|MOVEMENT DISORDERS: CURRENT UNDERSTANDING OF PATHOPHYSIOLOGY AND MANAGEMENT
|Year : 2018 | Volume
| Issue : 1 | Page : 55-62
Movement disorders: Current understanding of pathophysiology and management
Madhuri Behari, Abhilekh Srivastava
Department of Neurology, FL. Lt. Rajan Dhall Fortis Hospital, Vasant Kunj, New Delhi, India
|Date of Web Publication||28-Jan-2019|
Department of Neurology, FL. Lt. Rajan Dhall Fortis Hospital, Vasant Kunj, New Delhi - 110 070
Source of Support: None, Conflict of Interest: None
In the last four decades, great strides have been made in understanding the pathophysiology and management of movement disorders. Several new molecules and methods of their delivery have made management of these disorders free of complications. New discoveries of genetic abnormalities have helped in better classification of these disorders along with improved prognostication. Improved imaging techniques that help in better localization of target for deep brain stimulation, refinement of stereotactic procedure, and development of safer anesthetic procedure have together encouraged more patients opting for deep brain stimulation for treatment. In the near future, it is expected that more genetic varieties of disorders will be known which may help in genetic intervention for therapy.
Keywords: Alpha-synuclein, biomarkers, deep brain stimulation, Huntington's disease, Parkinson's disease
|How to cite this article:|
Behari M, Srivastava A. Movement disorders: Current understanding of pathophysiology and management. Astrocyte 2018;5:55-62
| Introduction|| |
Movement disorders are one of the most dynamic areas of neurology with rapid strides in the development of knowledge about their phenomenology, pathophysiology, and consequently treatment. Currently, most of the new developments of research has been focused on Parkinson's disease (PD). New modalities of treatments in PD have led to significant improvement in quality of life of these patients. Lately, however, our understanding of the hyperkinetic disorders has also improved dramatically and significant advancements are being made in their management. For the purpose of this review we will enquire into new developments in PD and related disorders in the first section and latest updates in the field of hyperkinetic disorders in the subsequent section.
| Parkinson's Disease|| |
PD is the prototype of hypokinetic disorders. It is characterized by progressive neurodegeneration in brain, as well as parts of the body outside the central nervous system (CNS) lead to various motor and nonmotor symptoms.
Identification of existence of nonmotor features in recent years has helped in our understanding of pathophysiology and progression of PD as it advances. This has been made possible due to seminal work of Braak et al. examining postmortem brains of individuals who died of PD and other causes. Their work suggested that PD starts from two areas, namely (a) nasal mucosa and (b) gastrointestinal (GI) tract, since earliest changes were observed in olfactory bulb and autonomic nerve endings of GI tract, after which the pathophysiology spreads to the olfactory bulb and lower brainstem through vagus nerve. From there it spreads to pons and then to midbrain. Motor symptoms appear when midbrain is affected. Until this stage only nonmotor symptoms are present. Further spread involves the cerebral cortex, resulting in features of advanced PD such as dementia and hallucinations. The concept of deposition of alpha synuclein (SNCA) outside the CNS in the prodromal phase of the disease, thus, became recognized. Hence, we see SNCA deposition beginning in salivary glands, gut, autonomic plexus in the gut, and eventually in the brain stem, olfactory bulb, and the cortex. This hypothesis explains all the premotor symptoms of PD, namely early GI motility disturbances, rapid eye movement (REM) sleep behavior disorders (RBD), and hyposmia/anosmia.
Recent studies have also shown migration of Lewy body from host issue tissue to grafted tissue in PD patients who received embryonic mesencephalic stem cell implant, suggesting prion-like activity of Lewy bodies, thereby causing cell-to-cell spread of SNCA, suggesting that PD may indeed be a prion disease. This hypothesis has been confirmed in some animal models in which interneuronal spread of SNCA to brain was shown by elegant experiments. However, it is still unclear if deposition of synuclein is sufficient or necessary to cause PD. It has been observed that some of the genetic subtypes of PD such as those with LRRK-2 mutations or Parkin mutations (PARK-2) lack SNCA deposition in brain on autopsy, even though the clinical features are indistinguishable from idiopathic PD. As a result, latest literature has suggested a separate subcategory of “clinicogenetic PD,” i.e. those individuals who carry identified genetic mutations for Parkinsonism More Details, without pathological evidence of degeneration of neurons in the substantia nigra (SN), not meeting the clinical criteria for PD, and without any synuclein deposition.
Disorder Society criteria in view of rising importance of early premotor features manifesting years before motor features of PD have revised diagnostic criteria by including these features in the new diagnostic criteria for prodromal PD. They distinguished into following phases: Genetic PD (those who carry the gene without neurodegeneration and symptoms of PD), preclinical PD where neurodegeneration is present but clinical symptoms are absent (diagnosed by imaging or biomarkers), prodromal PD where neurodegeneration has started but symptoms are not severe enough yet to fulfil the criteria of clinical PD, and the last phase, i.e., clinical PD with motor symptoms and fulfilling the clinical Movement Disorder Society (MDS) criteria. Identification of prodromal PD is expected to be beneficial in research for neuroprotective therapies and better understanding of the disease progression. Most of the features of this phase are nonmotor clinical manifestations of PD, but the drawback is some of these features such as constipation and depression are very nonspecific and without biochemical backup and do not always progress to clinical PD.
Even though PD is classically considered as a sporadic disorder, up to 15% of cases of PD have a positive family history and up to 10% of cases have identified monogenic mutations. A lot of research are currently focused on these monogenic forms, and using linkage analysis or whole-genome sequencing and whole-exon sequencing has identified numerous mutations responsible for genetic forms of PD. Almost 23 monogenic forms of PD have been identified so far and knowledge about these genes has significantly added to our understanding of the pathophysiology of PD. [Table 1] summarizes the ever-growing list of identified genetic subtypes, along with their genetic loci and prominent clinical features.
Diagnosis of PD is based on UK PD Brain Bank clinical diagnostic criteria requiring bradykinesia and one or more of rigidity, tremor, and/or postural instability. Diagnostic accuracy of PD using the existing criteria varies from 65 to 90% at first presentation and improves to 75–99% with subsequent follow-up over years., This is slightly better in the hands of movement disorders specialists.
Nonmotor features arising due to nondopaminergic deficiency and involvement of other parts of brain important in the diagnosis of PD were recognized in the early part of the year 2000. These included hyposmia, depression, constipation, and RBD. Subsequently, many researchers noted that nonmotor symptoms often precede motor symptoms by several years, and including them in diagnostic criteria can help diagnose PD at an early stage, before motor symptoms become well established. This will help in providing a unique window of opportunity to intervene with neuroprotective strategies when one becomes available.
The task force of MDS was set to upgrade the diagnostic criteria of PD by including some nonmotor features. In 2015, new clinical criteria for PD were published which also defined a group of prodromal PD, lacking in the earlier set of criteria. These criteria apart from specifying same positive and negative inclusion/exclusion criteria as earlier version also included certain ancillary diagnostic tests with specificity more than 80% for diagnosis of PD. These ancillary tests included smell test documenting unequivocal hyposmia or anosmia out of proportion to that expected for age and sex, and metaiodobenzylguanidine cardiac scintigraphy demonstrating clear evidence of cardiac sympathetic denervation.
Another unique feature of the new MDS criteria was inclusion of tests to identify “Red Flags” or absolute exclusion criteria. The members of the task force also mentioned that a completely normal (clearly in the normal range and not a borderline scan) functional neuroimaging of the presynaptic dopaminergic system argues against a diagnosis of idiopathic PD. However, inclusion of this criteria came with a rider and was not recommended as a test to be done routinely in all patients with PD. It could be used in the case of diagnostic dilemma, to be performed as part of the diagnostic workup, and if completely normal, diagnosis of PD would be excluded. Functional neuroimaging of dopaminergic function of presynaptic nerve terminal can be performed with either positron emission tomography (PET) or single-photon emission computed tomography (SPECT) using a variety of ligands., The most commonly used ligands such as 123I-FP-CIT and 99mTc-TRODAT assess the presynaptic dopamine transporters as an indirect marker of the dopamine levels in presynaptic terminals. Other functional imaging methods use either assessment of activity of aromatic acid decarboxylase (enzyme which converts levodopa to dopamine, using 18F-dopa PET), or assessment of vesicle monoamine transporter binding in presynaptic dopaminergic nerve terminals using PET with dihydrotetrabenazine-based ligands.
PD patients usually show bilaterally asymmetrical putamen dopaminergic loss (more reduced on the side contralateral to the side with first onset of symptoms), with a postero-anterior gradient (posterior uptake reduced more and earlier than anterior) on functional neuroimaging. PET and SPECT-based dopaminergic imaging are capable of detecting prodromal cases of PD, particularly in genetically proven carriers.
Biomarkers presence and SNCA
Alpha synuclein (SNCA), the precursors of Lewy body have been shown in tissues by in vitro examination of biopsy material from nasal mucosa, salivary gland, GI tract (esophagus, stomach, ileum, colon, and rectum in rostro-caudal gradient), and skin, suggesting involvement of these structures in addition to brain, which may be present in premotor stage of PD.,
Another novel way for diagnosis of premotor PD is based on ultrasonography of the midbrain. This technique is based on the work of Becker et al. who discovered high echogenic area within the SN in patients with PD on ultrasound. The sensitivity and specificity of this method vary based on the expertise of the operator, the study population, and temporal window with sensitivity from 62 to 95% and specificity of 77–85%., A meta-analysis concluded sensitivity of 83% and a specificity of 87% for transcranial ultrasound to diagnose PD, thus making it a very reliable, sensitive, noninvasive test for diagnosis of PD albeit with high dependence on operator skill.
In addition, certain biomarkers in cerebrospinal fluid (CSF) and serum are also identified such as CSF levels of SNCA and DJ-1, but the technique of measurement, collection, and interpretation awaits standardization. Analysis of several metabolome is underway and the results are still awaited.
Despite excellent response to levodopa therapy, which is the cornerstone of management of PD, its use is marred with several troublesome side effects. After its introduction in clinical use in late 1960s, it was observed that levodopa provides an initial honeymoon phase lasting for 4–6 years. However, prolonged use leads to development of some side effects such as motor fluctuations and dyskinesias, which still remain the biggest hurdle of good quality of life in PD patients. An unmet need was felt, for a drug which could overcome these side effects and provide smooth CSF/blood levels of dopamine, i.e. continuous dopaminergic stimulation without side effects. In this direction, several new drugs and new methods of drug delivery were developed in recent times. Controlled release preparations of levodopa/carbidopa were used for PD, but it did not live up to the expectation. Extended release preparations of levodopa/carbidopa in capsule form (Rytary), available in US, has its duration of as long as 4–5 h. Its side effects include psychosis, dyskinesia, and melanoma among others. Dopamine agonists introduced in 1990s were found to have longer half-life and provided more sustained dopaminergic stimulation. However, these too were found to be ineffective and were associated with dopamine dysregulation. Sustained release preparations of dopamine agonists, pramipexole and ropinirole, were introduced and aimed to smoothen out the motor fluctuations and reduce the off-time of patients on LD therapy, with ease of administration with once a day dosing. Another dopamine agonist apomorphine is now available for parenteral therapy (subcutaneous route) and to be used as rescue therapy in cases of sudden gait freezing and/or sudden off-periods or as continuous infusion via a subcutaneous pump as a means for continuous dopaminergic stimulation. It has fast onset of action and short duration of action and hence best suited for rescue therapy.
More recently, amantadine with extended release action has just been introduced in US market for the management of levodopa-induced dyskinesia. Other medications currently in use for the management of PD include catechol-O-methyltransferase inhibitor (entacapone), which inhibits the enzyme responsible for peripheral and central metabolism of levodopa—thus increasing the availability of levodopa at the presynaptic terminal extending its duration of action. The other group of medications available for PD is selective monoamine oxidase B (MAOB) inhibitors (selegiline and rasagiline) which also inhibit the metabolism of dopamine by increasing striatal dopamine concentration. Early in 2017, safinamide has been added to the list of drugs that can be used, both in early as well as advanced PD. Safinamide is a selective MAOB inhibitor, has good oral bioavailability, a long half-life (once daily dosing), and is approved in addition to levodopa and dopamine agonists for management of motor symptoms in PD, particularly in late stages with motor fluctuations (dose: 50–100 mg/day). In addition to MAOB inhibition, safinamide is also believed to have antiglutaminergic effects which may be responsible for its antidyskinesia effects. Strong evidence for efficacy of safinamide came from the recent SETTLE trial. In comparison to placebo, safinamide significantly increased mean daily ON time with no additional dyskinesias in patients with PD who are already on levodopa therapy. Another advance in therapy is delivery of levodopa/carbidopa directly into the jejunum through percutaneous port and delivered through battery-operated pump (duodopa)—again aimed at delivering continuous dopaminergic therapy to reduce motor fluctuations.
On the pharmacological front, some trials report improvement of levodopa-induced dyskinesias with levetiracetam in doses up to 1000 mg/day with relatively few side effects. However, other studies have failed to show this benefit and the benefit of this agent still remains in doubt.
Botulinum toxin has revolutionized the management of hyperkinetic movement disorders, however, its use in PD has been considered to be rather limited. Some of the manifestations in PD such as drooling of saliva, freezing of gait, apraxia of lid opening, and camptocormia may be amenable for botulinum toxin therapy. Of these, most of the literature show use of botulinum toxin in cases of drooling or sialorrhea. Drooling or sialorrhea in PD is due to bradykinesia in the swallowing muscles. Botulinum toxin injected into parotid and submandibular salivary glands can effectively block cholinergic transmission and thus reduce secretion of saliva. Another role of botulinum toxin in PD is in the management of axial dystonia (camptocormia and the Pisa syndrome). Injections into the rectus abdominis and external oblique muscles have been found to be helpful in cases that are often refractory to both levodopa-based therapies and to deep brain stimulation (DBS)., With time, use of botulinum toxin is expected to increase in the management of these and some of the other symptoms that are often refractory to other medications used in the management of PD.
In the last few decades, DBS has revolutionized management of advanced PD. Patients of PD with severe motor fluctuations, levodopa-induced dyskinesias, as well as severe resting tremors have all undergone DBS with excellent results. The two most common targets to DBS for PD include subthalamic nucleus (STN) and globus pallidus interna (GPi). High-frequency stimulation of STN or GPi improves most of the levodopa responsive symptoms of PD but can occasionally result in cognitive and psychiatric side effects. A meta-analysis compared side effects of the STN-DBS vs. GPi-DBS therapy and reported that motor benefit was almost similar in the two groups as well as psychiatric side effects but cognitive decline was more in patients with STN-DBS. In general, if dose reduction is the primary objective as in drug-induced psychosis, STN-DBS is the preferred target. On the contrary, when patients with mild cognitive disturbances and predominant axial symptoms or dyskinesias need DBS, GPi-DBS is considered the preferred target. Neither of the two sites, however, are helpful in management of freezing of gait and in some cases, they even worsen symptoms of freezing. In patients with prominent gait disturbance, stimulation of pedunculopontine nucleus (PPN) provides meaningful improvement in gait disturbances in PD. PPN is located at the junction of midbrain with pons and is believed to play a key role in locomotion system. However, more trials of PPN-DBS are needed to provide unequivocal results and the technique also needs to be fully optimized. However, it is hoped that in future PPN-DBS in combination with STN-DBS and GPi-DBS may be the answer for gait problems in PD albeit at the cost of increased financial burden to patient. Recently, there has been a trend to offer DBS at an early stage in the course of PD (3–5 years) after onset of motor symptoms (Early-Stim). The argument in favor of this approach is to provide better quality of life from early time in the course of disease, better general health of the patient when younger, and release of protective neurotransmitters in patients with DBS as shown in some animal experiments and hence, slower progression of disease.
The field of PD has, therefore, seen a lot of new development in recent years and a lot of exciting developments are in the pipeline. The most important need for the hour is to develop a reliable and predictable biomarker which can detect PD in its early stages and effective neuroprotective therapy which can halt the neurodegeneration of parkinsonism.
| Other Movement Disorders|| |
In the field of other movement disorders, the development has not been as fast as compared to PD. Much research and development has occurred in the field of dystonia especially cervical dystonia, ET, HD, Tourette syndrome, and a host of other movement disorders. Not only have these researches improved understanding of these disorders but also some newer treatment modalities have emerged.
There is identification of new group of disorders such as autoimmune encephalitis presenting as various movement disorders, particularly dystonias, myoclonus, and tremors predominantly.
Dystonia is defined as sustained or intermittent muscle contractions causing abnormal often repetitive movements or postures or both. A new method of classification of dystonia has been described by Albanese et al., which is easy and more relevant clinically. According to this schema, dystonia is classified according to two axes: (1) clinical axis: in which (a) age of onset, (b) body part affected, and (c) the temporal pattern of disease is considered and (2) etiological axis: in which (a) presence or absence of neurodegeneration and (b) sporadic or inherited nature (and mode of inheritance) of disease is described.
Genetic basis of primary dystonia is recognized which helps in prognostication, treatment, and genetic counseling in these cases. Several new genes have been recognized for generalized forms of childhood-onset dystonia, but a genetic diagnosis for the most common form of dystonia—adult-onset focal dystonia still remains elusive. Next-generation sequencing, exon sequencing, and whole-genome sequencing are new development in the field of genetics that can help in identification of new genes. In the childhood-onset dystonia there has been an explosion of identified genes [Table 2]. An expert committee has recommended that all identified genetic forms henceforth be identified as “DYT—GENE NAME”; for example, DYT1 would be named as DYT-TOR1A, and so on. Among this group, DYT-5 or dopa responsive dystonia (or Segawa disease) is characterized by lack of GTP cyclohydrolase-1 enzyme resulting in lack of dopamine and hence is dramatically responsive to levodopa. This is a disorder in which the symptoms respond to a small dose of levodopa/carbidopa and it does not suffer from long-term complications of levodopa use as happens in PD. Identifying such monogenic forms and advancements in genetic therapies such as gene editing provides hope that soon genetic treatment will be available for these difficult-to-treat forms of dystonia.
Paroxysmal dystonias are increasingly being identified. They are of mainly three types: (a) paroxysmal kinesigenic dyskinesia (DYT10)—due to mutations in the PRRT2 gene—leading to appearance of choreo-athetosis or dystonia precipitated by sudden changes in posture or transition from walking to running—and responds very well to antiepileptics such as carbamazepine; (b) paroxysmal exertion-induced dyskinesia (DYT18)—the rarest of the paroxysmal dyskinesia is caused by mutations in SLC2A1—attacks are precipitated by prolonged exercise or exertion—and lead to dystonic symptoms ranging from few minutes to half an hour; and (c) paroxysmal nonkinesigenic dyskinesia (DYT8)—caused by mutations in the MR-1 or the PNKD gene—wherein attacks are precipitated by alcohol consumption, mental stress, or fatigue—and the attacks can be prolonged up to hours occasionally responding to clonazepam.
In the field of therapeutics, botulinum toxin has emerged as the most effective as well as safest option for focal dystonia. It is reversible and leads to significant improvement in the quality of life of patients with dystonia. However, it is not useful for generalized childhood-onset forms of dystonia. In patients with generalized dystonia and some segmental and focal dystonia refractory to other medications, DBS has emerged as a feasible therapeutic option. The most common target of DBS for dystonia is GPi. Best response to GPi-DBS in dystonia is seen in DYT1 patients. In pediatric population the timing of surgery is important since delay can lead to development of permanent skeletal deformities.
Essential tremor (ET)
ET is one of the commonest movement disorders seen in general population, though most of these patients never consult a doctor as it runs in family and has benign course. It is characterized by postural/kinetic tremor which sometimes in severe cases can also be seen at rest and is highly sensitive to alcohol. Recent research suggests involvement of cerebellar circuit in its pathogenesis. Since it is present on activity, it can sometimes be severely disabling. Besides beta-blockers and primidone, medical management of these forms of tremors is limited. Botulinum toxin has been in the forearm flexors to reduce severity of the tremors tried with good results though with significant weakness, which is often unacceptable. DBS targeting the ventral intermediate (VIM) nucleus of thalamus is an option for those with severe disabling tremors interfering with activities of daily living. DBS to the VIM can, however, be associated with postoperative paresthesia. Refinement of the technique in future can offer good treatment option with minimal risk for cases of ET refractory to medical treatment. The most novel treatment option for ET is magnetic resonance imaging (MRI)-guided focused ultrasound thalamotomy (FUT). FUT is noninvasive as compared to DBS but side effects (gait disturbances, paresthesias) are more common. With more experience FUT could become more utilized than DBS for ET patients who require surgical intervention for management of their disease.
Huntington's disease (HD) and other hyperkinetic movement disorders
HD is an autosomal dominant neurodegenerative disorder characterized by a triad of chorea, dementia, and psychiatric disturbances. Unfortunately, we do not have any definitive treatment for HD so far and it is relentlessly progressive. The hyperkinetic movement disorder component can vary from chorea to severe ballismus which often severely impairs the quality of life. Only symptomatic treatment is currently available for management of the symptoms. In a recent study, deutetrabenazine led to significant improvement in chorea as compared to tetrabenazine with a better side effect profile and convenient once daily dosing. DBS is an upcoming option with GPi as the most common target for HD. In trials, it has shown to reduce choreo-ballismus but can worsen cognitive function. Further studies are required on the optimal site and stimulation parameters. Gene therapy in the future, however, is likely to hold the key to a definitive management for HD.
Tourette syndrome (TS)
TS is a disease of childhood characterized by multiple motor and vocal tics associated with multiple behavior and psychiatric comorbidities. At times motor tics are so severe and multifocal that they are resistant to all forms of medical treatment and severely hamper the quality of life. Botulinum toxin can be used for focal simple and vocal tics, however, for complex tics it is usually not desirable. When both behavioral and medical therapy fail, patients of TS can be considered for DBS. The targets that are being studied for DBS in TS include the centromedian parafascicular (Cm-Pf) nucleus and the ventralis oralis in thalamus and the GPi. More studies are required in the field of DBS in TS to identify the best target for stimulation—till then DBS remains the last hope for TS treatment refractory.
In conclusion, in the last 30–40 years, improvement in diagnostic field, particularly molecular and genetic evaluation using whole-genome sequencing and exon sequencing, has helped in diagnosing as yet unidentified genetic disorders. These techniques have helped in better understanding of these disorders and at times provide focused therapy to the affected individual. Second, better technology in operative procedures along with microscopic operative techniques, use of intraoperative MRI with better localization of operative targets, and safer anesthesia have all improved the results of operative treatments. Better imaging technique that can image up to molecular level has improved the understanding of several movement disorders and their diagnosis. Newer drug development after understanding of these disorders has tackled some side effects seen in the past. Refinement in molecular methods provides opportunity for genetic modifications and delivery of drugs in nano-dosages precisely at the site of action, minimizing side effects. Botulinum toxin and DBS have revolutionized treatment of not only movement disorders but also epilepsy and some psychiatric disorders as well. Continued refinement of these advances is making management of these disorders less challenging.
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Conflicts of interest
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[Table 1], [Table 2]