Movement Disorders

Parkinson’s Disease

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A

B

Figure 8–1 (A) normal basal ganglia function. (B) Basal ganglia function in Parkinson’s disease.

Table 8–1 Familial Parkinson’s Disease

3.Symptoms: onset is typically 50–60 years of age in patients with sporadic Parkinson’s disease; a younger age of onset suggests an inherited form

a.initially presents as a unilateral resting tremor, bradykinesia, or limb stiffness; progressive rigidity and bradykinesia eventually will become bilateral and will involve freezing episodes and dysphagia

i.progression involves hypophonia, dysarthria, dysphagia, and an expressionless face

ii.symptoms are slowly progressive, presenting asymmetrically or unilaterally

iii.symptoms most commonly begin in the upper extremities, but occasionally may initiate in the lower extremities or jaw (particularly with tremor)

b.depression (50%)

c.dementia (30%): half of demented Parkinson’s disease patients have no other pathological cause, but 35% exhibit Alzheimer’s-like histological changes

d.restless legs syndrome; akathisia; REM sleep behavioral disorder (see pp. 169–170)

e.autonomic symptoms (urinary urgency, constipation {intestinal pseudoobstruction}, sexual dysfunction) and oculomotor abnormalities are mild and develop only late in the disease course

i.20% of patients develop significant orthostatic hypotension often due to medication side effects, but this can represent the misdiagnosis of a multisystem atrophy disorder

f.dementia develops in 30% of patients with advanced disease

4.Treatment (Table 8–2)

i.management of autonomic dysfunction

(1)orthostatic hypotension

(a)nonpharmacological treatments: graded position changes; avoid Valsalva maneuvers; squatting or flexing of the lower extremity musculature prior to standing; increase fluid and salt intake; lower extremity compressive garments

(b)pharmacological treatments

(i)fludrocortisone

(ii)midodrine, ephedrine, pseudoephedrine, methylphenidate

(iii)desmopressin acetate (ddAVP); erythropoietin; caffeine

(2)bladder hyperactivity: reduce drinking in the evening; anticholinergic medications (oxybutynin, propantheline)

(3)constipation: dietary modification and stool softeners; discontinuing anticholinergic medications

ii.management of side effects of medical treatment

(1)“off”/freezing phenomenon

(a)combine a dopamine agonist with Sinemet

(b)increase the frequency of combined medications

(c)substitute or add a sustained-release preparations of Sinemet

(2)dyskinesia/dystonia

(a)occurring with the peak in drug levels (“on” dyskinesia/ dystonia)

(i)lower the dose of dopamine agonists or Sinemet

(ii)substitute sustained-release preparations of Sinemet for shorter-acting medications

(iii)add a catechol-O-methyltransferase (COMT) antagonist

(iv)consider neurosurgical intervention

(b)occurring a minimal drug levels (“off” dyskinesia/dystonia)

(i)evening “off” dyskinesia: add sustained-release Sinemet in the evening

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(1)thalamotomy: targets the ventral intermediate nucleus

(a)improves only tremor, therefore not often used in Parkinson’s disease

(b)not effective against bradykinesia, and may exacerbate hypophonia and gait abnormalities; avoid bilateral procedures due to cognitive impairment

(2)pallidotomy: targets the posterolateral region of the internal globus pallidus to avoid impairment of memory and cognitive function

(a)effective against all major Parkinson’s disease symptoms and dyskinesias

(b)limited to a unilateral procedure due to high incidence of cognitive impairment with bilateral procedures

ii.deep brain stimulator procedures: over stimulation may produce dyskinesias

(1)thalamic stimulation: effectiveness as per thalamotomy, but fewer side effects

(2)globus pallidus stimulation: effectiveness as per pallidotomy, but fewer side effects; bilateral stimulation has pronounced benefits for gait abnormalities

(3)subthalamic stimulation: most effective surgical procedure for bradykinesia, and is effective for all other major Parkinson’s disease symptoms; bilateral stimulation has pronounced benefits for gait abnormalities

II.Progressive Supranuclear Palsy (PSP) (Box 8.3)

1.Pathophysiology: Gliosis and neuron loss predominantly in the frontal cortex, globus pallidus, substantia nigra, and mesencephalic nuclei

a.histology: affected areas exhibit Alzheimer’s disease-like neurofibrillary tangles (with hyperphosphorylated tau protein) and neuropil threads

i.D2 receptors in the basal ganglia are reduced, unlike Parkinson’s disease where they are increased; this likely reflects the loss of cholinergic striatal interneurons in PSP (see p. 11)

b.genetics

i.90% of sporadic cases are associated with homozygous H1 alleles of the tau gene, although 60% of normal people also are homozygous for the H1 allele

ii.families with autosomal dominant inheritance patterns have been described

2.Symptoms: develop between 60–70 years of age

a.axial rigidity limb rigidity, leading to an abnormal gait and falls early in the disease (particularly backward falls, unlike Parkinson’s disease patients who fall forward)

b.cortical-type dysarthria; hypophonia

c.reduced voluntary saccades, particularly a vertical gaze palsy involving downward upward gaze; voluntary smooth pursuit movements become impaired thereafter

i.involuntary (vestibulo-ocular) eye movements are preserved until late in the disease

3.Diagnostic testing: loss of saccadic fast-phase on optokinetic testing may distinguish early PSP from Parkinson’s disease

4.Treatment: none specific

5.Prognosis: usually fatal within 6 years

Progressive Supranuclear Palsy (PSP)

Box 8.3

The tau-opathies—Alzheimer’s disease, frontotemporal lobar degeneration/Pick’s disease; cortical-basal ganglionic degeneration; progressive supranuclear palsy

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III. Cortical-Basal Ganglionic Degeneration

1.Pathophysiology: Gliosis with neuronal loss and vacuolation in cortical layers III–V (like frontotemporal lobar degeneration/Pick’s disease), the basal ganglia, and the substantia nigra; depigmentation of the substantia nigra also occurs

a.surviving neurons exhibit accumulations of hyperphosphorylated tau

b.genetics: associated with the H1 allele of the tau gene, as per PSP

2.Symptoms: develop 60 years of age; symptoms occur in a random order and may relapse and remit, but they all are concentrated initially in one limb

a.subcortical symptoms: Parkinsonism; postural and/or action tremor; limb dystonia; reflex myoclonus

b.cortical symptoms: dementia similar to frontotemporal lobar degeneration (see p. 160); apraxia (e.g., constructional dyspraxia); cortical sensory loss; weakness

i.Gerstmann’s syndrome and alien-hand syndrome is a rare complication of corticobasal ganglionic degeneration

3.Diagnostic testing: MRI may reveal regional degeneration in frontal and parietal cortex

4.Treatment: none specific

5.Prognosis: symptoms remain focally in one limb for several years, but eventually progress to involve other limbs; severe dysphagia eventually develops

IV. Multiple System Atrophy (MSA)

1.General histology: exhibits multiple types of inclusion bodies to varying degrees; the most typical for MSAs are

a.an argentophilic cytoplasmic inclusion in neurons and glia that resemble neuropil threads but that contain only ubiquitin and no tau protein

b.a flame-shaped glial cytoplasmic inclusion similar to the neurofibrillary tangles of Alzheimer’s disease but that do not contain tau protein

2.The old classification scheme

a.olivopontocerebellar degeneration (OPCD)—idiopathic degeneration of the inferior olivary nuclei, ventral pontine nuclei, and cerebellar cortex with relative preservation of the substantia nigra and striatum

b.striatonigral degeneration—idiopathic degeneration of the putamen and substantia nigra with relative preservation of the globus pallidus, caudate, and subthalamic nucleus

c.Shy-Drager syndrome—idiopathic degeneration of the intermediolateral cell column in thoracic and lumbar spinal cord, the dorsal motor nucleus of the vagus, and in the sympathetic chain ganglia

3.The new classification scheme: The Shy-Drager syndrome has been eliminated because autonomic dysfunction is present in all types of multiple-system atrophy

a.multiple system atrophy with predominant parkinsonian features (MSA-P)/striatonigral degeneration form of MSA

i.histology: the pattern of degeneration is as for striatonigral degeneration Shy-Drager syndrome

(1)despite pronounced Parkinsonian features, does not have Lewy bodies, neurofibrillary tangles, or even many of the MSA inclusion bodies in the surviving neurons of substantia nigra

ii.epidemiology: sporadic occurrence only

iii.symptoms: bradykinesia, rigidity, autonomic dysfunction; less commonly involves myoclonus, neck anteroflexion, or dysarthria

Dystonias

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a.primary dystonias (Table 8–3)

b.secondary dystonias

i.neurodegenerative disorder-related dystonias: Parkinson’s disease, multiple-system atrophies, progressive supranuclear palsy, corticobasal ganglionic degeneration, spinocerebellar atrophies (particularly

Table 8–3 Primary Dystonias

Note: Dark gray primary dystonias with parkinsonian features; light gray primary dystonias with choreoathetosis.

Abbreviations: AD, autosomal dominant; GTP, guanosine 5 -triphosphate.

Figure 8–4 Biosynthesis of dopamine, norepinephrine, and epinephrine.

Box 8.5

GTP cyclohydrolase I synthesizes tetrahydrobiopterin cofactor for DA synthesis.

Box 8.6

Tyrosine hydroxylase is directly involved in DA synthesis.

Box 8.7

Localize to the same region of chromosome 16 as benign familial infantile convulsions

Box 8.8

Other sarcoglycans are mutated in autosomal recessive limb-girdle muscular dystrophy

Machado-Joseph’s disease/SCA-3), ataxic telangiectasia, Huntington’s disease, dentatorubropallidoluysian atrophy (DRPLA)

ii.autoimmune: related to antibasal ganglia antibodies, which occur in 65% of patients with atypical dystonia; probably these antibodies are a reaction to a Streptococcus infection similar to Sydenham’s chorea and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS syndrome; see p. 193)

iii.disorders of metal overload: Wilson’s disease, Hallervorden-Spatz disease

iv.leukodystrophies, particularly metachromatic leukodystrophy

v.metabolic diseases of the nervous system: ceroid lipofuscinosis, methylmalonic academia, aromatic amino acid decarboxylase deficiency, homocystinuria, Lesch-Nyhan’s disease

vi.acquired conditions: biopterin deficiency (due to failure of dopamine synthesis), basal ganglia injury

vii.neuroacanthocytosis (see p. 193)

viii.complex regional pain syndrome I/reflex sympathetic dystrophy

ix.iatrogenic: dopamine antagonists (cocaine, amphetamines, antipsychotics); dopamine agonists

3.Subtypes of dystonia by age groups

a.childhoodand adolescent-onset dystonias typically develop in lower extremities and progress to involve other body parts

b.adult-onset dystonias typically develop in the upper extremities or head, and do not progress

4.Symptoms

a.slow, sustained, and repetitive twisting and flexion movements and/or posturing, with normal muscle tone between episodes; may involve a degree of tremulousness, but unlike true tremor dystonic movements have a significant directional component

i.often dystonia movements become painful, particularly if they are prolonged

ii.dystonic movements can be triggered by specific activities involving the affected muscles (e.g., writer’s cramp triggered by the act of writing) or by emotional states

iii.dystonic movements may be aborted or broken by sensory stimulation (usually touch) to specific parts of the body (usually the dystonic region)

b.subtypes of dystonia by symptoms

i.focal dystonias

(1)cervical dystonias: rotation {torticollis}, extension {retrocollis}, flexion {anterocollis}, or abduction {laterocollis} of the head

(2)blepharospasm—blinking and squeezing of the orbicularis oculi muscles, may be preceded by sensation of eye irritation: often triggered by bright light

(a)typically bilateral but with a significant asymmetry

(3)Meige’s syndrome—orolingual dystonias with blepharospasm

(4)Brueghel syndrome—jaw opening with lip retraction, tongue protrusion, and platysma contraction

(5)facial/oromandibular dystonias—can involve facial, masticatory, lingual, and/or oropharynx muscles; commonly occurs with blepharospasm or cervical dystonias

(6)spastic dysphonia—dystonia of the laryngeal muscles causing the voice to become hypophonic and strained with frequent tone breaks

(7)limb dystonias

ii.multifocal dystonia, segmental dystonia, hemidystonia (rare)

iii.generalized dystonia (Box 8.9)

Box 8.9

Status dystonicus—A severe, prolonged period of dystonic posturing often preceded by increasingly frequent and prolonged episodes

Can develop out of any type of dystonia, often precipitated by changes in medications or intercurrent illness

May develop rhabdomyolysis due to prolonged muscle contraction

Requires sedation or even paralysis and ventilation if fatigue or severe pain develop

Dystonias

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5.Diagnostic testing

a.levodopa–carbidopa or anticholinergic medication trial to distinguish DOPA-responsive dystonias

b.genetic analysis for torsin-A gene (DYT1) mutations

c.routine evaluations to evaluate for the possibility of secondary causes of dystonia

i.ceruloplasmin, slip-lamp evaluation for Kayser-Fleischer rings, and 24-hour urine copper to evaluate for the possibility of Wilson’s disease

ii.neuroimaging to evaluate for basal ganglia lesions

6.Treatment

a.medical treatment

i.botulinum toxin: effective in 75% of focal dystonias

(1)clinical resistance may develop due to blocking antibodies, especially with frequent injections; this can be overcome by changing botulinum toxin serotypes

(2)the only frequent side effect is excessive local weakness or weakness in neighboring muscles

ii.carbidopa–levodopa: effective in 15% of dystonias

iii.anticholinergic agents (benztropine, trihexyphenidyl): effective in 40% of dystonias but limited use because of side effects

iv.muscle relaxants: baclofen, tizanidine, cyclobenzaprine

(1)intrathecal baclofen is unlikely to be of benefit if baclofen given orally was not effective

v.clonazepam, gabapentin

b.surgical treatment: for patients who have failed medical therapy

i.lesion procedures

(1)rhizotomy, myomectomy: for focal dystonia

(2)thalamotomy: has a high rate of complications, particularly dysarthria and cognitive impairment

(a)bilateral thalamotomy for generalized dystonia

(b)contralateral thalamotomy for segmental dystonia

(3)pallidotomy: fewer side effects than thalamotomy

ii.deep brain stimulation in the globus pallidus: particularly effective for early-onset dystonia (DYT1), cervical dystonias, and blepharospasm

VI. Tic Disorders

1.Pathophysiology: likely related to abnormal dopaminergic activity in the basal ganglia, leading to inappropriate cortical arousal; mild abnormalities in the size and symmetry of the basal ganglia and cortical regions are apparent, as are abnormal accumulations of dopamine and D2 receptors in the basal ganglia

2.Subtypes

a. idiopathic tic disorders

i.simple or multiple motor tics: e.g., blinking, snarling, tongue protrusion, neck stretching, finger or toe curling

ii.complex motor tics: e.g., spitting, foot stomping, teeth grinding, obscene gesturing {copropraxia}

iii.simple phonic tics: e.g., grunting, throat clearing, coughing

iv.complex phonic tics: e.g., unintelligible wordor stuttering-like utterances

v.Tourette’s syndrome: combination of multiple motor tics and at least one phonic tic that begins at 20 years of age

(1)most cases are sporadic, but can exhibit polygenic inheritance with variable penetrance

b.secondary tic disorders

i.posttraumatic

ii.postinfectious: occurring after group A -hemolytic Streptococcus infections, typically pharyngitis

(1)PANDAS infection syndrome: develops acutely shortly after an infection; no relation to rheumatic fever

(a)neuropsychiatric symptoms is typically an obsessive– compulsive disorder

(2)Sydenham’s chorea—develops several months after an infection, spontaneously resolves after several weeks; involves both chorea and tic behaviors

(a)typically occurs in conjunction with symptoms of rheumatic fever (carditis, arthritis, subcutaneous nodules, erythema marginatum), and chorea may recur within a few years

(b)particularly common in patients with B cell alloantigen D8/17

iii.neuroacanthocytosis—a disorder characterized by spiny erythrocytes {acanthocytes} caused by an abnormality in membrane lipids; neurological abnormalities include orofacial dystonias involving mutilation of the facial soft tissues, choreiform movements, tic behaviors, behavioral changes, and a motor neuropathy

(1)autosomal recessive inheritance with linkage to chromosome 9

iv.drug-induced: amphetamines, dopaminergic agonists, antipsychotics, antiepileptics

3.Symptoms: idiopathic and postinfectious tic disorders generally have onset in childhood, whereas noninfectious secondary tic disorders have an adult onset

a.involuntary movements or vocalizations that can be transiently suppressed although they are associated with a subjective urge to perform them that builds up over time as they are suppressed; movements are jerky in nature (i.e., resembling myoclonus or clonus), but are characteristically stereotypical and coordinated

i.the type of tic behavior and its severity may change over time

ii.tics are exacerbated by stress (as are all dyskinesias), but also by relaxation

iii.vocalization of understandable words indicates Tourette’s syndrome, which also must involve multiple motor tics

b.tic disorder is associated with choreiform movements, dystonias, learning disorders, attention-deficit hyperactivity disorder, and obsessive–compulsive disorder (50%)

4.Treatment: antipsychotics (haloperidol, pimozide, risperidone), clonidine, clonazepam

a.selective serotonin reuptake inhibitors (SSRIs) reduce obsessive–compulsive behaviors but they do not reduce tic severity

5.Prognosis: idiopathic forms usually peak in severity during adolescence then spontaneously remit in early adulthood

VII. Huntington’s Disease

1.Pathophysiology: expansion of a trinucleotide repeat in the huntingtin gene on chromosome 4 that appears to cause cell death by NMDA excitotoxicity and/or abnormal activity of mitochondrial oxidative phosphorylation

a.requires 40 repeats for symptoms; 30–45 repeats may not produce symptoms, but are thought likely to increase in size in future generations

i.a larger number of repeats causes symptomatic presentation at a younger age {anticipation} and also a more severe course

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VIII. Wilson’s Disease/Hepatolenticular Degeneration

1.Pathophysiology: Autosomal recessive mutations in a membrane-bound cop- per-transporting ATPase that secretes excess copper into the bile; accumulation of copper causes degeneration of the putamen globus pallidus, caudate, cortex mesencephalic nuclei, dentate nucleus

a.histology: hyperpigmented areas from copper deposition are associated with neuronal degeneration and local demyelination that eventually will form cavitary lesions; reactive gliosis in these areas involves

i.Alzheimer glia type 1: a multinucleated astrocyte; specific for Wilson’s disease

ii.Alzheimer glia type 2: greatly enlarged astrocytes with oval nuclei (Box 8.10)

iii.Opalski cells: large cells with coarsely granular cytoplasm that are possibly derived from histiocytes (Fig. 8–6)

2.Epidemiology: Bimodal distribution

Box 8.10

Alzheimer glia type 2 are also seen in Canavan’s disease, hepatic encephalopathy, and urea cycle disorders.

Figure 8–6 Opalski cell (left) characterized by its large size and lobulated nucleus. (From Hirano A. Color Atlas of Pathology of the Nervous System, 2nd Ed. Tokyo/New York: Igaku-Shoin Press; 1988:117, Fig. 283. Reprinted by permission.)

3.Symptoms: majority of patients begin with liver disease; however, neurological and/or psychiatric symptoms can be the initial presentation

a.neurological symptoms: dysarthria progressing to anarthria; mood lability, psychosis; rest and wing-beating tremor, ataxia, dystonia; loss of postural reflexes; seizures

b.systemic symptoms

i.eye: copper deposits in Descemet’s membrane of cornea {KayserFleischer rings} are asymptomatic (Fig. 8–7) (Box 8.11)

ii.hepatitis leading to liver cirrhosis

iii.splenomegaly with hemolytic anemia

iv.bone fragility due to osteoporosis

4.Diagnostic testing: decreased serum ceruloplasmin levels (Box 8.12); elevated urine copper excretion

5.Treatment: tetrathiomolybdate; chronic penicillamine vitamin B6; zinc supplements; low copper diet

6.Prognosis: uniformly fatal without treatment; with treatment, neuropsychiatric disease improves in 50% and remains stable in 15%, whereas liver disease is reversible in only 25%

Figure 8–7 Kayser-Fleischer ring. (From Lee DA, Higginbotham. Clinical Guide to Comprehensive Ophthalmology. Stuttgart, Germany: Georg Thieme; 1999:9, Fig. 1–10. Reprinted by permission.)

Wilson’s Disease/Hepatolenticular Degeneration

Box 8.11

Kayser-Fleischer rings are present in 100% of patients with neuropsychiatric Wilson’s disease, 85% of patients with liver disease

Box 8.12

Aceruloplasminemia is similar to Wilson’s disease, but central nervous system damage is due to iron accumulation.

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IX. Amyotrophic Lateral Sclerosis (ALS)

Box 8.13

Common causes of head drop—Myasthenia, polymyositis, ALS

Hereditary Spastic Paraplegias

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Table 8–5 Hereditary Spastic Paraplegias

Note: White autosomal dominant; light gray autosomal recessive; dark gray sex-linked.

i.weakness is predominantly in tibialis anterior, biceps femoris, and iliopsoas (i.e., muscles of the triple flexion response)

ii.spasticity, particularly of the biceps femoris that causes a characteristic bent-kneed gait

b.mild lower extremity large fiber sensory loss, with preservation of small fiber sensation

c.urinary urgency due to spastic bladder

d.pes cavus, hyperlordosis

3.Subtypes (Table 8–5)

4.Diagnostic testing

a.MRI may show atrophy of thoracolumbar spinal cord

b.somatosensory evoked potentials demonstrate delayed conduction and cortical potential from the lower extremities but normal responses from the upper extremities

c.genetic testing: available only for spastic paraplegia genes SPG-4 and SPG-3; SPG-2 does not involve gene duplication of the proteolipid PLP gene as does Pelizaeus-Merzbacher disease, therefore it cannot be tested with the available PLP genetic tests

5.Treatment: none specific

6.Prognosis: progressive gait disturbance may ultimately require wheelchair; normal lifespan

a.childhood-onset subtypes generally have mild progression despite their early onset

b.severity of disease cannot be predicted by course in other family members

Box 8.15

Spastin is also mutated in distal spinal muscular atrophy.

Box 8.16

LICAM is also mutated in mental retardation, aphasia, shuffling gait, adducted thumbs (MASA) disorder and X-linked hydrocephalus disorders

Box 8.17

PLP is also mutated in Pelizaeus-Merzbacher disease

Table 8–6 Spinocerebellar Ataxias

*CACNA1A gene mutations also cause episodic ataxia type 2 and familial hemiplegic migraine.

ii.symptoms: onset typically in childhood or young adult; most exhibit anticipation with successive generations

(1)general symptoms: gait and limb ataxia, dysarthria

(2)subtypes: all have noncerebellar motor dysfunction and some sort of ocular dysfunction (Table 8–6)

b.dentatorubropallidoluysial atrophy (DRPLA)—could be considered an autosomal dominant spinocerebellar ataxia

i.pathophysiology: caused by a trinucleotide repeat in the DRPLA gene of chromosome 12, which has no known function but is located inside the nucleus

(1)histology: atrophy and gliosis in the cerebellum (particularly the dentate nucleus) and globus pallidus mesencephalon with sparing of the red nucleus, caudate, putamen, substantia nigra, and inferior olivary nucleus

(a)cerebellar atrophy may be based upon a preexisting hypoplasia

(b)subcortical demyelination is also observed

(2)more severe disease occurs with paternal inheritance

ii.epidemiology: common in Japan

iii.symptoms: onset between 10–60 years of age; involves ataxia, dementia, choreoathetosis (usually in adult-onset disease), seizures (65%), myoclonus (in 55%, usually in juvenile-onset disease), and myelopathy (only in homozygotes with long repeats)

iv.diagnostic testing: genetic testing for the DRPLA gene repeat

v.treatment: none specific

2.Autosomal recessive ataxia disorders

a.Friedreich’s ataxia—could be considered an autosomal recessive spinocerebellar ataxia

i.pathophysiology: caused by mutations in the frataxin gene, the protein of which may function in iron transport into the mitochondria

(1)mutations include

(a)trinucleotide repeats (95%): age of onset and severity proportionate to number of repeats

(b)point mutations (5%)

(2)histology: degeneration of projections from dentate nucleus, corticospinal tract, spinocerebellar tract, dorsal columns

(a)minimal involvement of cerebral or cerebellar cortices

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ii.symptoms (Box 8.18)

(1)neurological symptoms: ataxia (trunk limbs), nystagmus, dysarthria; spasticity; large-fiber sensory loss with hyporeflexia (despite a Babinski reflex); weakness

(2)systemic symptoms: hypertrophic cardiomyopathy, subaortic stenosis; scoliosis, pes cavus; diabetes mellitus

iii.diagnostic testing: genetic testing of the frataxin gene

iv.treatment: none specific for the neurological disorder; idebenone for hypertrophic cardiomyopathy

v.prognosis: death by 40 years of age; time to wheelchair dependence is shorter in females

b.ataxia-telangiectasia (AT)

i.pathophysiology: caused by mutations of AT mutant (ATM) gene, the protein of which likely acts in the control of mitosis as a tumor suppressor

(1)histology: degeneration of cerebellar cortex and dentate nucleus, inferior olive, substantia nigra, and posterior columns

ii.symptoms: onset at 1–2 years of age

(1)neurological symptoms: ataxia (trunk limbs), dysarthria; oculomotor apraxia; dystonia, choreoathetosis; large-fiber sensory neuropathy with hyporeflexia that can occur in the presence of Babinski signs

(2)systemic symptoms

(a)ocular and cutaneous telangiectasias

(b)cancer (40%), typically leukemia or lymphoma may be presenting feature of the disease

(c)diabetes mellitus; gonadal hypoplasia

(d)chronic anemia and lymphopenia; recurrent infections

(e)hirsutism

iii.diagnostic testing

(1)serology demonstrates reduced immunoglobulins (Ig) (except IgM), an oligoclonal or monoclonal gammopathy (10%), and increased-fetoprotein

(2)chromosomal analysis for 7 → 14 translocation

(3)neuroimaging demonstrates an atrophic cerebellum

iv.treatment: none specific; frequent evaluation for cancer; avoid radiation exposure

v.prognosis: 20–50 year lifespan

c.Cockayne’s syndrome (see p. 286)

3.Episodic ataxias

a.type I inherited episodic ataxia

i.pathophysiology: caused by mutations of voltage-gated potassium channel (Box 8.19)

ii.symptoms: onset between 20–30 years of age

(1)episodic symptoms: last 1–2 minutes; triggered by changes in position or emotion

(a)ataxia without nystagmus or vertigo

(b)blurred vision

(2)chronic symptoms: myokymia

iii.treatment: antiepileptics; avoid acetazolamide

b.type II inherited episodic ataxia

i.pathophysiology: caused by mutations of P/Q-type voltage-gated calcium channel (CACNA1A) gene (Box 8.20)

Box 8.18

Friedrich’s ataxia is similar to vitamin E deficiency and to abetalipoproteinemia (which also has vitamin E deficiency)

Box 8.19

This voltage-gated potassium channel is bound by paraneoplastic antibodies in Isaac’s syndrome/neuromyotonia and limbic encephalitis.

Box 8.20

The P/Q-type voltage-gated calcium channel is bound by paraneoplastic antibodies in Isaac’s syndrome/neuromyotonia and limbic encephalitis.

ii.symptoms: onset between 20–30 years of age

(1)episodic symptoms: last 10 minutes to hours; triggered by exercise or stress

(a)ataxia, nystagmus, vertigo

(b)dysarthria

(c)generalized weakness

(d)headache

(2)chronic symptoms: nystagmus, ataxia

iii.treatment: acetazolamide

XII. Stiff Man’s Syndrome

1.Pathophysiology: unknown, but is associated with

a.anti-glutamate decarboxylase (-GAD) antibodies (40%)

b.autoimmune diseases, particularly diabetes (40%)

i.80% of type I diabetics exhibit antibodies against GAD, as well as other autoantibodies

2.Symptoms: onset in adulthood

a.painful muscle spasms with rigidity in axial and facial muscles extremities that initially is intermittent but eventually becomes continuous

i.spasms are exacerbated by voluntary movements and startle, and may be associated with myoclonus

3.Diagnostic testing: serology for anti-GAD antibodies; EMG demonstrates continuous motor unit potentials in agonist and antagonist muscles at rest

4.Treatment: benzodiazepines, clonidine, baclofen, prednisone, plasma exchange, IV Ig

XIII. Essential Tremor

1.Pathophysiology: none established, but may be a neurodegenerative disease a. risk factors: increasing age, White, family history

2.Symptoms: Kinetic tremor (Box 8.21) that typically develops in the arms and spreads to the head, neck, and oropharynx over several years; severe disease also involves postural tremor and/or an irregular, jerky resting tremor (20%)

3.Diagnostic testing: Evaluate for hyperthyroidism and Wilson’s disease

4.Treatment: Propranolol, primidone

Box 8.21

In comparison to physiological tremor, essential tremor’s amplitude is higher and its frequency is lower.

Iatrogenic Movement Disorders

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