8

I. Parkinson’s Disease (Box 8.1)

1. Pathophysiology: increased inhibition of the ventral anterior and lateral thalamic output to the motor cortex caused by loss of dopaminergic input to the striatum (Fig. 8–1)

a. D2 receptors in the striatum are expressed on aspiny and spiny neurons (see p. 11); activation of the D2 receptor causes acetylcholine release onto muscarinic receptors that inhibits glutamatergic input to the striatum from the cortex and the GABAergic neurotransmission within the basal ganglia (i.e., D2 receptor activation inhibits most of the basal ganglia circuit)

b. histology: degeneration of the dopaminergic substantia nigra pars compacta neurons and, to a lesser extent, the basal forebrain (e.g., nucleus basalis of Meynert), the hypothalamus, and brainstem pigmented neurons (locus coeruleus, dorsal vagal motor nucleus) probably due to dysfunction in the ubiquitin–proteosome system

i.    neuron loss is pronounced in lateroventral part of pars compacta, and is usually asymmetric; symptoms appear typically when 80% of substantia nigra pars compacta neurons are lost

ii.   surviving neurons often exhibit eosinophilic inclusions surrounded by a halo that contain α-synuclein and ubiquitin {Lewy body (see p. 162)} (Box 8.1)

(1) α-synuclein is a presynaptic protein thought to be involved in dopamine release and/or synaptic plasticity; in Parkinson’s disease it becomes insoluble and aggregates into fibrils that attract ubiquitin and neurofilaments, thereby forming Lewy bodies

c. genetics: the majority of cases are sporadic, but several inherited forms exist (Table 8–1)

i.    parkin: acts to covalently link proteins targeted for destruction to ubiquitin, which then can be recognized by proteosomes; mutations cause accumulation of intracellular proteins that form Alzheimer’s-like neurofibrillary tangles instead of Lewy bodies

(1) accounts for the majority of early-onset Parkinson’s disease

ii.   ubiquitin C-terminal hydrolase L1 acts to release ubiquitin from its conjugated protein after delivery of the conjugated protein to the proteosome

iii.  PINK1: a mitochondrial protein kinase that regulates the electron transport chain

2. Epidemiology: exhibits increased incidence according to geographic (industrialized countries > nonindustrialized countries) and racial factors

a. risk factors for sporadic Parkinson’s disease include drinking well water, rural residence, farming (possibly related to pesticide exposure in industrialized countries), and employment in wood pulp mills or steel industries; risk may be reduced by cigarette smoking and caffeine use

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

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; anti-cholinergic 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

(c) add a low-dose atypical antipsychotic medications (clozapine, quetiapine) (Box 8.2)

b. surgical treatment: best response to medication postoperatively is equal to the patient’s best response to medication preoperatively, and the chief improvement is in terms of reduced fluctuations and dyskinesias

i.    lesion procedures: usually done with stereotactic and intraoperative electrophysiological confirmation of location, but can be done by means of radiosurgery (e.g., gamma knife)

(1) thalamotomy: targets the ventral intermediate nucleus

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

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

III. Cortical-Basal Ganglionic Degeneration

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

(1) autonomic dysfunction usually predates parkinsonian features

(2) hyperpigmentation of the extremities

(1) T2 hypointensity in the globus pallidus with a lateral linear hyperintensity, and putamen atrophy (Fig. 8–2)

(2) loss of pontine fibers {hot-cross bun sign} (Fig. 8–3)

v.    treatment: dopaminergic agents usually have little effect against the parkinsonism because D2 receptors are lost in the striatum; management of autonomic dysfunction as per Parkinson’s disease

b. multiple system atrophy with predominant cerebellar features (MSA-C)/OPCD form of MSA

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

ii.   epidemiology: peak incidence at 50–60 years of age; usually sporadic, but may have autosomal dominant or recessive patterns of inheritance (usually such cases are classified under spinocerebellar ataxias)

iii.  symptoms: ataxia in the lower extremities > upper extremities; cerebellar-type dysarthria; autonomic dysfunction (Box 8.4)

(1) subtypes of MSA-C include

(a) parkinsonian symptoms (50%)

(b) retinal degeneration

(c) spastic paraplegia and areflexia

(d) dementia, ophthalmoplegia, and extrapyramidal signs

iv.   diagnostic testing: late in the disease, neuroimaging demonstrates atrophy of the brainstem and cerebellum

v.    treatment: none specific; management of autonomic dysfunction as per Parkinson’s disease

V. Dystonias

1. Pathophysiology: primary dystonias result from dysfunction the dopaminergic systems (Fig. 8–4) in the of basal ganglia without apparent neuron loss or neurochemical deficit; abnormal function of the motor and sensory cerebral cortex and in lower motor neuron reflexes are likely reactions to the basal ganglia dysfunction

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

Related posts:

Behavioral Neurology and Psychiatry Diseases of the Muscles Infections of the Nervous System Diseases of the Nerves Tumors of the Nervous System Seizures and Epilepsy

Stay updated, free articles. Join our Telegram channel

Join

Full access? Get Clinical Tree