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Tremor, Tics, & Other Hyperkinetic Disorders

Notes

Tremor, Tics, & Other Hyperkinetic Disorders

Sections






Overview

Involuntary Movements

  • The involuntary movement disorders we'll address are:
  • Tremor, which is a rhythmic oscillatory movement.
    • It can be subdivided to tremors at rest (eg, Parkinson's disease) and tremors with action (eg, essential tremor and enhanced physiologic tremor).
  • Chorea, which comprises brief, irregular, quasi-purposeful-appearing movements that flow from one body part to another.
    • We can divide chorea into the neurodegenerative causes (eg, Huntington's disease) and the sporadic (aka acquired) causes (eg, Sydenham's chorea).
  • Next, we'll distinguish a series of abnormal movements as tics, twitches, or dystonia.
    • Tics are suppressible (eg, Tourette syndrome)
    • Twitches are NON-suppressible (eg, hemifacial spasm)
    • Dystonia is sustained (eg, cervical dystonia, blepharospasm)

Imbalanced Movements

Clinical Correlation: Ataxia & Incoordination

  • For the voluntary hyperkinetic movement disorders, we'll focus on ataxia.
  • Ataxia describes incoordinated movement: patients appear jerky, unsteady, and off-balance. This category is so broad that we'll focus our efforts on two key concepts:
    • Localization via the cerebellar modules; this is an especially useful bit on knowledge to tackle the major acquired causes of ataxia: stroke, malignancy and other structural causes, cerebellitis, etc...
    • Syndromes, in which we'll focus on some key causes of ataxia: spinocerebellar ataxia (SCA), Freidreich ataxia (FA), episodic ataxia (EA), fragile X-associated tremor/ataxia, etc....

Tremor

General Characteristics

We will focus on three forms of tremor:

  • Parkinsonian
  • Essential
  • Enhanced Physiologic

Parkinsonian Tremor

  • For Parkinson's disease, indicate that there can be an asymmetric, rest tremor.
    • Meaning it typically begins on one side before the other and predominates on that side throughout the progression of the illness and it is most prominent at rest and resolves with action.
  • Draw a hand with a rest tremor and show pill-rolling circular motion of the index finger and thumb, which is characteristic of this tremor that notably resolves with action.

Essential Tremor

  • Next, for essential tremor, indicate that there is typically a symmetric, kinetic tremor.
    • Meaning it effects both sides equally (although there is still often some asymmetry) and it worsens with particular actions (eg, writing or eating).
  • Draw someone bringing a spoonful of soup towards the mouth: this is a classic challenge for patients with essential tremor.
    • Whereas with a Parkinsonian tremor, the action will dampen the tremor; in essential tremor, the action amplifies the tremor.
  • Also, indicate that alcohol characteristically dampens the tremor and as a major differentiator from parkinsonism, muscle tone is normal in essential tremor (it rigid with parkinsonism).

Enhanced Physiologic Tremor

  • Now, indicate that enhanced physiologic tremor is symmetric and invariable.
    • Meaning it effects both sides equally and does not change throughout rest and activity.
    • On exam, it's notable that on finger to nose testing, the tremor is the same throughout the action: there is no intentional component. Essential tremor, instead, will typically accentuate as the patient reaches the tip of the examiner's finger.
  • Draw a cup of coffee and indicate that stress and caffeine accentuate this tremor.

Amplitude & Frequency

Before we move on, let's address the difference in amplitude and frequency of these tremors:

  • Parkinson's tremor is high amplitude but slow frequency (4 – 6 Hz).
  • Essential tremor is mid amplitude and is also mid frequency (5 – 8 Hz).
  • Enhanced physiologic tremor is low amplitude but high frequency (8 – 12 Hz).

Wilson's Disease

Next, we will address Wilson's disease.

Demographics

  • Prevalence: 3/100,000
  • Hepatic symptoms begin in childhood/adolescence (~ 11yo) and are multivariate.
  • Neurologic manifestations present in adolescence/early adulthood (~ 19yo).

Hepato- Degeneration

  • Indicate that it can result from any of several hundred mutations in the ATP7B gene on chromosome 13.
  • Write out the "Hepato-" portion of the name and draw a liver.
  • Show that ATP7B gene mutation results in elevated in liver copper, secondary to a biochemical defect in copper metabolism (specifically a failure of incorporation of copper into apoceruloplasmin which results in low ceruloplasmin levels), which results in an impairment of biliary excretion of copper (and a back-up of copper in the liver).
    • Thus, the liver is the initial site of toxicity from copper accumulation (~ 25% of cases will first present with acute hepatitis). As well, elevated copper levels on liver biopsy is the gold standard diagnostic test (in the appropriate clinical setting).
  • Note that in addition to fulminant hepatitis, copper release can disseminate to numerous organs and cause many systemic manifestations, including "sunflower catarcts" or skin pigmentary changes; renal, cardiac, skeletal, and endocrine disease; and an acute intravascular hemolysis is an especially worrisome complication.

Kayser-Fleischer Rings

  • Now, draw an eye.
  • Show release of nonceruloplasmin-bound copper into the bloodstream, which occurs once the liver is overloaded with copper and indicate that it forms Kayser-Fleischer rings (K-F rings): gold/greenish/brown rings at the outer rim of the cornea.
    • They form when copper complexes with sulfur in Descemet's membrane. As we show, they begin superiorly, so they can hide under the eyelid and they may require a slit-lamp examination to be observed.

Diagnostic Testing

  • Then, indicate that in symptomatic Wilson's disease, when copper spills out of the liver into the circulation, we detect high urine copper levels on 24-hour urinary copper excretion testing.
  • As well, indicate that we detect LOW serum ceruLOplasmin levels because of an associated apoceruloplasminemia, due to failure of incorporation of copper into apoceruloplasmin.
  • And we detect a HIGH free copper level, which is tricky because the total copper can be low. # In our notes, we address a few conditions to be aware of when interpreting diagnostic tests in Wilson's disease.

Caveats in Diagnostic Testing

  1. Ceruloplasmin can be normal or elevated because it is an acute phase reactant and its levels can spike in an inflammatory condition.
  2. Urine copper will only be elevated once copper has spilled out of the liver into the bloodstream.
  3. Total copper levels can be low because they are directly tied to ceruloplasmin levels, since ~90% of copper is bound to ceruloplasmin.For these reasons, in the appropriate clinical setting, liver biopsy to look for elevated copper is the best diagnostic tool. We address the full pathophysiology in our notes, which will help us understand serum copper and ceruloplasmin levels.

Lenticular Degeneration

Wing-beating tremor

  • Indicate that it manifests with a characteristic coarse, proximal wing-beating tremor, which refers to when the patient holds his/her arms up in a winged position, the arms appear to flap, as if there is a pair of wings on the patient's shoulders.
    • Note that this tremor can be found elsewhere, as well, such as in essential tremor.

Additional Manifestations

  • Also, note that a variety of movement disorders, such as other tremors; dysarthria; dystonia; gait abnormalities; chorea; and tics can be seen, as can neuropsychiatric manifestations.

"Face of the Panda" Sign on MRI

  • Finally, let's draw the "Face of the Panda" sign, which is a common MRI finding in Wilson's disease (and also Leigh disease).
  • Draw an outline of the midbrain.
  • Shade in the normal gray appearance on T2-weighted MRI imaging.
  • Next, show the pathology, which is a loss of this intensity in the center of the midbrain (hypointensity on T2-weighted imaging).
  • Include the dark red nuclei (the eyes) and the dark substantia nigra, (the ears). There is also hypointensity of the superior colliculus.

Details Regarding Wilson's Disease Genetics

  • Wilson's disease is an autosomal recessive disorder that can result from any of several hundred mutations in the ATP7B gene on chromosome 13. The numerous potential combinations of heterozygous mutations that lead to Wilson's disease has made it nearly impossible to create a coherent genotype–phenotype correlation but the pathophysiology, itself, is well understood. The ATP7B gene produces copper-transporting ATPase 2, a key transporter of hepatic copper into the bile, thus the underlying pathophysiology results from a characteristic reduction of copper excretion into the bile. As well, there is also reduced incorporation of copper into ceruloplasmin, which contains six copper atoms per molecule and is primarily synthesized in the liver. The ATP7B gene is key to the incorporation of copper into apoceruloplasmin, thus in Wilson's disease, there is typically reduced circulating levels of ceruloplasmin. However, because ceruloplasmin is an acute phase reactant, it may be spuriously normal secondary to active inflammation.
  • The ATP7B gene mutation causes low ceruloplasmin levels and copper accumulation and, as expected, free copper (non-ceruloplasmin bound) levels will be elevated. But total serum copper levels combine both free copper (which is the toxic component) and ceruloplasmin-bound copper (which comprises ~ 90% of total copper), so total copper can be low because the ceruloplasmin, itself, is low.

CHOREA

Overview

  • Draw a human being demonstrating choreiform movements, which are brief, irregular, random quasi-purposeful-appearing movements that flow from one body part to another.
  • We'll specifically address Huntington's disease, which affects ~ 1/10,000 in the Western World, and Sydenham's chorea, which is the most common cause of acute onset chorea in childhood, but there are numerous other causes of chorea beyond our scope, here.

Huntington's disease

See more regarding Huntington's disease.

Genetics

  • Indicate that Huntington's disease is secondary to a mutation on the short arm of chromosome 4, in the HTT (aka IT15) gene: a CAG trinucleotide repeat, which encodes for the huntingtin protein. It encodes a polyglutamine ('polyQ') stretch at the N-terminus of the huntingtin protein.
  • Indicate that HD is an autosomal dominant disorder with significant genetic anticipation: the sequence length is unstable and can expand during meiosis, especially down paternal inheritance lines.
  • The anticipation helps us remember that this is a trinucleotide repeat disorder, specifically a CAG repeat disorder:
    • Note that Huntington's disease (CAG), myotonic dystrophy (CTG), and fragile X syndrome CGG) are the three classic trinucleotide repeat expansion disorders: the trinucleotide sequence is repeated many times in a row.
    • Additional CAG repeat disorders include: Kennedy's disease (aka X-linked spinal and bulbar muscular atrophy), spinocerebellar ataxia type 1 (SCA 1) and type 3 (SCA3, aka Machado-Joseph disease).

Pathology ("CAG" mneomnic)

  • Let's use the acronym CAG to highlight some key aspects of HD neuropathology:
  • On gross examination, there is caudate (C) and putamen (aka striatum) atrophy (A) with resultant anterior horn dilatation.
  • Accordingly, there is a loss of striatal GABAergic (G) medium spiny neurons, which is what primarily constitutes the striatum.

Mneomnic via Number 4

Now, as a menomnic, let's use the number "4" to add in some core features of HD:

  • The HD gene is on chromosome 4
  • Greater than 40 CAG repeats is abnormal (but, truly, anything more than 36 can be symptomatic)
  • The average age of onset is 40 years-old but the longer the repeat length, the earlier the age of onset.
    • Onset younger than 20 years old, is referred to as Juvenile HD; it manifests with an akinetic-rigid syndrome, rather than chorea, referred to as the Westphal variant, which is typically the end-stage of HD in adults.

Clinical Manifestations

  • Finally, indicate that HD is predominantly a neuropsychiatric and movement disorder.
  • As a helpful visual, it's often mistaken as alcoholism early on but ultimately becomes parkinsonian, later. As well, typical survival from onset is 15 years, much like the timeline of degeneration in Parkinson's disease.

Clinical Progression

Clinical progression involves the following key domains.

  • Psychiatric. Depression and anxiety, early, and obsessive/compulsive thoughts, profound apathy, and physical aggression, later. Note that suicide is the 2nd most common cause of death in HD.
  • Cognitive. Executive dysfunction, early, such as trouble with organizational tasks, planning, and task sequencing.
  • Simple abnormal involuntary movements: tics, dystonia, myoclonus.
  • Complex abnormal involuntary movements: Chorea (excessive movements that flow from body part to body part).
  • Failure of voluntary movements: Akinetic, rigid syndrome (parkinsonism).

Sydenham's chorea

See more regarding Sydenham's chorea.

Key Features

  • Indicate that it is characterized by acute onset (w/in hours) asymmetric chorea.
    • The chorea is of the entire body, including the face and tongue (called serpent tongue).
  • It typically arises in childhood/adolescence (5 to 15 years old).
    • Females more commonly than males.
  • It arises anywhere from weeks to months (7 to 180 days) following group A beta-hemolytic streptococcal infection (typically manifesting with pharyngitis).
  • The pathology involves an autoimmune attack of the basal ganglia, most likely.
  • The symptoms resolve within weeks to months (21 – 180 days) but can return in adulthood, especially during the 1st trimester of pregnancy (called: chorea gravidarum).

Additional Features

  • Additional manifestations include motor impairment (eg, incoordination, gait abnormality, impairment of activities of daily living), flaccid muscle weakness, and psychological and behavioral issues (eg, anxiety, depression, obsessive compulsive behaviors (along with tics)) accompany the chorea.
  • High blood titers of streptococcal antibodies (ASO and antiDNAseB) and rheumatic heart disease (see below) can support the diagnosis.
  • Treatment typically involves: chorea suppressing medication (eg, haloperidol or tetrabenazine); antibiotic therapy to prevent rheumatic heart disease; short-term immune therapy.

Sydenham's Chorea & Rheumatic Fever

  • Sydenham's chorea may occur independently or as part of acute rheumatic fever.
  • JONES criteria:
    • J (Joints): Polyarthritis
    • O (looks like a heart): Cardiomyopathy (also, antistreptolysin O titre)
    • N: Nodules
    • E: Erythema marginatum
    • S: Sydenham chorea

Hemiballismus

  • Hemiballismus presents with an acute onset of asymmetric, nonsuppressible, choreiform-like movements. However, the movements are wild and ballistic (flinging), typically of the proximal arm or leg and classically due to a stroke in the contralateral subthalamic nucleus.
  • The pathology can be due to injury in more widespread regions, including the thalamus, caudate, and putamen, and the pathogenesis can be due to a variety of structural or metabolic causes, including, notably, nonketotic hyperglycemia.
  • In contrast to chorea, the movements are more pronounced and forceful, more rapid, and more proximally distributed.

Tics, Twitches, & Dystonia

Tics

Key Points

  • 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).

Additional 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

Twitches

  • Indicate that, in contrast to tics, 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

Overview

  • Dystonia 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 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

Cerebellar 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

  • 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.

Somatotopic/Functional Modules

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 Syndromes

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.

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