ARCHIVE: Twitches, Tics, Dystonia, Ataxia

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THIS TUTORIAL HAS BEEN UPDATED AND COMBINED INTO TREMORS, TICS, & OTHER HYPERKINETIC DISORDERS.

hyperkinetic movement disorders, Part 2: TWITCHES, TICS, DYSTONIA, & Ataxia

Tics

Clinical Correlation: Tics & Tourette Syndrome

Overview

• Tics are brief, involuntary actions.
• Indicate that they can be simplex or complex, motor movements or vocal sounds.
• Importantly, they are suppressible, meaning the individual can stem the compulsion to generate the tic but, unfortunately, there is a rebound flurry of tics that follows the period of suppression.
• And they are suggestible, just asking the individual about their tics tends to provoke them.
• Indicate that Tourette syndrome involves a childhood onset of motor and vocal tics that persist into adulthood but do fluctuate in severity (and often lessen in intensity and frequency).

Tics: Details

• Simple motor tics are abrupt, isolated movements: blinking, wrinkling the nose, shoulder shrugging, facial grimace, or head jerking.
• Simple vocal tics are simple sounds: coughing or throat clearing.
• Complex motor tics are sequential, patterned movements that can appear purposeful: skipping or jumping or smelling objects or body parts.
• Complex vocal tics involve words or phrases, sometimes obscenities.

Twitches

Clinical Correlation: Twitches & Hemifacial spasm

Twitches

• Indicate that, on the contrary, twitches are involuntary muscle spasms that are NOT suppressible or able to be volitionally initiated. Along with that, there is no compulsion to generate the movement.

Hemifacial Spasm

• Let's look at hemifacial spasm, in which there are unilateral repetitive, paroxysmal, uncontrollable spasmodic contractions of facial nerve innervated musculature.
• Draw half of a face with the eyelid closed and in a smile.
• Show that in hemifacial spasm, there is a unilateral spasmodic twitch of the eyelid, along with a facial grimace (twitch of the side of the face).
• Indicate that it is most commonly secondary to neurovascular compression of the facial nerve; hence microvascular decompression is sometimes done to prevent the twitching.
• It typically starts in the orbicularis oculi and then propagates via ephaptic transmission: the impulse passes between facial nerve branches.

Dystonia

Clinical Correlation: Dystonia: Cervical dystonia & Blepharospasm

Overview

• Now, let's address dystonia. Indicate that it involves involuntary, sustained, intermittent muscle contraction that causes abnormal posturing or movements.
• Dystonia can affect a wide variety of body parts, can occur in a wide variety of distributions, patterns, and speeds.
• Seemingly almost any body part can be affected but the most common are the limbs, neck, trunk, eyelids (blepharospasm) and other facial muscles, or even the vocal cords, themselves.
• It can occur in a continuous or intermittent pattern and it can be focal or generalized or almost anything in between (segmental, multifocal, hemi-body).
• The speed of contraction can be quick and fleeting like chorea or myoclonus, often called dystonic spasm, or it can be slow and sustained or cramp-like (athetoic), in which it is often called a dystonic posture.
• If generalized (generalized dystonia, DYT), large body parts are typically involved, which can cause extreme distortion from the sustained writhing and twisting that can occur.

Focal Dystonia

Let's focus on common focal dystonias.

Cervical Dystonia

• Begin with cervical dystonia, the most common form of focal dystonia.
• Draw a head in lateral rotation.
• Show that in cervical dystonia, there is, most commonly, spasmodic torticollis (turning or twisting: a rotation) of the neck.
  • Less commonly, there may be retrocollis (backward, extension) or anterocollis (forward, flexion) or laterocollis (tilted to the side).
  • Importantly, via a sensory trick (geste antagoniste), individuals can perform a maneuver such as lightly touching their face to release the dystonic posture.

Writer's cramp

• The next most common focal dystonia (after cervical dystonia) is writer's cramp, which is brought on by that very action (writing).

Blepharospasm

• Now, let's compare blepharospasm, the next most common focal dystonia to hemifacial spasm (a twitch).
• Draw a set of closed eyes.
• Show that blepharospasm (aka nictitating spasm) involves bilateral (rather than unilateral) repetitive involuntary squeezing of the eyelids (eyelid closure) via spams of the orbicularis oculi and frontalis muscles and is most often idiopathic (not secondary to neurovascular compression), although it can be part of various syndromes, such as parkinsonism and Wilson's disease.

Blepharospasm is a dystonia...

• Finally, as a helpful review, let's see why blepharospasm is best categorized as a dystonia rather than a twitch or tic.
  • The eyelid closure in blepharospasm is typically brief (like a twitch) but the patient can experience persistent squeezing to the point of sustained eyelid closure (typical of dystonia), in which case the patient can be functionally blind. And just like with cervical dystonia, a light touch to the lateral aspect of the eye can interrupt the eyelid closure.
  • When involuntary blinking is a motor tic, it is suppressible and the patient experiences a compulsion to shut the eyes, neither of which are part of blepharospasm.

Meige Syndrome

• Lastly, it's helpful to be aware that Meige syndrome refers to blepharospasm in combination with oromandibular dystonia (lower facial and jaw muscle involvement).

Ataxia

Now, let's address ataxia.

Functional Modules

Modular Anatomy

• We'll break ataxia down into the functional modules of the cerebellum, so we can learn some principles of cerebellar localization as we study this movement disorder, using a flattened perspective of the cerebellum.
• Draw the bulk of the cerebellum (the corpus cerebelli): it comprises the anterior and posterior cerebellar lobes.
• Below it, draw the propeller-shaped flocculonodular lobe: the nodule is in midline and flocculus out laterally. Note that the vermis (which means wormlike) is a key, commonly referenced midline structure.
• Show that the somatotopic map looks like someone lying in a bathtub with the legs and trunk in the anterior lobe and in the posterior lobe the arms and hands are extended outward.
• Draw a pair of eyes in the midline flocculonodular lobe because, as we'll see ocular ataxia, nystagmus, and vertigo stem from lesions in this region.

Sagittal View of the Cerebellum

To understand how this relates to actual cerebellar anatomy.

• Draw a sagittal view of the cerebellum: show the anterior lobe (A) lies anteriorly and superiorly, the posterior lobe (P) lies posteriorly and more inferiorly and the flocculonodular lobe (F) refers to the small region of cerebellum in the anterior center.
• Show that we peel this entire structure back and flatten it to provide our flattened perspective.

Functional Modules

Now, let's address the functional modules that stem from this anatomy.

Spinocerebellum

• First, draw the limbs and trunk.
• Indicate that they constitute the spinocerebellum, which are primarily involves the anterior lobe and vermis. The spinocerebellum receives its name from its major input fibers: the spinocerebellar tracts and, as we can imagine, plays a major role in postural stability.

Pontocerebellum

• Next, draw the arms.
• Indicate that they constitute the pontocerebellum (aka neocerebellum), which primarily derives from the posterior lobe. It is geared towards fine motor movements, which are typically goal-oriented (it primarily acts through the corticopontocerebellar pathway).

Vestibulocerebellum

• Now, the face: try to represent ocular ataxia and dysarthria.
• Indicate that the vestibulocerebellum is derived from the flocculonodular lobe, primarily, and receives its name because of its midline vestibulo- and olivocerebellar fibers, which project to the deep, medial-lying cerebellar fastigial nuclei. It is important for equilibrium and eye movements.

Alcohol Toxicity

Acute Toxicity

• Let's use acute alcohol intoxication, in which there is toxicity to the entire cerebellum, to list the key pathologic findings the stem from toxicity to each cerebellar module:
  • Spinocerebellar toxicity causes truncal ataxia.
  • Pontocerebellar toxicity causes incoordination.
  • Vestibulocerebellar toxicity causes nystagmus.

Chronic Toxicity

• Note that chronic alcohol toxicity, which causes anterior superior cerebellar vermian degeneration, which leads to truncal ataxia. This is easily missed, if we fail to ask our patients to stand during the exam.

Ataxia

Finally, let's address some key ataxia syndromes; we'll divide them based on their inheritance patterns:

Autosomal Recessive:

• Friedreich's ataxia (FA), which notably manifests with arreflexia (from the neuropathic component) but also pathologic reflexes (eg, Babinski sign).
  • Remember that this mixed pattern can also present in subacute combined degeneration from Vitamin B12 deficiency: ataxia (from dorsal column degeneration), pathologic reflexes (from the myelopathy), arreflexia (from neuropathy).
• Ataxia with Vitamin E Deficiency, which is far more rare than FA but presents similarly, and, importantly, vitamin E repletion can halt the progression of the disease.

Autosomal dominant:

• Spinocerebellar ataxias (SCAs), which we generally divide into the pure cerebellar disorders and the ataxias with extra-cerebellar signs, as well (see below for details).
• Episodic ataxias, which most notably, cause ataxia attacks. There are currently 7 types of episodic ataxia, but, importantly, EA1 and EA2 respond to pharmacological treatment (Both respond to acetazolamide, EA2 also responds to dalfampridine (4-aminopyridine), which we use in multiple sclerosis).

X-linked disorders:

• Mitochondrial disorders (eg, MERRF)
• Fragile X-tremor/ataxia
• X-linked adrenoleukodystrophy

Sporadic:

• Finally, as an example of an important sporadic syndrome, include multiple systems atrophy (MSA), which as we learn elsewhere is an atypical parkinsonian disorder that involves autonomic dysfunction + cerebellar disease or parkinsonism.

SPINOCEREBELLAR ATAXIAS

• There are greater than 30 SCAs, so we'll limit our review to the most common: SCAs 1, 2, 3, 6, 7, and DRPLA, which account for 50 – 75% of the cases, worldwide, and all of which are expanded exon-coding CAG repeat disorders. The SCAs comprise a variety of autosomal dominant mutations in addition to the expanded exon-coding CAG repeat mutations (eg, non-coding region expansion mutations and other conventional mutations).
• We'll categorize these into their Harding Classification of Autosomal Dominant Cerebellar Ataxias (ADCA I – III) to help group them by their clinical phenotypes.

ADCA 1

ADCA 1 are ataxias that also share any of the following features: ophthalmoplegia with or without optic atrophy, extrapyramidal features, dementia, extrapyramidal features, and/or amyotrophy.

• SCA1 manifests with ataxia along with, most notably, pyramidal tract signs and slowing of saccades to the point of ophthalmoplegia.
• SCA2 has a similar clinical phenotype to SCA1 but with slow saccades early-on.
• SCA3 (Machado-Joseph disease) is the most common SCA, worldwide, and, in addition to ataxia, notably, has features of levodopa-responsive parkinsonism (making it key part of the atypical parkinsonism differential), brainstem and ophthalmologic signs, amyotrophy, and polyneuropathy.
• DRPLA (Dentatorubral-Pallidolusian Atrophy), which, as a simplification, we can think of as Japanese Huntington's disease with atrophy of the brainstem and cerebellum, since most cases are from Japan and because of the overlap in symptomatology, and because the atrophy in HD it is the caudate whereas in DRPLA it is the brainstem and cerebellum. However, there are notable differences in the disorders that are beyond our scope, here.

ADCA 2

ADCA 2 is most easily thought of as ADCA 1 plus pigmentary retinal degeneration

• SCA7 most notably presents with severe visual loss from maculopathy, along with numerous other signs similar to SCAs 1 – 3.

ADCA 3

ADCA 3 is a pure cerebellar syndrome (with later age of onset, typically)

• SC6 presents as a benign, slowly progressive ataxia, typically in the 50s to 60s; accordingly the pathology is confined to the cerebellum.

Hypokinetic movement disorders, Part 1 – Parkinson's disease

Overview of Hypokinetic Movement Disorders

Here, we'll learn about the hypokinetic movement disorders in two parts.

• Start a table.
• Denote that in part 1, we'll address Parkinson's disease (PD): the prototypical hypokinetic movement disorder.
• Denote that in part 2, we'll address atypical parkinsonian syndromes.

Atypical Parkinsonian Syndrome Highlights:

• Progressive supranuclear palsy (PSP), which involves early gait instability and falls.
• Multiple systems atrophy (MSA), which involves autonomic, extrapyramidal, and cerebellar disease.
• Corticobasal degeneration (CBD), which involves cerebrocortical and basal ganglia degeneration.

Parkinson's Disease - Highlights

• Denote that the clinical hallmarks of PD are asymmetric bradykinesia, muscle rigidity, and tremor.
• Denote that the pathologic hallmark of PD is loss of dopaminergic cells in the substantia nigra pars compacta, within the midbrain and the build-up of Lewy bodies – abnormal neuronal inclusions of alpha-synuclein.

Histopathology: Overview

• Indicate that we can group these disorders based on their histopathology:
• Immunohistochemistry demonstrates alpha-synuclein in PD and MSA whereas it demonstrates tau protein in PSP and CBD.

Parkinson's disease: Clinical Hallmarks

Let's now address PD

• First, let's examine the clinical hallmarks, from top to bottom.

Masked Facies

• Begin with masked faces: draw a face with a wide-eyed stare and indicate immobility of facial muscles.

Rest Tremor

• Next, draw a hand in a 4-6 hz oscillatory tremor.
• Indicate that it can involve the elbow (flexion/extension); the forearm (pronation/supination); the fingers (pill-rolling).
  • For the pill-rolling component, draw circular movements of the fingertips against the thumb, as if the patient is trying to roll a small pill in the tips of the fingers.
• Most importantly, however, write that it is prominent at rest but extinguishes with action, which distinguishes it from essential tremor, which is absent at rest but prominent with action.

Gait & Tone

Now, let's show how gait and tone are affected.

• Draw an upper torso and head hunched forward in a stooped posture.
• With an arrow, illustrate the forward tilt.
• Indicate the prominent rigidity by showing the elbows and wrists in flexion.
• Also, draw a pair of legs falling because we have to remember to assess for the shuffling, short-stepped gait that results in frequent falls; this can be the most dangerous aspect of the disorder.

Parkinson's disease: Pathological Hallmarks

Next, let's address the pathological hallmarks of PD.

Gross Pathology

• Draw a midbrain in anatomical view – label one half as normal and the other half as having PD.
  • We can use this as a reminder that the disorder is asymmetric at onset and the affected side remains worse throughout the progression of the disorder.
• Draw some key landmarks, from posterior to anterior:
  • The red nuclei (think: rubralspinal tract)
  • Substantia nigra (pars compacta, posteriorly, and pars reticulata, anteriorly)
  • The crus cerebri (which carry the descending corticobulbar and corticospinal tracts).
  • On the normal side, show that the pars compacta is highly pigmented (it's melanin-rich).
• On the affected side, show that the pars compacta is pale and degenerated.

Histopathology

• Now, for the histology of the substantia nigra pars compacta, on the normal side, using H&E staining, show a slew of cortical neurons that are filled with neuromelanin – these are dopaminergic neurons.
• On the abnormal side, show severe neuronal loss (dropout of neurons).
• Next, add in Lewy bodies – show one in expanded view; these are intraneuronal cytoplasmic inclusions (conglomerations of abnormal protein) primarily comprised of alpha-synuclein.
• To identify these on histopathology, show that we use alpha-synuclein staining.
• Redraw the slide and show a few neurons, here, with darkly stained Lewy bodies, from immunoreactivity with alpha-synuclein; they reside within the neuronal perikarya.
• Again, draw a neuron in expanded view so we can appreciate how heavily these cytoplasmic inclusions stain with synuclein.
• Also, draw Lewy neurites within the histological section, which are unbranched, elongated alpha-synuclein stained filaments within the cell processes (vs the neuronal perikarya (the site of Lewy bodies)).

Parkinson's disease: Pharmacotherapy

Now, let's address some of the basics of PD pharmacotherapy; we discuss the details of this pharmacotherapy and basal ganglia physiology, separately.

• Indicate that we will address the essentials of dopamine replacement therapy.
• Draw a body and label it as the periphery. Then, draw a brain.
• Indicate that levodopa (L-DOPA) passes through the periphery to enter the brain.
• Show that an L-amino acid transporter regulates levodopa transport into the brain.
• Then, indicate that via dopa decarboxylase, levodopa converts to dopamine.
• Levodopa is used in conjunction with carbidopa, which provides peripheral DOPA decarboxylation inhibition (we don't want peripheral dopaminergic excitation). Instead it increases the circulating concentration of L-DOPA in the brain where it's intended.
• Specify that levodopa (and other PD meds) primarily act stimulate D2 receptors within the basal ganglia (there are two main classes: D1 (direct pathway) and D2 (indirect pathway), which we address in the basal ganglia physiology tutorial).

Parkinson's disease: Parkinson's Genetics

Lastly, let's address some key aspects of the genetics of PD. As a background:

• Idiopathic PD stems from a combination of numerous genetic and environmental effects.
• Less than 30% of PD patients claim a familial history of PD but idiopathic PD can still come from spontaneous AD gene mutations.
• Siblings of patients with PD have at least a 6-fold risk of developing the disease; those with early-onset PD are at greater risk than those with late-onset.

Now let's list out some causes of Mendelian Parkinson's disease. Indicate that we'll divide the genetic causes of PD into the:

• Autosomal dominant
• Autosomal recessive

Just as with neuropathy, there are many causes and so we'll focus on the 5 of the most common currently identified causes.

Autosomal Dominant (AD)

• LRRK2 gene mutation (Leucine Rich Repeat Kinase 2), which codes for dardarin; its functions are still not fully understood but for our purposes it helps to know that dardarin means "tremor" (from the Basque (northern Spain) word dardara).
• SNCA gene mutation (Synuclein Alpha), which codes for alpha-synuclein (remember this is primary component of Lewy bodies, the major neuropathologic neuronal inclusion in PD).

Autosomal Recessive (AR)

• PRKN (Parkin RBR E3 ubiquitin protein ligase) gene mutation; it codes for Parkin, a key degradative protein (it tags proteins meant for degradation with ubiquitin). Fortunately, parkin is an easy protein name to remember.
• PINK1 (PTEN induced kinase 1 (protein)) gene mutation, which codes for mitochondrial protein. Mitochondrial protein dysfunction leads to neuronal death due to failure of energy metabolism.
• PARK7 (Parkinsonism associated deglycase), which is important in the management of oxidative stress. Dysregulation of oxidative stress leads to neuronal death.

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