Clinical Aspects of Movement Disorders:

Transcription

1 Clinical Aspects of Movement Disorders: 2 Effects on Walking and Posture Henrique Ballalai Ferraz and Roberta Arb Saba Abstract Movement disorders are a group of syndromes which includes parkinsonism, chorea, dystonia, myoclonus, tremor, and tics. Many of the diseases of this group manifest disturbances of gait and posture along with other abnormalities. Parkinsonism is characterized by rest tremor, muscular rigidity, bradykinesia, flexed posture of the trunk, and loss of postural reflexes. Parkinson s disease (PD) is the most prevalent of the diseases of this group and patients usually manifest problems of gait and posture in late phases. On the other hand, atypical parkinsonism diseases (multiple-system atrophy, progressive supranuclear palsy, dementia with Lewy bodies, and corticobasal ganglionic degeneration) manifest gait problems and falls very early and are much more incapacitating than PD. Vascular parkinsonism manifests itself with lower limb rigidity and bradykinesia and affects gait very early. Huntington s disease is a genetic disorder characterized by behavioral and cognitive disturbances associated with chorea, dystonia, and loss of equilibrium. Sometimes, especially in subjects with the juvenile form of Huntington s disease, it may manifest with a very severe parkinsonism. Keywords Movement disorders Parkinsonism Parkinson s disease Parkinson-plus syndromes Multiple-system atrophy Progressive supranuclear palsy Dementia with Lewy bodies Corticobasal ganglionic degeneration Vascular parkinsonism Huntington s disease H.B. Ferraz (*) R.A. Saba Movement Disorders Unit Department of Neurology, Universidade Federal de S~ao Paulo Escola Paulista de Medicina, S~ao Paulo, Brazil henrique_ferraz@uol.com.br; roarbsaba@gmail.com # Springer International Publishing AG 2017 F.A. Barbieri, R. Vitório (eds.), Locomotion and Posture in Older Adults, DOI / _2 21

2 22 H.B. Ferraz and R.A. Saba 2.1 Introduction Some of the diseases of the spectrum of movement disorders are associated with abnormalities of posture and locomotion. We can mention the multiple forms of parkinsonism, Huntington s disease, and generalized dystonia, among others. Posture and walking may be affected by the involuntary movements per se or by degeneration or lesions of neural pathways involved in tonus and balance. In this chapter we will present some of the diseases associated with abnormal involuntary movements and impairment of posture and gait. 2.2 Parkinsonism Parkinsonism is a syndrome characterized by the combination of bradykinesia, also called akinesia, with any of the three: muscular rigidity, rest tremor, or impairment of postural reflexes. Bradykinesia is the reduction of the global repertoire of automatic movements, and the decrease of the amplitude and the speed of the voluntary movements. We can detect bradykinesia in a parkinsonian patient either by observing the lack of facial expression while talking or listening with the examiner or by the reduced arm and hand gestures during a conversation. In other words, bradykinetic patients tend to have a poor repertoire of body language [1]. Muscular rigidity is observed by a resistance while manipulating a joint of a limb. Resistance is present both during passive flexion and extension of a limb. We can also feel the sensation of being manipulating a lead pipe, and sometimes this is associated with the clinical sign called cogwheel rigidity. This is perceived as an intermittent and very short-lived release of the resistance during a full extension or flexion movement [2]. Rest tremor can be observed in any part of the body. Hand tremor manifests as a rhythmic flexion and extension of the fingers and it is called pill-rolling tremor. Tremor can also affect the lower limbs, trunk, chin, head, and larynx. It may cycle in a fashion varying from 4 to 6 Hz. Sometimes, parkinsonian patients may present with a postural and kinetic hand tremor associated or not with the resting tremor [1]. Impairment of postural reflexes is characterized by an inability to correct sudden shifts of the normal upright position. People with this kind of impairment usually have frequent falls and assume a stooped posture. The more the trunk is bent forward, the higher the risk of having falls [2]. The combination of the four cardinal symptoms results in the typical parkinsonian gait and posture. Patients tend to flex the trunk forward and the arms are flexed close to the level of the hip. The arms do not harmonically sway while the body is moving. The turning of the body is made by slow and fragmented successive short movements. The length of the steps is very short, and heels drag to the floor. Sometimes, due to the flexed posture, parkinsonian people tend to fall forward, and to avoid it they shift the slow steps to a running pace. This is called festination or festinating gait and when present is a classical manifestation of parkinsonism.

3 2 Clinical Aspects of Movement Disorders: Effects on Walking and Posture 23 Too many clinical conditions may precipitate parkinsonism. The most frequent is idiopathic Parkinson s disease (PD). Other situations are pharmacologically induced parkinsonism (mainly antipsychotics), metal or poison exposure (manganese, pesticides, carbon monoxide), vascular lesions of the central nervous system (CNS), hereditary diseases, some dementia syndromes (Alzheimer s disease and frontotemporal dementia), and other degenerative diseases called atypical parkinsonism or Parkinson-plus syndromes (progressive supranuclear palsy, multiplesystem atrophy, dementia with Lewy body, and corticobasal ganglionic degeneration). We will discuss some of the specific diseases associated with parkinsonism Parkinson s Disease PD is characterized by motor and non-motor symptoms and is associated with a progressive degeneration of neurons of the CNS. The degenerative process seems to start in the medulla and pons and progresses to a wider distribution in the encephalon. Motor symptoms (parkinsonism) begin when dopaminergic neurons of the substantia nigra are affected. Nigral neurons become progressively scarce and there is the presence of Lewy bodies, an eosinophilic intraneuronal inclusion, the classical pathological hallmark of PD [3]. PD may affect adult individuals of both gender and at any age, although most frequently those with 50 or more years of age. Unilateral symptoms are the most common way of starting the disease, and the other side tends to be affected in the following months or years. Patients may manifest rest tremor in one arm or feel difficulty in moving one limb. In a few months, the symptoms tend to become more and more intense and eventually will interfere with daily activities. Difficulty in arising from chair or bed is also common complaints in the early phase of the disease. Gait and postural impairment are usually present after a few years of onset [4]. Fully manifested PD includes bradykinesia, rigidity, and postural abnormalities with gait and balance impairment. PD patients tend to have a shuffling gait and a tendency to have falls. Festinating gait is a classic parkinsonian sign and results from the combination of the flexed forward posture, the short steps, and the loss of postural reflexes. In this case, patients tend to accelerate the steps in order to catch up the center of the gravity abnormally placed forward. Freezing of gait may be present in many patients and is characterized by a difficulty in taking out the feet off the floor while attempting to start the gait. Freezing of gait is more frequent when patients try to turn around or during the passage of narrow spaces. The pull test is the clinical way to detect impairment of postural reflexes. Patients are put standing with feet comfortably apart. The doctor stands backward and pulls him or her briskly and forcefully. The balance is considered impaired if the patient has to move backward for at least three steps of recovery. In severely affected patients, the examiner has to catch the patients to prevent the fall.

4 24 H.B. Ferraz and R.A. Saba Considering only the clinical presentation of PD, there are two main subtypes: a tremor-dominant form and a postural impairment with gait disturbance (PIGD). The first one is characterized by a more benign progression, with excellent response to levodopa and late development of cognitive decline. The PIGD form has a faster progression, with less response to levodopa and early development of falls and cognitive decline [5]. Non-motor symptoms include mood disorders (depression), cognitive decline (in late stages of the disease), olfaction impairment, and disturbances of autonomic function (also in late stages). Sleep disorders, especially rapid eye movement behavioral disorder, are quite common and may be present years before the development of motor symptoms. Treatment is based in dopaminergic reposition. Levodopa is the mainstay of pharmacological treatment. The drug is taken by mouth and in the brain, particularly in neuron and glial cells, is converted into dopamine. If the conversion to dopamine is made by a nigral dopaminergic neuron, it can be stored in vesicles inside the synaptic terminal and can be released afterward. If the conversion is made in glial cells or in non-dopaminergic neurons, dopamine cannot be stored and is immediately released to the postsynaptic receptor. Long-term use of levodopa may be associated with motor fluctuations and dyskinesias. These complications are more common if higher doses of levodopa are used (more than 500 mg a day) and if patients are more severely affected. Dopamine agonists may be also prescribed and act directly at the postsynaptic receptors of striatum. Most commonly prescribe dopamine agonists are pramipexole, ropinirole, and rotigotine. Other drugs are entacapone (catechol-o-methyltransferase inhibitor), rasagiline or selegiline (monoamine oxidase inhibitor), amantadine (glutamate receptor inhibitor), and anticholinergics [6]. Surgery treatment is indicated when patients are optimized receiving levodopa combined with other adjuvant medications but present uncontrolled motor fluctuations and dyskinesias. There are two main surgery procedures: ablative lesions and deep brain stimulation (DBS). The targets indicated are thalamic nuclei, subthalamic nucleus, and globus pallidus interna [7]. Physical and speech therapy are useful for any phase of the disease, but are particularly indicated in patients experiencing balance disturbances and fall (physical therapy) and those with swallowing difficulties and significant dysarthrophonia (speech therapy) Atypical Parkinsonism Atypical parkinsonism is also called Parkinson-plus syndromes since most of the patients of this group manifest motor symptoms similar to PD. The difference between PD and these diseases is that atypical parkinsonian patients manifest other neurological abnormalities, such as cerebellar ataxia, autonomic dysfunction, paralysis of the vertical gaze, early-phase cognitive decline, and behavioral disturbances.

5 2 Clinical Aspects of Movement Disorders: Effects on Walking and Posture 25 All the diseases of this group are neurodegenerative in origin and display neuronal loss in different structures of the central nervous system. None of the diseases of this group have a curative or evolution-modifying pharmacotherapy. Levodopa rarely induces some benefit to this group of patients. Alpha-synuclein inclusions are seen in multiple-system atrophy and dementia with Lewy bodies, while tau protein fibrils are seen in progressive supranuclear palsy and corticobasal ganglionic degeneration Multiple-System Atrophy (MSA) MSA is characterized by the combination of parkinsonian signs with autonomic, pyramidal, and cerebellar signs. There are two forms: MSA-P (parkinsonism), with a predominance of parkinsonian signs, and MSA-C (cerebellar), where there is a predominance of cerebellar signs. The most common form is the MSA-P. The most common signs are dysautonomic: postural hypotension, constipation, urinary incontinence, erectile dysfunction, and cold and cyanotic extremities ( cold blue hands ). Parkinsonian signs are bilateral from the start with the absence of rest tremor. Gait ataxia and balance disturbances can arise from the very beginning, as well as frequent falls. Pyramidal signs as the Babinski sign are present; dysphagia and dysarthria also manifest in the early stage. Other symptoms such as laryngeal stridor, trunk dystonia, and cerebellar signs may be observed. Neuroimaging studies show atrophy of the pons and the cerebellum and usually the presence of the hot-cross bun signal, a characteristic hyperintensity on FLAIR of the transverse fibers of the pons and cerebellar peduncle with normal sign of the corticospinal tract and pontine tegmentum [8] Progressive Supranuclear Palsy (PSP) It was described in the 1960s by Steele, Richardson, and Olszewski. Patients manifest the first symptoms around 50 to 60 years which are characterized by gait disturbance block and trunk hyperextension, postural instability with falls, lower vertical gaze palsy, and cognitive impairment and do not respond to levodopa treatment. The classic form or Richardson syndrome occurs in about 55 % of subjects and presents the peculiar symptoms of PSP, as parkinsonism, paralysis of vertical gaze, bilateral bradykinesia, frequent falls, and cognitive decline. PSP-parkinsonism (PSP-P) is the way of presentation in 30 % of the subjects and the clinical picture is very similar to PD, and only on late stages patients develop gaze palsy and prominent cognitive decline. Fifteen percent of PSP patients present atypical forms. On imaging techniques, particularly in magnetic resonance imaging (MRI), enlargement of the third ventricle and atrophy of midbrain are prominent in late phases of the disease [9].

6 26 H.B. Ferraz and R.A. Saba Dementia with Lewy Bodies (DLB) DLB starts between 60 and 70 years and is characterized by the presence of parkinsonian signs closely resembling DP associated with cognitive decline. Cognitive symptoms precede or follow up to 12 months after parkinsonism starts. The patient may present, in addition to parkinsonism and dementia, behavioral symptomatology such as hallucinations and delusions, with fluctuation of these symptoms (worse at night). It is quite common patients manifest great sensitivity to the exposure to neuroleptics (rapid development of severe stiffness and tremor) and rapid eye movement (REM) sleep behavioral disorder [10] Corticobasal Ganglionic Degeneration (CBGD) CBGD is characterized by progressive and asymmetric stiffness associated with upper limb apraxia. The phenomenon of alien limb is commonly present and characterized by involuntary movements of the upper limb, with levitation. Most patients present aphasia, unilateral dystonia, myoclonus, and rapidly progressive dementia of the frontotemporal type. Asymmetric atrophy of the cerebral hemisphere, mainly in the parietal region, is usually seen on MRI studies [1] Vascular Parkinsonism Vascular parkinsonism (VP) accounts for % of the total cases of parkinsonism. VP patients exhibit lower disease duration, older age at onset, and higher frequency of cardiovascular risk factors. This disease can be clinically distinguished from PD based on sudden onset of parkinsonism at older age, characterized by lower body predominance, urinary incontinence, pyramidal signs, postural instability with freezing of gait and falls, and dementia. The upper limbs in VP are less symptomatic in terms of parkinsonism throughout the course of disease. This is in clinical contrast to PD, in which patients generally present with tremor, rigidity, or slowness of the upper limbs. Thus, VP is also called lower body or lower half parkinsonism. VP patients developed cognitive impairment in comparison with same age individuals. These patients had a global pattern of cognitive impairment, including executive function, verbal memory, and language [11]. The main differential diagnosis of VP is PD, frontal lobe tumors, obstructive hydrocephalus, normal pressure hydrocephalus, and progressive supranuclear palsy. Imaging studies serve two purposes in a VP patient. First, it rules out other causes of parkinsonism, both degenerative (progressive supranuclear palsy) and secondary (tumors, hydrocephalous). Second, it may show ischemic lesions to support the clinical diagnosis. MRI or computerized tomography (CT) is supportive, but not conclusive, of the diagnosis of VP because there are no characteristic features of VP in CT/MRI. However, white matter lesions and lacunes are also common observations among the older people who do not have parkinsonism.

7 2 Clinical Aspects of Movement Disorders: Effects on Walking and Posture 27 This causes difficulty in determining the etiological mechanisms of VP. A study showed that most patients with VP had brain MRI changes with multiple lacunar infarcts (66.7 %) or extensive white matter (WM) disease (26.7 %) [12]. Others investigated the WM microstructure using diffusion tensor imaging in patients with VP, and specific fiber tract involvement, with respect to clinical severity, showed disruption of the microstructural organization of frontal lobe WM is associated with the severity of VP [13]. These findings are in accordance with the frontal lobe disconnection hypothesis for gait problems and reinforce the paradigm that the involvement of fibers related to the prefrontal cortex is crucial for the core features of VP [13]. Clinical features of VP phenotype are early postural instability and gait difficulty (PIGD). PIGD as the initial symptom is significantly more common in VP than in PD. Gait disturbance was reported as the initial symptom in 90 % of patients with VP as compared to 7 % of patients with PD [14]. The gait in VP is like a parkinsonian-ataxic gait. The stance is wide based. The posture is upright at least in the earlier stages and a much lesser degree of flexion is seen at the knees and hips than in PD. Steps are slow, short, and with a tendency to shuffle, particularly at the start and while turning the corners. Freezing of gait can be seen, but festination is absent. In severe cases, the patient is unable to initiate a step and the feet remained fixed to the floor (magnetic gait). Postural instability and falls dominate the gait at this advanced stage and render the patient unable to walk or even stand without support. Another factor contributing to the impaired mobility in advanced stages is truncal ataxia. These patients also have truncal and axial immobility. Sideways turning of the head is limited and patients turn their heads, neck, and shoulder in block to be able to look sideways. The change of posture while lying in bed is also difficult and limited. An interesting feature in obvious PIGD, at least in the earlier stages, is that many patients can perform simple tasks with their legs, like imitating bicycling or walking movements, when seated or lying. However, these movements are also slow. The treatment should be directed at secondary stroke prevention in an attempt to halt further disease progression although, understandably, it would not reverse or provide symptomatic relief to the existing clinical manifestations. The management of conventional vascular risk factors such as diabetes, hypertension, dyslipidemia, and smoking cessation would probably have the maximal impact in this approach to treatment. The levodopa response rates in VP vary from 20 to 40 %. A dose of up to 1000 mg/day should be given for at least 3 months before labeling the patient as a non-responder or poor responder. In good responders the duration of sustained response is typically less than in PD, with the drug becoming non-beneficial after one to two years [15]. 2.3 Huntington s Disease Huntington s disease (HD) is a progressive neurodegenerative disease, rare and fatal, characterized by a movement disorder mostly manifesting as choreic and dystonic movements, psychiatric abnormalities, and cognitive decline.

8 28 H.B. Ferraz and R.A. Saba HD is a genetic disease of autosomal dominant inheritance. An expansion occurs in the number of repeats of CAG pair of nitrogenous bases (adenine, cytosine, guanine) in unstable regions of DNA HTT gene, which is located on the short arm of chromosome 4 (4p16.3). Twenty-seven or fewer repetitions of CAG have a normal phenotype. Intermediate alleles with 27 to 35 CAG repeats are unstable and may be transmitted as an expanded allele to offspring. However, the carriers of the normal intermediate allele also have a normal phenotype. These intermediate expanded alleles occur, particularly, during male gametogenesis, as the same is subjected to a larger number of division cycles and duplication of genetic material. Thus, there is a greater likelihood of an error in DNA replication during spermatogenesis, which increases the risk of mutated alleles to be paternal inheritance [16]. Alleles with CAG repeats indicate incomplete penetrance and can generate both normal phenotypes with the disease. Alleles with more than 39 CAG repeats have complete penetrance and inevitably cause, in any phase of life, the phenotype of HD. Symptoms usually start between ages 35 and 55 and duration of disease can vary from 15 to 20 years. In some cases, it may manifest after 80 years of age or earlier, in adolescents or children, due to anticipation phenomenon, which occurs in 20 % of cases. Due to the variability of the clinical signs and symptoms, the molecular test is required for the diagnosis. The most frequent isolated initial complaint is the lack of coordination and occasional involuntary tremors in several body segments, which usually can be attributed to the presence of chorea. Other early motor abnormalities include saccadic eye movements, interrupted or slow, inability to sustain tongue protrusion, and difficulty in performing rapid alternating movements. Behavioral changes are often reported to precede movement disorder over a decade. Symptoms of emotional nature or personality changes may antedate these movements in at least half of patients with DH. Patients are excessively irritable, impulsive, unstable, and aggressive. The most common early symptoms are mental depression. In some of the cases, the opening frame can be a frank psychosis. The most striking feature of HD is the presence of choreic movements seen in approximately 90 % of the affected individuals. At first, chorea may be mild, affecting only the face or distal portions of limbs, but, with time, it becomes widespread, interfering with any voluntary movement [17]. Gradually, with the progress of the disease, the patients are becoming slower in nature, taking an athetoid character, and, subsequently, dystonic [18]. Other involuntary movements, such as tremors and intention myoclonus, can rarely be present. Dysarthria is another prominent symptom that appears early in the course of disease, as slowing or hesitancy in speech, which gradually becomes explosive, irregular, and interspersed with long silences, and an increase of chances for a complete disorganization and mutism. Dysphagia, common in the advanced stages of HD, is often responsible for choking and aspiration, bronchopneumonia aspiration, being reported in up to 85 % of mortality. The causes of death are related complications of immobility, such as food or trauma, and asphyxia aspirations. The patient s gait

9 2 Clinical Aspects of Movement Disorders: Effects on Walking and Posture 29 is characterized, constantly parasitized, by choreic movements, taking uncoordinated character in appearance, and it can become impossible. Patients also exhibit postural instability and primary changes in the balance, with frequent falls and fractures. Bradykinesia, with or without stiffness, occurs in the later stages of disease with extreme slowness of all movements. This symptom is directly related to the disability of patients and it occurs regardless of chorea [17]. Sphincter incontinence, both urinary and anal, is common, especially in the terminal stages of HD. There is evidence of autonomic dysfunction as hyperhidrosis and changes in blood pressure regulation. Generalized tonic-clonic seizures may occur in up to 3 % of adults with DH and in approximately 40 % of patients with early disease onset (under 20), as other types of seizures can happen [18]. Psychiatric and cognitive changes may precede the motor manifestations, accompany them, or occur after [19]. Dementia is considered one of the cardinal signs of the disease. Patients with DH are more impaired in learning, mental flexibility, and attention. Executive function is compromised and is noted early, even in the absence of complaints from patients or family members. It includes difficulty in planning, organizing, and scheduling activities. The executive functions are related to the frontal lobe and its connections. Cognitive functions are more strongly correlated with the functional capacity of the motor symptoms. The psychiatric symptoms occur in about % of cases. Patients may present frameworks of personality change, mood disorders, and psychosis. The most commonly found personality changes are psychiatric and include irritability, apathy, emotional lability, impulsivity, and aggressiveness. Depression may precede motor symptoms. The frequency of suicides in HD is four to six times higher than that in the general population. Suicidal ideation is present in approximately 10 % of individuals diagnosed with HD. Episodes of mania can also be found, less commonly, and schizophreniform psychosis occurs in 6 25 % of cases; this is characterized by paranoid tables with persecutory delusions, jealousy, and auditory hallucinations. Other psychiatric conditions include irritability, agitation and aggression, disorder and obsessive-compulsive behavior, psychosomatic complaints, anxiety, sexual paraphilias, and behavioral changes [20]. Symptomatic treatment reduces motor and behavioral symptoms and thus maximizes functional capacity of the affected individual. The treatment is done with chorea antagonists dopaminergic with high affinity for D2 receptors. Among the drugs which may be used to control abnormal movements, there are risperidone and olanzapine (typical neuroleptic), and haloperidol (atypical neuroleptic). Tetrabenazine is also indicated for the control of choreic movements. However, due to the high incidence of depression in patients treated with this drug, its use is limited. The dose should be individualized, starting always with low doses and increasing until the control of involuntary movements is satisfactory from a functional point of view [21]. Patients generally tolerate high doses of conventional neuroleptics, showing no symptoms of impregnation. The inhibitors of N-methyl- D-aspartate (NMDA) glutamate receptors, such as amantadine, can be used for the motor s movement control. Depression usually responds to classical antidepressants such as selective inhibitors or serotonin reuptake dual inhibitors.

10 30 H.B. Ferraz and R.A. Saba Excessive irritability can be treated with benzodiazepines. Aggressive patients can benefit from both antidepressants and neuroleptics. There is not a specific treatment for HD dementia [21]. 2.4 Final Remarks Gait and balance are usually impaired in many neurodegenerative diseases, but parkinsonism and Huntington s disease are the most frequent, with the higher impact on daily activities of patients. Although these conditions usually do not have a definite treatment to control axial symptoms, pharmacological and rehabilitation approaches are essential to improve quality of life of the patients. References 1. Fahn S, Jankovic J. Principle and practice of movement disorders. Philadelphia: Churchill Livingstone; p Campbell WW. DeJong s. The neurologic examination. 7th ed. Philadelphia: Lippincott Williams & Wilkins; Jellinger KA. Neuropathological spectrum of synucleinopathies. Mov Disord. 2003;18 suppl 6:S Kalia LV, Lang AE. Parkinson s disease. Lancet. 2015;386: Jankovic J, McDermott M, Carter J, et al. Variable expression of Parkinson s disease: a baseline analysis of the DATATOP cohort. Neurology. 1990;41: Connolly BS, Lang AE. Pharmacological treatment of Parkinson s disease. A review. JAMA. 2014;311: Wagle Shukla A, Okun MS. Surgical treatment of Parkinson s disease: patients, targets, devices, and approaches. Neurotherapeutics. 2014;11: Fanciulli A, Wenning GK. Multiple-system atrophy. N Engl J Med. 2015;372: Golbe LI. Progressive supranuclear palsy. Semin Neurol. 2014;34: Walker Z, Possin KL, Boeve BF, Aarsland D. Lewy body dementias. Lancet. 2015;386: Benítez-Rivero S, Lama MJ, Huertas-Fernández I, et al. Clinical features and neuropsychological profile in vascular parkinsonism. J Neurol Sci. 2014;345: Vale TC, Caramelli P, Cardoso F. Clinicoradiological comparison between vascular parkinsonism and Parkinson s disease. J Neurol Neurosurg Psychiatry. 2015;86(5): Wang HC, Hsu JL, Leemans A. Diffusion tensor imaging of vascular parkinsonism: structural changes in cerebral white matter and the association with clinical severity. Arch Neurol. 2012;69: FitzGerald PM, Jankovic J. Lower body parkinsonism: evidence for vascular etiology. Mov Disord. 1989;4: Constantinescu R, Richard I, Kurlan R. Levodopa responsiveness in disorders with parkinsonism: a review of the literature. Mov Disord. 2007;22: Wheeler VC, Persichetti F, McNeil SM, et al. Factors associated with HD CAG repeat instability in Huntington disease. J Med Genet. 2007;44: Tabrizi SJ, Langbehn DR, Leavitt BR, TRACK-HD Investigators, et al. Biological and clinical manifestations of Huntington s disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data. Lancet Neurol. 2009;8: Cardoso F. Huntington disease and other choreas. Neurol Clin. 2009;27:

11 2 Clinical Aspects of Movement Disorders: Effects on Walking and Posture Andrew SE, Goldberg YP, Kremer B, Telenius H, et al. The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington s disease. Nat Genet. 1993;4: Morreale MK. Huntington s disease: looking beyond the movement disorder. Adv Psychosom Med. 2015;34: Bonelli RM, Hoffman P. A systematic review of the treatment studies in Huntington s disease since Expert Opin Pharmacother. 2007;8:

12