325
http://dx.doi.org/10.1002/mds.23325...
,
2929 Marras C, Schule B, Munhoz RP, Rogaeva E, Langston JW, Kasten M et
al. Phenotype in parkinsonian and nonparkinsonian LRRK2 G2019S mutation
carriers. Neurology. 2011;77(4):325-33.
http://dx.doi.org/10.1212/WNL.0b013e318227042d
http://dx.doi.org/10.1212/WNL.0b013e3182...
.
The main longitudinal study showing that the olfactory deficit may precede PD was
held in Honolulu, Hawaii, by the group of Ross et al.3030 Ross GW, Petrovitch H, Abbott RD, Tanner CM, Popper J, Masaki K et
al. Association of olfactory dysfunction with risk for future Parkinson’s
disease. Ann Neurol. 2008;63(2):167-73.
http://dx.doi.org/10.1002/ana.21291
http://dx.doi.org/10.1002/ana.21291...
who published a series of articles showing that in the longitudinal
follow-up of more than 2,000 neurologically healthy elderly individuals, those
with proven olfactory deficit had a higher risk of developing symptomatic PD
clinical and when they remained asymptomatic, these individuals presented LB in
the SNc on post- mortem examination. Other studies that strengthen the idea that
the olfactory disorder precedes the motor onset of PD include those by include
Berendse et al.3131 Berendse HW, Booij J, Francot CM, Bergmans PL, Hijman R, Stoof JC et
al. Subclinical dopaminergic dysfunction in asymptomatic Parkinson’s disease
patients’ relatives with a decreased sense of smell. Ann Neurol.
2001;50(1):34-41. http://dx.doi.org/10.1002/ana.1049
http://dx.doi.org/10.1002/ana.1049...
, and its follow-up after three years3232 Ponsen MM, Stoffers D, Booij J, Eck-Smit BL, Wolters ECH, Berendse
HW. Idiopathic hyposmia as a preclinical sign of Parkinson’s disease. Ann
Neurol. 2004;56(2):173-81. http://dx.doi.org/10.1002/ana.20160
http://dx.doi.org/10.1002/ana.20160...
showing the development of PD signals in cases of a group of “high
risk”, which included family members of patients with PD who had hyposmia, while
family members without hyposmia remained asymptomatic after two years. Finally,
a study that evaluated possible associations between olfactory deficit and the
risk of developing dementia in PD with an observation period of three years
using functional imaging techniques showed that changes in the areas associated
with olfactory function have a close relationship with cognitive decline. In
addition, the study also showed that more severe hyposmia represents a prominent
factor for the development of dementia3333 Baba T, Kikuchi A, Hirayama K, Nishio Y, Hosokai Y, Kanno S et al.
Severe olfactory dysfunction is a prodromal symptom of dementia associated with
Parkinson’s disease: a 3 year longitudinal study. Brain. 2012;135(1):161-9.
http://dx.doi.org/10.1093/brain/awr321
http://dx.doi.org/10.1093/brain/awr321...
.
REM sleep behavior disorder
Physiologically, patterned changes of neuronal activation and release of specific neurotransmitters in the brain stem occur during the REM sleep phase, inducing, among other phenomena, motor inhibition and muscle atonia. RBD is a parasomnia characterized by the loss of this normal muscle atonia during this sleep stage3434 Schenk CH, Mahowald MW. REM sleep behavior disorder: clinical, developmental, and neuroscience perspectives 16 years after its formal identification in SLEEP. Sleep. 2002;25(2):120-38..
The gold standard for diagnosis requires polysomnography demonstrating excessive
muscle activity, continued or intermittent tone of submentonian during REM
sleep3535 Postuma RB, Montplaisir J. Predicting Parkinson’s disease: why,
when, and how? Parkinsonism Relat Disord. 2009;15 Suppl 3:S105-9.
http://dx.doi.org/10.1016/S1353-8020(09)70793-X
http://dx.doi.org/10.1016/S1353-8020(09)...
. Clinically, the diagnosis can also be established using historical data
using instruments that range from formal criteria of the Manual of Disorders of
Sleep of the American Academy of Sleep Medicine3636 American Academy of Sleep Medicine. ICSD - International
classification of sleep disorders: diagnostic and coding manual. Westchester:
American Sleep Disorders Association; 1990. to the use of a single question with a categorical “yes or no” type
answer3737 Postuma RB, Arnulf I, Hogl B, Iranzo A, Miyamoto T, Dauvilliers Y et
al. A single-question screen for rapid eye movement sleep behavior disorder: a
multicenter validation study. Mov Disord 2012;27(7):913-6.
http://dx.doi.org/10.1002/mds.25037
http://dx.doi.org/10.1002/mds.25037...
. The typical clinical picture includes a description of movements
associated with dream content and aggressive behavior with interpretation of
such contents. Since the dream content in these cases tends to involve conflict
situations, there is usually sleep disruption of patients and/or their bed
partner, who are occasionally victims to physical harm, including descriptions
of trauma with significant severity3535 Postuma RB, Montplaisir J. Predicting Parkinson’s disease: why,
when, and how? Parkinsonism Relat Disord. 2009;15 Suppl 3:S105-9.
http://dx.doi.org/10.1016/S1353-8020(09)70793-X
http://dx.doi.org/10.1016/S1353-8020(09)...
. Patients with PD and RBD probably have a different distribution of the
degenerative process compared to those without this parasomnia, once it’s the
most probable substrate involves the pons tegmentum and the medial nuclei of the
medulla3838 Postuma RB, Gagnon JF, Montplaisir J. Rapid eye movement sleep
behavior disorder as a biomarker for neurodegeneration: the past 10 years. Sleep
Med 2013;14(8):763-7.
http://dx.doi.org/10.1016/j.sleep.2012.09.001
http://dx.doi.org/10.1016/j.sleep.2012.0...
. Clinically, RBD may be linked to particular manifestations such as
worse scores of postural instability and gait, lower amplitude of motor response
to levodopa, higher frequency of orthostatic hypotension and visual color
perception deficit. From a behavioral point of view, RBD is associated with
vivid dreams and visual hallucinations, and is a warning sign for the occurrence
of dementia and other cognitive deficits involving specific episodic verbal
memory, executive functions and visuospatial and visuoperceptual processing3535 Postuma RB, Montplaisir J. Predicting Parkinson’s disease: why,
when, and how? Parkinsonism Relat Disord. 2009;15 Suppl 3:S105-9.
http://dx.doi.org/10.1016/S1353-8020(09)70793-X
http://dx.doi.org/10.1016/S1353-8020(09)...
.
Interestingly, a study that analyzed the quality of the movements during episodes
of RBD showed that they do not have the standard asymmetric signs of
parkinsonism observed during wakefulness, and are rapid, large, coordinated and
symmetrical, however violent, ballistic and occasionally repetitive, suggesting
that during REM sleep there may be a transient re-establishment of more
physiological basal ganglia function. Alternatively, parkinsonism may disappear
during REM sleep because at this stage the movements generated follow directly
to pyramidal tract neurons and sequentially to the peripheral motor neuron,
bypassing the extrapyramidal system and the physiological barrier responsible
for atonia during this sleep stage in the brainstem3939 De Cock VC, Vidailhet M, Leu S, Teixeira A, Apartis E, Elbaz A et
al. Restoration of normal motor control in Parkinson’s disease during REM sleep.
Brain. 2007;130(2):450-6.
http://dx.doi.org/10.1093/brain/awl363
http://dx.doi.org/10.1093/brain/awl363...
.
RBD occurs in up to half of PD patients and, as in the case of hyposmia, is
considered an established pre-motor symptom. Also, in almost half of PD patients
and RBD, the sleep complication precedes the onset of parkinsonism by several
years. The mean interval from the onset of symptoms of RBD and motor signs is 11
to 12 years, but may range from 1 to up to 203535 Postuma RB, Montplaisir J. Predicting Parkinson’s disease: why,
when, and how? Parkinsonism Relat Disord. 2009;15 Suppl 3:S105-9.
http://dx.doi.org/10.1016/S1353-8020(09)70793-X
http://dx.doi.org/10.1016/S1353-8020(09)...
. Moreover, cases of apparently idiopathic RBD are uncommon and have a
chance of more than 50% to develop neurodegenerative diseases after 12 years of
follow up, including more commonly PD, followed by LB dementia, Alzheimer’s
disease and MSA4040 Munhoz RP, Teive HA, Eleftherohorinou H, Coin LJ, Lees AJ,
Silveira-Moriyama L. Demographic and motor features associated with the
occurrence of neuropsychiatric and sleep complications of Parkinson’s disease. J
Neurol Neurosurg Psychiatry. 2013;84(8):883-7.
http://dx.doi.org/10.1136/jnnp-2012-304440
http://dx.doi.org/10.1136/jnnp-2012-3044...
. Another important aspect is that individuals with idiopathic RBD with
the highest chance of developing PD have peculiar sleep characteristics,
including higher proportion of REM sleep, more periodic lower limb movements per
hour during of non-REM sleep and abnormal intensity of muscle atonia4141 Vendette M, Gagnon JF, Décary A, Massicotte-Marquez J, Postuma RB,
Doyon J et al. REM sleep behavior disorder predicts cognitive impairment in
Parkinson disease without dementia. Neurology. 2007;69(19):1843-9.
http://dx.doi.org/10.1212/01.wnl.0000278114.14096.74
http://dx.doi.org/10.1212/01.wnl.0000278...
. Finally, although RBD is described in atypical forms of parkinsonism
associated with the pathological background of synucleinopathies, particularly
multiple system atrophy and LB dementia, their occurrence in PSP, although less
common, is significant, indicating the concept that this parasomnia is not
related to a specific molecular form, but rather to a specific topographic
progression of the degenerative process4242 Munhoz RP, Teive HA. REM sleep behaviour disorder: how useful is it
for the differential diagnosis of parkinsonism? Clin Neurol Neurosurg.
2014;127:71-4. http://dx.doi.org/10.1016/j.clineuro.2014.09.014
http://dx.doi.org/10.1016/j.clineuro.201...
.
Behavioral disorders
Mood disorders are common in PD, occurring in more than a quarter of newly
diagnosed cases. Several studies have also shown that individuals with
depression are 2.2 to 3.2 times more likely to develop PD compared to healthy
controls4343 Starkstein SE, Brockman S, Hayhow BD. Psychiatric syndromes in
Parkinson’s disease. Curr Opin Psychiatry. 2012;25(6):468-72.
http://dx.doi.org/10.1097/YCO.0b013e3283577ed1
http://dx.doi.org/10.1097/YCO.0b013e3283...
. Although the available data regarding this correlation are less
conclusive than for hyposmia and RBD, the onset of depressive symptoms may
precede the motor signs, with a peak around 3-6 years before the diagnosis of
PD. One of these studies evaluated 1,358 patients with depression and 67,570
healthy individuals matched for age and sex for an average period of 15 years,
showing a chance of occurrence of PD in those with a history of depression 13.3
times higher than controls without depression. Another epidemiological study
found similar results with a chance of 2.95 times for the occurrence of PD in
individuals with depression. In these studies and in the literature in general,
depression is considered a risk factor, as well as family history and life in a
rural environment, but not necessarily a pre-motor symptom4444 Leentjens AF, Van den Akker M, Metsemakers JF, Lousberg R, Verhey
FR. Higher incidence of depression preceding the onset of Parkinson’s disease: a
register study. Mov Disord. 2003;18(4):414-8.
http://dx.doi.org/10.1002/mds.10387
http://dx.doi.org/10.1002/mds.10387...
.
In the course of the disease, depression is one of the major indicators of a poor
quality of life and functional disability, occurring in about 40% of patients in
cross-sectional studies and almost 70% in longitudinal studies88 Schrag A. Quality of life and depression in Parkinson’s disease. J
Neurol Sci. 2006;248(1-2):151-7.
http://dx.doi.org/10.1016/j.jns.2006.05.030
http://dx.doi.org/10.1016/j.jns.2006.05....
. The diagnosis of depression in PD may be complex because some of the
signs of the disease itself may mimic it. Moreover, there are peculiar aspects
regarding the presence and severity of depressive symptoms compared to the
general population with depression (Table
2) PD depression tends to manifest with more intense anxiety,
pessimism, hopelessness, social withdrawal, self-depreciative thoughts, and
introversion, but, on the other hand, less felling of guilt, ideation of death
and suicide88 Schrag A. Quality of life and depression in Parkinson’s disease. J
Neurol Sci. 2006;248(1-2):151-7.
http://dx.doi.org/10.1016/j.jns.2006.05.030
http://dx.doi.org/10.1016/j.jns.2006.05....
.
Clinical differentials in presentation of depression in Parkinson’s disease (PD) versus the general population.
Depression in PD is probably multifactorial, involving a neurobiological
substrate permeated by evidence of a reactive component related to living with a
chronic neurodegenerative disease and its complications and limitations. For
example, a study by Rickards et al.4545 Rickards H. Depression in neurological disorders: Parkinson’s
disease, multiple sclerosis, and stroke. J Neurol Neurosurg Psychiatry. 2005;76
Suppl 1:i48-52. http://dx.doi.org/10.1136/jnnp.2004.060426
http://dx.doi.org/10.1136/jnnp.2004.0604...
showed that the frequency of depression is high in the early stages of
PD, when the patient is diagnosed, decreasing when starting treatment,
reflecting the classic “honeymoon phase”, and increasing again with the
progression of symptoms in later stages. In addition, depression in PD is
directly related to the severity of motor symptoms and may fluctuate along with
motor fluctuations, reflecting the pharmacological effect of levodopa. The
biological basis of depression also has a pathological basis, related to the
presence of PD’s own degeneration markers in serotonergic and noradrenergic
structures as the raphe nuclei and limbic structures88 Schrag A. Quality of life and depression in Parkinson’s disease. J
Neurol Sci. 2006;248(1-2):151-7.
http://dx.doi.org/10.1016/j.jns.2006.05.030
http://dx.doi.org/10.1016/j.jns.2006.05....
.
Still under the behavioral aspect, a premorbid personality in PD has been
observed, including a relatively uniform description that often uses terms such
as introversion, behavioral inflexibility, difficulty with abstraction thought,
more reliability, responsibility, loyalty, subordination, less tendency to
leadership, conservative attitude with self-protection, intense self-control and
difficulty expressing aggression. Unfortunately, these aspects are all very
common in the general population and have a low specificity for PD4646 Ishihara L, Brayne C. What is the evidence for a premorbid
parkinsonian personality: a systematic review. Mov Disord. 2006;21(8):1066-72.
http://dx.doi.org/10.1002/mds.20980
http://dx.doi.org/10.1002/mds.20980...
.
Constipation
The clinical history of constipation is common at diagnosis in cases of PD, and
is also described before the emergence of motor signs. As a pre-motor symptom,
it was described in a variable period that can reach up to 24 years before the
onset of parkinsonism in studies using different methodologies. In a
longitudinal study of 6,790 males with constipation, the risk of occurrence of
PD was 2.7 times higher than in those without this symptom. In this study, the
mean time interval between the detection of constipation to diagnosis of PD was
12 years, ranging from two months to 24 years4747 Abbott RD, Petrovitch H, White LR, Masaki KH, Tanner CM, Curb JD et
al. Frequency of bowel movements and the future risk of Parkinson’s disease.
Neurology. 2001;57(3):456-62.
http://dx.doi.org/10.1212/WNL.57.3.456
http://dx.doi.org/10.1212/WNL.57.3.456...
.
The pathological support of this relationship comes from the observation that 9%
to 17% of healthy subjects have alpha synuclein aggregates in the peripheral
autonomic system, including abdominal-pelvic, cardiac and myenteric plexus of
the esophagus, sympathetic ganglia and vagus nerve. Thus, from the
pathophysiological point of view, constipation may reflect not only this
peripheral involvement but also central mechanisms that cause pelvic floor
dysfunction. Some of these individuals with peripheral autonomic disorder still
present LB in the central nervous system and others have other pre-motor signs
such as RBD, striatal abnormalities in functional tests or even pre-diagnostic
PD as described above, in another words, the presence of a subtle cardinal sign
that did not fill formal criteria for PD4747 Abbott RD, Petrovitch H, White LR, Masaki KH, Tanner CM, Curb JD et
al. Frequency of bowel movements and the future risk of Parkinson’s disease.
Neurology. 2001;57(3):456-62.
http://dx.doi.org/10.1212/WNL.57.3.456
http://dx.doi.org/10.1212/WNL.57.3.456...
,
4848 Cersosimo MG, Benarroch EE. Autonomic involvement in Parkinson’s
disease: pathology, pathophysiology, clinical features and possible peripheral
biomarkers. J Neurol Sci. 2012;313(1-2):57-63.
http://dx.doi.org/10.1016/j.jns.2011.09.030
http://dx.doi.org/10.1016/j.jns.2011.09....
.
Weight loss
Several studies have found that PD patients have lower body mass index (BMI),
compared to healthy controls matched for sex and age. The etiology seems to be
multifactorial, related to the presence of dyskinesias, change in eating habits,
effect of medication (mainly levodopa), longer time for the ingestion of meals
leading to lower energy intake and earlier satiety, in addition to being
potentially related to intrinsic physiological changes of the neurodegenerative
process. For example, the concentration of leptin, insulin-like growth factor
type 1 (IGF-1), and thyroid-stimulating hormone were investigated in patients
with PD and weight loss compared to controls with PD but no weight loss, finding
lower levels of leptin and higher IGF-1 in the study group4949 Cheshire Jr WP, Wszolek ZK. Body mass index is reduced early in
Parkinson’s disease. Parkinsonism Relat Disord. 2005;11(1):35-8.
http://dx.doi.org/10.1016/j.parkreldis.2004.07.001
http://dx.doi.org/10.1016/j.parkreldis.2...
,
5050 Munhoz RP, Ribas CB. Body mass index in Parkinson’s disease.
Parkinsonism Relat Disord. 2005;11(6):407.
http://dx.doi.org/10.1016/j.parkreldis.2005.02.001
http://dx.doi.org/10.1016/j.parkreldis.2...
.
The onset of weight loss in PD does not have a defined correlation with the
stages of the disease, and may be an early expression or even precede the onset
of motor signs. A prospective study that examined the changes in BMI in 468
patients with PD using anthropometric data collected before the onset of motor
symptoms, followed during the course of the disease showed that the average body
mass remained stable in most subjects up to a variable period before the onset
of motor signs. This period ranged from a few months up to four years.
Interestingly, this study showed a tendency to the increase in caloric intake
while the BMI decreased. In the course of the disease, the reduction of BMI
followed a continuous process with the same tendency of the pre-motor period,
indicating that, regardless of the process that triggers this early change in
BMI, it is relatively uniform and follows the disease progression5151 Chen H, Zhang SM, Hernán MA, Willett WC, Ascherio A. Weight loss in
Parkinson’s disease. Ann Neurol. 2003;53(5):676-9.
http://dx.doi.org/10.1002/ana.10577
http://dx.doi.org/10.1002/ana.10577...
.
Cognitive deficit
Several degrees of cognitive impairment are common features of PD and,
considering the model of disease progression described by Braak, may be a
natural consequence of end-stage disease22 Braak H, Del Tredici K, Rüb U, Vos RA, Steur ENJ, Braak E. Staging
of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging.
2003;24(2):197-211.. The diagnosis of dementia is also especially common in PD, It has been
described in about 20% of PD cases in cross-sectional studies5252 Munhoz RP, Werneck LC, Teive HA. The differential diagnoses of
parkinsonism: findings from a cohort of 1528 patients and a 10 years comparison
in tertiary movement disorders clinics. Clin Neurol Neurosurg.
2010;112(5):431-5.
http://dx.doi.org/10.1016/j.clineuro.2010.03.003
http://dx.doi.org/10.1016/j.clineuro.201...
, and almost 80% in longitudinal studies, with an incidence at least four
times greater than in the general population5353 Aarsland D, Beyer MK, Kurz MW. Dementia in Parkinson’s disease. Curr
Opin Neurol. 2008;21(6):676-82.
http://dx.doi.org/10.1097/WCO.0b013e3283168df0
http://dx.doi.org/10.1097/WCO.0b013e3283...
. Furthermore, despite being more common and severe in the later stages,
cognitive impairment that does not cause enough dysfunction to fulfill
diagnostic criteria for dementia may be present early in the course of the
disease, with abnormalities in neuropsychological tests detected in up to 24% of
patients at diagnosis of PD. Finally, those with the formal diagnosis of
dementia will present it for an average period of four years during the course
of the disease5353 Aarsland D, Beyer MK, Kurz MW. Dementia in Parkinson’s disease. Curr
Opin Neurol. 2008;21(6):676-82.
http://dx.doi.org/10.1097/WCO.0b013e3283168df0
http://dx.doi.org/10.1097/WCO.0b013e3283...
.
Cognitive disorders tend to exacerbate the motor symptoms disabilities in PD. In
fact, the presence of cognitive impairment or dementia in PD patients is
associated with loss of independence, poor quality of life and shortening of
lifespan. Moreover, individuals in advanced stages of PD who develop dementia,
often present a functional decline that follows a stereotyped pattern,
indicating that the beginning of this sign announces the need for a more
intensive care and increased risk of mortality5454 Levy G, Schupf N, Tang MX, Cote LJ, Louis ED, Mejia H et al.
Combined effect of age and severity on the risk of dementia in Parkinson’s
disease. Ann Neurol. 2002;51(6):722-9.
http://dx.doi.org/10.1002/ana.10219
http://dx.doi.org/10.1002/ana.10219...
. Thus, the onset and progression of cognitive impairment in PD have an
important influence on patient management and prognosis.
The phenomenology of specific cognitive symptoms associated with PD varies and
probably reflects the heterogeneous underlying neuropathological substrate. The
most common cognitive impairments are attention, executive behavior and
visuospatial processing deficits, although patients may also exhibit different
degrees of loss of memory, which could be, in some cases, a dysfunction
secondary to a frontal (i.e., executive behavior) rescue information. In the
same way, dementia in PD is not characterized by an intrinsic deficit of
language, but may be associated with difficulty in processing and composition of
phrases, which are also executive dysfunctions5353 Aarsland D, Beyer MK, Kurz MW. Dementia in Parkinson’s disease. Curr
Opin Neurol. 2008;21(6):676-82.
http://dx.doi.org/10.1097/WCO.0b013e3283168df0
http://dx.doi.org/10.1097/WCO.0b013e3283...
. Some lines of research suggest that the executive impairments in PD are
an early signal due to changes in dopaminergic stimulation in the frontal
cortex, whereas impairments in semantic memory and visuospatial working
correspond to the posterior neuropathological involvement of temporal and
parietal cortex, conferring a higher risk of dementia in PD5353 Aarsland D, Beyer MK, Kurz MW. Dementia in Parkinson’s disease. Curr
Opin Neurol. 2008;21(6):676-82.
http://dx.doi.org/10.1097/WCO.0b013e3283168df0
http://dx.doi.org/10.1097/WCO.0b013e3283...
.
Among the risk factors for dementia in PD, age is the most important. On the
other hand, the increased age-related dementia risk does not seem to be
associated with the possible influence of age of onset of motor symptoms; in
other words, patients develop dementia in a similar mean age, regardless of when
the motor signs appear5454 Levy G, Schupf N, Tang MX, Cote LJ, Louis ED, Mejia H et al.
Combined effect of age and severity on the risk of dementia in Parkinson’s
disease. Ann Neurol. 2002;51(6):722-9.
http://dx.doi.org/10.1002/ana.10219
http://dx.doi.org/10.1002/ana.10219...
. Other studies also showed that cognitive impairment in PD correlates
with the severity of motor disabilities, male gender, low education, visual
hallucinations and the presence of rigidity and axial bradykinesia5555 Buter TC, Hout A, Matthews FE, Larsen JP, Brayne C, Aarsland D.
Dementia and survival in Parkinson disease: a 12-year population study.
Neurology. 2008;70(13):1017-22.
http://dx.doi.org/10.1212/01.wnl.0000306632.43729.24
http://dx.doi.org/10.1212/01.wnl.0000306...
.
The pathological basis for dementia in PD is, in part, related to the spread of
LB to the cortex, which occurs in the later stages of disease22 Braak H, Del Tredici K, Rüb U, Vos RA, Steur ENJ, Braak E. Staging
of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging.
2003;24(2):197-211.. Moreover, other studies show that the pathology of the cognitive
impairment in PD is probably multifactorial, including LB and pathology
characteristic of Alzheimer’s disease, along with factors related to age and
other comorbidities5555 Buter TC, Hout A, Matthews FE, Larsen JP, Brayne C, Aarsland D.
Dementia and survival in Parkinson disease: a 12-year population study.
Neurology. 2008;70(13):1017-22.
http://dx.doi.org/10.1212/01.wnl.0000306632.43729.24
http://dx.doi.org/10.1212/01.wnl.0000306...
.
The effect of treatment must also be considered, since pharmacological and
non-pharmacological interventions could worsen incipient cognitive impairment.
The use of anticholinergics, for example, classically enhances the cognitive
symptoms of PD, as well as treatment with deep brain stimulation. In these
cases, although the motor function has a good response to surgery, quality of
life tends to decline after the first 6 months, probably, in part because of
cognitive decline, which seems to be more significant when the target of this
intervention is the subthalamic nucleus5656 Witt K, Daniels C, Reiff J, Krack P, Volkmann J, Pinsker MO et al.
Neuropsychological and psychiatric changes after deep brain stimulation for
Parkinson’s disease: a randomised, multicentre study. Lancet Neurol.
2008;7(7):605-14.
http://dx.doi.org/10.1016/S1474-4422(08)70114-5
http://dx.doi.org/10.1016/S1474-4422(08)...
.
Psychosis
Psychotic symptoms such as hallucinations and delusions are common in PD patients
and occur from 10% to 80% of cases, depending on the definition and the studied
population. Risk factors includes cognitive impairment, dementia, age greater
than 65 years, advanced disease, longer duration, presence of sleep disorders,
depression, visual disturbances and use of most of the drugs needed to treat
motor symptoms of PD, the commonest culprits been dopamine agonists, levodopa,
amantadine and anticholinergics5757 Munhoz RP, Espay AJ, Morgante F, Li JY, Teive HÁ, Dunn E et al.
Long-duration Parkinson’s disease: role of lateralization of motor features.
Parkinsonism Relat Disord. 2013;19(1):77-80.
http://dx.doi.org/10.1016/j.parkreldis.2012.07.008
http://dx.doi.org/10.1016/j.parkreldis.2...
. Psychosis is associated with different pathological and molecular
abnormalities, however the most consistent findings suggest the presence of LB
in the temporal/limbic cortex5858 Kalaitzakis ME, Christian LM, Moran LB, Graeber MB, Pearce RK,
Gentleman SM. Dementia and visual hallucinations associated with limbic
pathology in Parkinson’s disease. Parkinsonism Relat Disord. 2009;15(3):196-204.
http://dx.doi.org/10.1016/j.parkreldis.2008.05.007
http://dx.doi.org/10.1016/j.parkreldis.2...
.
Diagnostic criteria include the presence of one of the following symptoms:
illusions, false sense of presence, hallucinations and delusions in the context
of previous diagnosis of PD defined by Queen Square Brain Bank criteria. In
addition, symptoms should be recurrent or continuous for at least one month5959 Ravina B, Marder K, Fernandez HH, Friedman JH, McDonald W, Murphy D
et al. Diagnostic criteria for psychosis in Parkinson’s disease: report of an
NINDS, NIMH work group. Mov Disord. 2007;22(8):1061-8.
http://dx.doi.org/10.1002/mds.21382
http://dx.doi.org/10.1002/mds.21382...
visual hallucinations tend to be more common, including a wide range of
imagery, from simple indiscriminate shapes to well-formed entities with complex
interaction with patients. Auditory hallucinations and other sensory functions
are less common6060 Factor SA, Feustel PJ, Friedman JH, Comella CL, Goetz CF, Kurlan R
et al. Longitudinal outcome of Parkinson’s disease patients with psychosis.
Neurology. 2003;60(11):1756-61.
http://dx.doi.org/10.1212/01.WNL.0000068010.82167.CF
http://dx.doi.org/10.1212/01.WNL.0000068...
.
As mentioned before, psychotic symptoms are more frequent in patients with
cognitive impairment. In the case of a subclinical deficit, the presence of
psychosis must be considered as a predictor of imminent cognitive decompensation
and dementia. Thus, the so-called “benign” hallucinations are actually part of a
gradual process with a potentially malignant prognosis6060 Factor SA, Feustel PJ, Friedman JH, Comella CL, Goetz CF, Kurlan R
et al. Longitudinal outcome of Parkinson’s disease patients with psychosis.
Neurology. 2003;60(11):1756-61.
http://dx.doi.org/10.1212/01.WNL.0000068010.82167.CF
http://dx.doi.org/10.1212/01.WNL.0000068...
.
FINAL REMARKS
Despite the former cited observations about the functional and QoL related impact of NMS, until recently they received relatively little attention from clinicians. In part, that has happened due to unawareness and difficulties in conducting a more thorough and extensive assessment in a system that has limits of time and resources. Moreover, many patients and their caregivers tend to interpret NMS as being not “parkinsonian”, not deserving evaluation by a specialist in neurological diseases. On the other hand, our review shows that most of the NMS that have a significant impact on QoL and functionality are, at least in part, manageable and should be properly and promptly identified.
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Publication Dates
-
Publication in this collection
17 Apr 2015 -
Date of issue
May 2015
History
-
Received
20 Jan 2015 -
Accepted
09 Feb 2015