Neurodegeneration and movement disorders Flashcards
Essential tremor
Most common movement disorder with up to 5 million cases in the US
Positive family history in about 50% of cases - AD w/high penetrance, though no gene identified yet
A bilateral (though sometimes asymmetric) postural tremor, typically 4 to 8 Hz with or without a kinetic component (a tremor occurring with action) that may involve the limbs, head, chin, lips, tongue, and even voice. Predominantly affects hands, neck and voice Symptoms often respond to alcohol
Treatment 1. First-line: primidone, beta blockers 2. Second-line: Topiramate, gabapentin, benzos: Klonipin 3. Deep brain stimulation (target: VIM thalamus)
Vs physiological tremor - faster, 7 to 12 Hz. Both ET and enhanced physiologic tremor increase with anxiety, but in enhanced physiologic tremor, the frequency is variable and can be slowed by mass loading (increasing weight on the arm)
Vs rubral tremor, also known as Holmes tremor, a relatively low-frequency tremor typically present at rest, with posture, and with action. It results from lesions in the dentate nucleus of the cerebellum and/or the superior cerebellar peduncle, and is often seen in patients with multiple sclerosis.
Other causes of action tremor - drugs
Lithium, valproate, amiodarone, cyclosporin, stimulants
Other causes of action tremor - systemic disease
Hemochromatosis, hypoxia, thyrotoxicosis, peripheral neuropathy
Rubral tremor
Rubral tremor, also known as Holmes tremor, is relatively low-frequency tremor typically present at rest, with posture, and with action. It results from lesions in the dentate nucleus of the cerebellum and/or the superior cerebellar peduncle, and is often seen in patients with multiple sclerosis.
Clinical feature of Huntington’s disease
Motor: chorea, dystonia, parkinsonism, ataxia, ophthalmoparesis
Psychiatric: depression, impulsiveness, psychosis
Cognitive: dementia
In Huntington’s disease, neuronal degeneration is seen in the striatum, substantia nigra, globus pallidus, and other areas. MRI of the brain shows caudate and putamen atrophy.
The classic clinical features include chorea, gait instability, dystonia, and multiple neuropsychiatric symptoms including depression, psychosis, cognitive dysfunction, executive dysfunction, and personality changes. Other features include motor impersistence, demonstrated by inability of the patient to sustain tongue protrusion and impaired saccades and pursuits, with insuppressible head movements during eye movements. In some forms, particularly the juvenile form, chorea is absent and the more prominent features are myoclonus and parkinsonism, with significant rigidity (akinetic-rigid syndrome).
Genetics of Huntington’s disease
Autosomal dominant disorder with defect on short arm of chromosome four (4p16.3)
Complete penetrance: expanded trinucleotide (CAG) strongly related to age at onset
Trinucleotide repeat may increase in length with succeeding generations (anticipation)
Treatment of Huntington’s disease
There is no effective treatment for underlying degeneration
Tetrabenazine: Monoamine depletion can be used to control chorea in early disease
Symptomatic treatment for psychiatric disturbance (depression, psychosis) is effective
Differential diagnosis of chorea
Immune mediated: Sydenham’s chorea, chorea gravidarum (APLS), SLE
Hereditary chorea: Neuroacanthocytosis, DRPLA, HDL-1
Systemic disease: Hyperthyroid, polycythemia vera, metabolic disturbances
(dialysis)
Drugs: Neuroleptics, PD meds, stimulants (cocaine), SSRIs
Classification of dystonia
Age of Onset: Early vs. Adult onset
Body Distribution: Focal, multifocal, segmental, hemidystonia or generalize
Etiology: Primary dystonia, secondary dystoni, heredodegenerative
Special clinical features: Paroxysmal, exercise-induced, task- specific or dopa-responsive
Dystonia is classified as focal when it involves a single body part, as in cervical dystonia. If the dystonia spreads to a contiguous body part, it is termed segmental. Generalized dystonia refers to involvement of at least two segmental regions (such as leg plus trunk) with at least one other body part involved. Multifocal dystonia is used to describe the occurrence of dystonia in two noncontiguous body parts, such as foot and hand.
Torsion dystonia
AD, mutation in DYT1 gene - GAG deletion in the DYT1 gene results in loss of one glutamic acid residue in the ATP binding protein TorsinA (chsm 9)
Variable expressivity, low penetrance
Childhood or adolescent onset, always in arm or leg, rarely spreads to cranial muscles
Dopa responsive dystonia (DRD)
Genetic heterogeneity with autosomal dominant and recessive forms Reduced penetrance (i.e. 30-50%) Childhood onset with diurnal variation Affects girls more than boys (2:1 to 3:1) Excellent and persistent response to levodopa is diagnostic
This patient’s history is consistent with dopa-responsive dystonia, or Segawa’s syndrome. This disorder is more common in females and the occurrence of dystonia frequently shows a diurnal variation, being worse in the afternoon and evening. Mild parkinsonism may be seen on examination. It typically presents in childhood, but adult-onset forms exist as well. Response to low- dose levodopa is typically present, without risk of significant dyskinesias.
The most common hereditary form of dopa-responsive dystonia is autosomal dominant and results from a mutation in the enzyme GTP cyclohydrolase I (GCH1) on chromosome 14 (DTY5). GCH1 is the rate-limiting enzyme in tetrahydrobiopterin synthesis, which is a cofactor for tyrosine hydroxylase, the enzyme that catalyzes the rate-limiting step of dopamine synthesis.
Genes associated with dystonia
DYT3: x linked dystonia/Parkinsonism (Lubag, Filipino). DYT3 dystonia, or Lubag disease, is X-linked and is seen in males of Filipino descent and manifests with dystonia and parkinsonism.
DYT5: dopa responsive dystonia and parkinsonism= Segawa syndrome, gene product GTP cyclohydrolase I gene
DYT8: Paroxysmal non-kinesiogenic dyskinesia or dystonic choreoathetosis
Goes up to DYT23
DYT11 Hereditary myoclonus-dystonia
Associated with sarcoglycan (epsilon) gene on 7q21
Dramatic response to small amounts of alcohol
DYT11, or myoclonus-dystonia syndrome, results from a mutation in a sarcoglycan protein (though other mutated genes have been identified). It is phenotypically heterogeneous but typically manifests with tremor, myoclonus, and dystonia typically beginning in the teenage years and associated with various psychiatric symptoms.
THAP-1 (DYT6) mutations, are most often associated with adult-onset craniocervical dystonia with laryngeal involvement. GNAL mutations are most commonly associated with adolescent- or adult-onset craniocervical dystonia though the phenotype is broad.
Pharmacotherapy for dystonia
Levodopa—for dopa-responsive dystonia, for childhood or adolescent onset of generalized or segmental dystonia always try l-dopa to test for DRD, esponse expected with <300 mg/day of levodopa
Anti-cholinergics
Baclofen: Oral, Intrathecal
Clonazepam
Botulinum toxin
Produced by the bacterium Clostridium botulinum
Seven serotypes, A through G
Botulinum toxins type A (Botox, Dysport, Xeomin) and B (myobloc) approved for clinical use
- Most appropriate for focal and segmental dystonias
Hemifacial spasm
Involuntary, intermittent, tonic or clonic spasms of muscles innervated by facial nerve (CN 7), usually starts in periorbital muscles and then spreads to lower face
Most often unilateral (rarely bilateral, but asynchronous)
May be triggered by light, reading, fatigue, facial movement
Etiology (check brain MRI)
- 2/3 have vascular loop compressing CN 7 at CPA
- May be post-paralytic (e.g. history of Bell’s palsy)
- Less commonly, compressive lesion (e.g. tumor, AVM) or intrinsic brainstem pathology (e.g. stroke, MS)
Tx: Botulinum toxin injections (1st line), micro-vascular decompression
This patient’s history is consistent with hemifacial spasm, in which there are synchronous contractions of one side of the face. Some cases can occur after facial nerve paresis or due to identifiable compressive lesions of cranial nerve VII such as a tumor or a vascular loop. Contractions most often begin around the eye and spread to ipsilateral face muscles; bilateral involvement is rare but can occur, though contractions on each side of the face are asynchronous. Treatment may involve nerve decompression if there is a clear compressive lesion, but botulinum toxin therapy is otherwise the mainstay of treatment.
This disorder is hypothesized to occur due to a demyelinating lesion in the facial nerve that leads to abnormal spontaneous discharges, with ephaptic transmission or spread of electrical discharges between adjacent fibers of a demyelinated nerve. Because the blink reflex test (the electrophysiologic equivalent of the corneal reflex) is abnormal in patients with hemifacial spasm, another theory is that this disorder results from hyperexcitability in the facial nerve nucleus.
Acute dystonic reaction
Causes: Neuroleptics, Anti-emetic medications that block dopamine receptors (metoclopramide (Reglan), prochlorperazine (Compazine), promethazine (Phenergan)
Treatment: Benztropine 2mg IV followed by 1-2mg twice a day for 7
days, Diphenhydramine is an alternative: 10-50mg IM followed by oral doses of 25-50 mg TID
Wilson’s disease
Clinical features: Onset under age 40, hepatic, and neuropsychiatric
Diagnosis: Serum ceruloplasmin (which binds copper, low), slit lamp examination, urinary copper excretion (increased), liver biopsy, MRI with increased signal on T2- weighted images in the caudate and putamen, as well as the midbrain (with sparing of the red nucleus, leading to the so-called “double panda sign” or “face of the giant panda”)
Treatment: Agents that reduce intestinal copper absorption (zinc, tetrathiomolydate), chelating agents (penicillamine, trientine), Liver transplantation
An autosomal recessive disorder of copper metabolism resulting from mutations of the gene encoding the copper- transporting P-type ATPase (ATP7B) on chromosome 13. This enzyme normally binds to and transports copper across membranes. A defect in this enzyme leads to inability to excrete copper from the liver into bile, leading to copper accumulation.
Abnormal movements predominate the neurologic presentation, including parkinsonism, dystonia, tremor, ataxia, as well as dysarthria. The tremor may have a variety of features, but classically, it is proximal and of high amplitude, giving the appearance of “wing beating” when the arms are abducted and the elbows flexed. A characteristic grin with drooling also occurs.
Brain MRI findings in Wilson’s disease
Tardive dyskinesia
Characterized by irregular, stereotyped, involuntary hyperkinetic movements of the choreiform type
Lip smacking, lip pursing, tongue protrusion, licking and chewing movements
Muscles of upper face are less commonly involved
Truncal and limb muscles affected giving rise to respiratory dyskinesias, pelvic thrusting, and extremity chorea
Risk f(x)s Exogenous factors - linear relationship of incidence of TD to increasing length of exposure and dose of high potency neuroleptics/ dopamine antagonist Predisposition - older age, female gender, affective disorder
Tx: withdraw offending neuroleptic, switch to low-potency neuroleptic (clozapine), dopamine depleting agents (reserpine, tetrabenazine)
This disorder is an iatrogenic, typically late (hence the term tardive), adverse effect of dopamine- receptor antagonists, most commonly antipsychotics, but also seen with other therapies such as metoclopramide. It is more likely to occur with typical antipsychotics such as haloperidol and fluphenazine because of their greater antagonism at D2 receptors, but can also occur with the atypical antipsychotics such as risperidone, with clozapine and quetiapine being least likely to cause tardive dyskinesia. It may occur during therapy with dopamine-receptor antagonists or even years after the medication is discontinued. The manifestations of tardive dyskinesia include oro-bucco-lingual movements (as in this case), akathisia (inner restlessness), dystonia (often of the neck but also other body parts), tremor, parkinsonism, or a combination of these.
Abrupt cessation of a dopamine-receptor antagonist after prolonged use can lead to prominent involuntary dyskinetic movements involving various regions of the body as well as akathisia. A slow taper of the offending agent is therefore recommended when tardive dyskinesia occurs. When psychosis or other indications for dopamine-receptor antagonists persist, switching to an agent with less D2 antagonism should be attempted when possible. The treatments for tardive dyskinesia include clonazepam and the dopamine-depleting agent tetrabenazine. The rationale behind use of tetrabenazine is that it reduces dopaminergic synaptic activity without causing dopamine-receptor antagonism.
Some evidence also exists for use of amantadine. In pharmacotherapy-refractory cases, deep brain stimulation may be onsidered though high-level evidence for its utility is lacking. Anticholinergics and antihistamines can worsen tardive dyskinesia.
Vs dystonic reaction: This reaction typically occurs within the first few days of exposure to the agent and most often involves the ocular and face muscles, leading to oculogyric crisis (forced eye deviation) and other dystonic manifestations. Treatment involves cessation of the agent and administration of anticholinergics or antihistamines, with resolution of the dystonic reaction within hours.
Simple vs complex tics
Tics that are classified as simple motor consist of a simple isolated movement such as eye blinking or eyebrow raising. Complex motor tics on the other hand consist of coordinated sequenced movements that resemble normal movements such as truncal flexion or head shaking. Simple phonic tics include sniffing, throat clearing, grunting, or coughing. Complex phonic tics include verbalizations such as shouting obscenities (coprolalia), or repeating others (echolalia) or oneself (palilalia).
Tics and Tourette syndrome
Spectrum of tic disorders: Transient tics, Chronic tics, Tourette’s syndrome, tics preceded by premonitory sensation
In Tourette’s syndrome, at least one year of…1) motor tics: blinking, shrugging, head turning, 2) vocal tics: sniffing, throat clearing, occurring before age 18, with psychological co-morbidities: obsessive-compulsive behavior, attention deficit hyperactivity disorder
Pathophysiology: thought to involve dopaminergic hyper-stimulation of the ventral striatum and limbic system.
Treatment: neuroleptics (most effective, but limited by side effects), alpha-adrenergic agonists, cognitive behavioral therapy
*Clonidine, an α-2- adrenergic agonist, is useful for the treatment of ADHD and other behavioral aspects of Tourette’s syndrome, and improves tics as well. Levodopa would not be the first line of management in Tourette’s syndrome, as it may exacerbate tics (though some of the dopamine agonists have been shown in some studies to improve tics, possibly through reduction of endogenous dopamine turnover by action on D2 autoreceptors).
Restless leg syndrome
Criteria for diagnosis:
- Urge to move limbs often with uncomfortable sensations
- Symptoms are worse at night or exclusively at rest or during periods of inactivity
- Symptoms are partially or totally relieved by movement
- Circadian rhythm: symptoms must be worse or exclusively in the evening of night
Epidemiology:
- Very common: 5-15% of population
- Prevalence increases with age
- Gradually progressive, may not be diagnosed until mid-life
RLS causes and treatment
Primary (idiopathic): majority are AD
Secondary (symptomatic): Iron deficiency, pregnancy, end-stage renal disease, medications (TCA, SSRI, MAO, neuroleptics), peripheral neuropathy
Treatment
Medications: Iron replacement, dopaminergics agents, gabapentin, carbamazepine, opiods/narcotics
Non-medications: Hot or cold bath, delay sleep time, reduce evening exercise, alcohol, leg massage
Parkinson’s disease - epidemiology
Affects ~1% of individuals over the age of 65
Slightly more common in men than women
Multiple genes (e.g. α-synuclein, ubiquitin pathway) and environmental factors have been associated with an increased risk of developing Parkinson’s disease
Caffeine consumption and smoking appear to be inversely related to risk of developing PD, pesticide exposure, organic solvents and head trauma may be a risk factor
Parkinson’s disease - pathophysiology
Loss of dopamineric neurons in the substantia nigra–results in dopamine deficiency
Physiological effect is excessive inhibitory input from the basal ganglia on the thalamus (VA and VL nucleus) and cortex
More wide-spread degeneration occurs as the disease advances
Parkinson’s disease - pathology
Lewy Bodies in brainstem nuclei and cortex Neuronal***, round, intracytoplasmic eosinophilic inclusions surrounded by a clear halo Primary component is alpha-synuclein Wide-spread pathology not limited to substantia nigra, locus ceruleus, dorsal motor nucleus of vagus, anterior olfactory nucleus, rapine nucleus, etc Can be in dopaminergic and non-dopaminergic neurons Lewy neurites – abnormal alpha-synuclein filaments and granular material Cell loss
Also see tissues affected outside the CNS: enteric nervous system, possibly skin and salivary gland
Oligodendroglial inclusions in MSA
PARK1
AD, SNCA-synuclein on _4_q21 → abnormalities in synaptic vesicle trafficking
Risk factor for typical PD +/- dementia
PARK2
AR, PARK2/parkin: a ubiquitin E3 ligase on _6_q25-27
Risk factor for juvenile onset PD; atypical features
PARK8
AD, LRRK2/dardarin: leucine-rich repeat kinase on _12_p11.2
Typical PD
Gaucher
Glucocerebrosidase on 1q21
Risk factor for Typical PD, Ashkenazi Jews
FTDP-17
AD, MAPT/tau on 17q21
Risk factor for 1. Parkinsonism with FTD 2. Typical PD
Parkinson’s disease - symptoms
Progressive disorder
Motor features: - Tremor - Rigidity - Akinesia/ Bradykinesia - Postural instability/ gait disorder with loss of postural reflexes (several years after onset) and falls occurring later in the course (8-10 years after onset)
Freezing: with gait initiation, walking through a narrow space, approaching a target, and abnormal postures can also occur: striatal hand, striatal toe, camptocormia: extreme flexion of the spine that worsens with walking and improves with supine position
Non-motor features (neuropsychiatric, autonomic, sleep)
Can have unilateral onset and remain asymmetric
Parkinson’s disease - treatment
Medical treatment primarily based on replacement of dopamine
- Carbidopa/levodopa (Sinemet) is mainstay of therapy
- A large number of other options (dopamine agonists, MAO-B - inhibit conversion of dopamine to HVA in CNS, COMT inhibitors: inhibit conversion of dopamine to 3-O-methyldopa outside of PNS and amantadine)
Surgical treatment for advanced disease
Treatment for motor vs non-motor s(x)s
Motor symptoms
- Carbidopa-levodopa
- Dopamine agonists
- MAO-B inhibitors
- Catechol-O-methyl- transferase inhibitors
- Amantadine
- Anti-cholinergics
Non-motor symptoms
- Mood – anti-depressants
- Anxiety – anxiolytics
- Dementia – cholinesterase- inhibitors, memantine
- RBD – clonazepam
- Orthostatic hypotension – midodrine, fludrocortisone, droxidopa
- Sialorrhea – botulinum toxin, atropine gtt (under tongue)
Levodopa - side effects
_Dyskinesias -_ incidence related to dosage and duration of therapy, with increasing risk with increasing duration of therapy, also increase by combatant use by COMT Visual hallucinations (all PD meds)
Nausea secondary to peripheral conversion of levodopa into dopamine, administration of extra doses of dopamine* can reduce this side-effect, tolerance develops over time
Or C-dopa, I think
MAO-B inhibitors - side effects
Hypertensive “cheese reaction”
Potential for serotonin syndrome
The relatively selective inhibition of MAOB reduces the risk of the “cheese effect” that could be seen with concomitant intake of high levels of tyramine in certain cheeses, resulting in hypertensive crisis (the older MAO inhibitors that inhibited both MAOA and MAOB had a higher risk of this adverse effect).
Selegiline, a monoamine oxidase type B (MAOB) inhibitor, is metabolized to methamphetamine, which can lead to insomnia. The other MAOB inhibitor, rasagiline, does not have amphetamine-like metabolites.
Dopamine agonists - side effects
Drowsiness, D for drowsy
Impulse Control Disorders (gambling etc.) - present even in patients without a prior history of impulse control problems
COMT inhibitors - side effects
Diarrhea
Liver dysfunction (tolcapone)
Anti-cholinergics - side effects
Anticholinergic side effects (dry mouth, confusion, etc.)
Site of implantation for DBS
STN or GPI
PD ddx
- Idiopathic Parkinson’s disease or Parkinson’s Plus syndrome
- Drug-Induced Parkinsonism: neuroleptics, anti-emetics (esp. metaclopramide), valproate, calcium channel blockers
- Toxin-Induced Parkinsonism: MPTP—selective complex I poison, pesticides
- Heavy metals: manganese (syndrome distinct from PD)
- Vascular parkinsonism
- Hydrocephalus
- Post-Traumatic Parkinsonism
Parkinson’s plus syndrome
Poor response to levodopa, early autonomic dysfunction, and prominent ataxia distinguish the different types of MSA from idiopathic PD.
Prominent early falls and restricted downward gaze distinguish PSP from MSA; as mentioned in question 17, patients with PSP have hyperextension of the neck (retrocollis), whereas patients with MSA exhibit involuntary neck flexion (antecollis).
Clinical Features of Parkinson Dementia and Lewy Body Dementia
Synucleinopathy
Parkinsonism
- More axial symptoms, less tremor
- LD responsiveness less than in PD without dementia
- Neuroleptic super-sensitivity
Visual Hallucinations
- Formed non-threatening images (children, animals)
- Can occur without dopamine replacement in DLB
Fluctuations
- Level of consciousness, confusion, delusions
- Most difficult of the features to diagnose
Key features of Multiple Systems Atrophy
Synucleinopathy
Onset in 6th decade of life
Parkinsonism
Autonomic dysfunction (orthostasis wo compensatory increase in HR, urinary symptoms secondary to involvement of the group of anterior horn cells in the sacral cord known as Onuf’s nucleus, constipation)
Ataxia
Pyramidal findings (brisk reflexes, Babinski sign)
Particularly fatal manifestation - laryngeal dystonia
MRI with a hyperintense slit-like rim around the putamen, and the “hot-cross-buns sign,” or cruciform sign: transverse and vertical hyperintensity in the pons, due to loss of pontine neurons and pontocerebellar tracts with intact corticospinal tracts.
Pathology—glial cytoplasmic inclusions
Subtypes based on which s(x)s predominate - MSA-A (previously Shy-Drager, autonomic features predominant), MSA-P (parkinsonian symptoms predominate), MSA-C (cerebellar symptoms predominate). All these disorders share in common the presence of parkinsonism that is poorly responsive to levodopa and the neuropathologic finding of glial cytoplasmic inclusions with α-synuclein.
Key features of Progressive Supranuclear Palsy
Tauopathy
Late onset in 7th decade of life, compared to DB and MSA
Predominantly axial parkinsonism with loss of postural reflexes (rigidity, bradykinesia), which occurs early on - in the first 1.5-2 years, parkinsonian manifestations tend to be less asymmetric
Ophthalmoparesis - restricted vertical gaze (can be overcome by oculocephal maneuver), predominantly downward gaze, making going down stairs difficult, particularly when combined with the involuntary neck hyperextension (retrocollis [vs antecollis in MSA]) that occurs
Pseudo-bulbar symptoms
Dementia
MRI of the brain in PSP may show atrophy of the midbrain, leading to the so-called hummingbird sign.
Pathology: brainstem neurofibrillary tangles
Poor response to levodopa
Key features of Cortico-Basal Degeneration
Tauopathy
Cortical features
- Myoclonus
- Cortical sensory loss: astereognosis [inability to recognize objects placed in the hand in the absence of primary sensory loss], agraphesthesia [inability to recognize numbers or letters drawn on the hand in the absence of primary sensory loss], and loss of two-point discrimination
Frontal/subcortical features
- Cognitive dysfunction, apraxia, alien limb phenomena
Subcortical features
- Dystonia, non-levodopa responsive parkinsonism - focal limb rigidity and/or dystonia
Pathology
- Balooned hypo-chromatic neurons - nuclear inclusions
Alzheimer’s disease gross pathology
Temporopareital predominant cortical atrophy with thinning of cortex, widening of sulci (circle) and ventriclar ex-vacuo dilation
Alzheimer’s disease
Neurofibrillary tangles (top)
– intracytoplasmic neuronal aggregates of tau protein that take the shape of the neuron’s cell body. In pyramidal cells, they appear flame shaped (arrow).
Neuritic plaques (circle)
– extracellular accumulation of an amyloid core surrounded by swollen neuritic processes (look like burnt-out camp fires).
Granulovacuolar degeneration (top and bottom) in Alzheimer's disease – Small cytoplasmic vacuoles that contain a single granule (circles)
Hirano bodies in Alzheimer’s disease
– Rod-shaped eosinophilic inclusions that appear adjacent to neurons in the neuropil (arrow)
Frontotemporal dementia gross pathology
Severe focal atrophy of the frontal and temporal lobe (circle) with sparing of the posterior 2/3 of the superior temporal gyrus (knife-edge)
Pick bodies
– Intracytoplasmic neuronal oval aggregates (circle) of tau (arrow).
May also see
– Neuronal loss with gliosis
– Ballooned neurons with achromatic cytoplasmic inclusions
PSP
Intracytoplasmic neuronal aggregates of tau throughout the brainstem
These aggregates take the shape of the neuron’s cell body appearing “globose” (arrow).
Progressive supranuclear palsy is characterized by globose neurofibrillary tangles in subcortical nuclei and tufted astrocytes.
Parkinson’s disease
There is loss of pigmentation of the substantia nigra (arrows) and locus ceruleus.
There is loss of the pigmented neurons microscopically
Lewy body in Parkinson’s disease
The pigmented neurons contain a cytoplasmic sphere with a clear halo inclusions. (Lewy body) (arrow and circle).
– It is eosinophillic on H&E stain
Lewy body
Composed of multiple intracellular neuronal proteins
– Identified by staining for alpha-synuclein (arrow).
Maybe present in non- pigmented neurons such as hippocampus (circle) or cortex in diffuse Lewy body dementia (DLBD)
Multiple System Atrophy (MSA)
There are intracytoplasmic inclusions in oligodendroglia that stain positive for alpha- synuclein (arrow).
Huntington’s disease
Gross brain atrophy with ex-vacuo ventricular dilation
Focal atrophy of the caudate (arrow).
Neuronal loss and gliosis of the caudate and putamen (circle), particularly the medium spiny neurons.
Creutzfeldt-Jakob Disease (CJD)
Triad of rapidly progressive dementia, startle myoclonus, and ataxia
Severe cortical atrophy with cystic changes (arrow).
Spongiformchangesin neuropil (circle) with neuronal loss and gliosis.
New variant CJD
Caused by consumption of meat products contaminated by bovine spongiform encephalopathy
Patients are young and have prominent psychiatric manifestations and ataxia.
Characterized by a ring of spongiosis surrounding a central prion protein amyloid core (“florid plaque”) (circle).
Proteinopathies 1
Proteinopathies 2
Striatum
Caudate+Putamen
Lentiform
Globus pallidus+Putamen
Direct pathway
Projects from cortex -(+)-> striatum -(-)-> GPi/SNr -(-)-> thalamus (+). Named because signal heads directly to GPi/SNR.
(+) Glu, (-) GABA
Increases excitatory thalamic output to the cortex
INCREASES MOTOR ACTIVITY
Dopamine from SNc acts on striatum via D1 receptors, enhancing response to glutamate, resulting in increased motor activity
Indirect pathway
From cortex -(+)-> striatum -(-)-> GPe -(-)-> STN -(+)-> GPi/SNr -(-)-> thalamus (+). Detours at GPe and STN.
(+) Glu, (-) GABA.
Decreases excitatory thalamic output to the cortex
DECREASES MOTOR ACTIVITY
Dopamine from SNc acts on striatum via D2 receptors, decreasing response to glutamate, resulting in increased motor activity
Striatal projections in the basal ganglia
Primarily inhibitory
Dopamine in the direct pathway
From substantia nigra, pars compacta → striatum (via nigrostriatal projections)
Enhances striatal response to glutamate via D1 receptors (more activation)
Increases GPi and SNr inhibition by striatum
INCREASES MOTOR ACTIVITY
Dopamine in the indirect pathway
Substantia nigra, pars compact → striatum (via nigrostriatal projections)
Decreases striatal response to glutamate via D2receptors
Decreases striatal inhibition on GPe→Increases STN inhibition by GPe→Decreases activation of GPi and SNr
INCREASES MOTOR ACTIVITY
Acetylcholine in BG
Aspiny neurons – striatal interneurons, release ACh
Excite both pathways – BUT** **prefer the indirect pathway
**Anticholinergic medications (trihexyphenidyl, benztropine, procyclidine) can be beneficial in Parkinson’s disease
Primary output nuclei from the basal ganglia
The internal segment of the globus pallidus sends outputs to the thalamus through the ansa lenticularis and the lenticular fasciculus.
Each enters into the thalamic fasciculus to synapse on VL (ventrolateral) and VA (ventral anterior) of the thalamus.
VA nucleus of the thalamus later projects to the premotor cortex and is responsible for initiating movement.
VL nucleus of the thalamus projects to the primary motor, supplementary motor, and premotor cortices and assists with initiation and learning of skilled movements.
Parkinson’s disease BG lesion
SNc degeneration
Loss of dopamine→net inhibition of the thalamus
DECREASES MOTOR ACTIVITY
Hemiballismus BG lesion
Subthalamic nucleus lesion → reduced thalamic inhibition
INCREASES MOTOR ACTIVITY CONTRALATERAL TO THE LESION
Huntington’s disease BG lesion
Degeneration of striatal neurons in caudate and putamen
More severe damage to the indirect pathway→reduced thalamic inhibition
INCREASES MOTOR ACTIVITY
**Eventually all striatum degenerates à hypokinetic, parkinsonian
Basal ganglia circuity other. name
Cortico-striato-thalamo-cortical.
One hallmark of PD and HD each not explained by BG circuitry
Reduced direct pathway activity obviously does not explain the tremor that occurs in PD.
Bradykinesia is also a feature of HD. In fact, Parkinsonism in HD develops in the late stages where it eventually replaces chorea. Thus, a reduction in indirect pathway activity does not fully explain the abnormalities of movement seen in this disorder, again cautioning against the oversimplification of these models.
D2 receptors and prolactin
D2 receptors are found in the pituitary gland; activity at D2 receptors in the pituitary inhibits prolactin release, hence the hyperprolactinemia seen in patients taking antipsychotics (which antagonize D2 receptors).
Falling and loss of postural reflexes in Parkinson+ syndromes
PSP: Within 2 years
MSA: Within 5 years
Idiopathic PD: 8-10 years from disease onset
Nature of cogwheel tremor in PD
Rigidity, or increased resistance during passive range of motion, is a feature of idiopathic PD and is often cogwheeling, or ratchety (rather than spastic), due to the increased tone being superimposed on a tremor.
Shoulder/joint pain in PD
Shoulder pain is a frequent occurrence in PD and can be present years prior to the onset of motor symptoms. Other joints can also be involved. These pains likely result from rigidity and reduced motion at joints; that these pains are at least in part due to the underlying disorder rather than arthritis or other orthopedic problems is evidenced by improvement of these pains with dopaminergic therapy in some cases.
Tremors seen in PD
The tremor of idiopathic PD is moderate in frequency, 4 to 6 Hz, and is typically more distal than proximal. The tremor has been described as pill rolling, as if the individual is rolling a small pill between the index finger and the thumb. The tremor can involve the legs as well as the head region, most commonly the lips, chin, and jaw, and less often the neck. Although the tremor in idiopathic PD is typically a resting tremor (occurring at rest), postural tremor does occur as well. When a posture (such as outstretched arms) is assumed, there is usually a latency of a few seconds before the tremor appears (this so-called reemergent characteristic of the tremor contrasts with the postural tremor of essential tremor, in which the tremor appears immediately on assumption of a posture, as discussed in questions 22–24).
Nonmotor symptoms in PD
Urinary s(x)s - 2/2 generalized autonomic dysfunction with detrusor hyperreflexia
Constipation - may predate motor symptoms from years, 2/2 impaired GI motility due to involvement of the enteric nervous system with the disease
Shoulder and joint pain
Cramping pain from dystonia
Nonspecific sensory changes in the absence of exam findings c/f neuropathy, may or may not be responsive to dopaminergic therapy
Dopamine agonists
Ropinirole - agonist at D2 and D3 receptors
Pramipexole - agonist at D2 and D3 receptors
Bromocriptine, pergolide, cabergoline are older agonists that are not typically used in the treatment of PD
PD with dementia
Diagnosis made when the patient meets criteria for idiopathic PD for at least 1 year before dementia onset. The dementia in these patients is thought to result from involvement of the cortex with Lewy body pathology, though it may be accounted for by concurrent Alzheimer’s disease in some cases as well.
Versus dementia with LB, DLB - cognitive dysfunction and hallucinations antedate the Parkinsonism, though they may all occur concurrently
The term Lewy body dementia is as an umbrella term that encompasses both PDD and DLB as a spectrum of disorders with similar underlying pathologies though different clinical presentations and progressions.
Carbidopa-Levodopa
Levodopa is a dopamine precursor.
After levodopa is ingested, it is converted in the brain and peripherally into dopamine by the enzyme dopa-decarboxylase (also called aromatic amino acid decarboxylase). The peripheral conversion accounts for its side effects such as nausea (discussed in question 14).
Carbidopa is a peripheral dopa-decarboxylase inhibitor; it reduces conversion of levodopa into dopamine in the periphery while not inhibiting central conversion. Administration of carbidopa on its own is not of use; it is administered only in combination with levodopa.
MAO-B inhibitors
Rasagiline
Selegile
Trihexphenidyl in PD
An anticholinergic.
Its use in PD is limited to the treatment of tremor, as some of the tremor in PD is thought to result from a relative excess of acetylcholine.
Amantidine in PD
Another therapy used in PD includes amantadine, which has antiglutamatergic effects, increases presynaptic dopamine release, and inhibits reuptake of synaptic dopamine.
Amantadine is a weak antagonist of the NMDA-type glutamate receptor, increases dopamine release, and blocks dopamine reuptake.
DBS in PD
Target sites: STN, GPi typically; VIM is particularly effective for tremor and the VIM is thus the main nucleus targeted in essential tremor but occasionally in tremor-dominant PD as well.
Effective in reducing tremor and bradykinesia but not levodopa-unresponsive gait freezing, falls, or other axial symptoms
If s(x)s predominantly only affect 1 side of the body, unilateral DBS to a contralateral brain target is inappropriate
Significant cognitive impairment is a contraindication to DBS as significant worsening of cognitive dysfunction can occur postoperatively.
Secondary Parkinsonism
Manganese toxicity, rather than magnesium toxicity, can lead to parkinsonism. Other toxins→Parkinsonism: neurotoxin MPTP (which is now used to create primate animal models of Parkinson’s disease) and carbon monoxide (which leads to relatively selective toxicity to the globus pallidus interna).
Post-encephalitic/post-infectious parkinsonism has been with influenza virus, West Nile virus and Japanese encephalitis virus. Parkinsonism may also be a feature of the prion disease CJD.
Vascular parkinsonism results most often from multiple lacunes in the basal ganglia. It classically affects the lower extremities more than the upper extremities, with rigidity, bradykinesia, postural instability, dementia, corticospinal findings, and incontinence occurring. The upper extremities are often relatively spared in this disorder, and tremor is not a prominent feature. Some patients with vascular parkinsonism respond to levodopa therapy.
Parkinsonism can be a feature of normal-pressure hydrocephalus and other causes of chronic hydrocephalus.
Structural brain lesions affecting the basal ganglia, including strokes, hemorrhages, and tumors, can also lead to parkinsonism, as can paraneoplastic processes.
Vascular Parkinsonism
Secondary to multiple lacunes in the basal ganglia, affects BLE>BUE, rigidity and bradykinesia are prominent features with minimal tremor, some are responsive to levodopa
Mangagense toxicity
Seen in welders and miners, in chronic liver disease, and in patients on total parenteral nutrition, among other causes. It leads to psychiatric symptoms (“manganese madness”), parkinsonism (but usually without tremor), and a typical gait disorder characterized by toe walking with elbow flexion, the so-called cock walk. On brain MRI, hyperintensity in the basal ganglia on T1-weighted images is seen.
Secondary tourettism
The term given to conditions in which phonic and motor tics are present but an underlying neurologic disorder accounts for the presence of tics; for example, secondary tourettism is seen in autistic spectrum disorders, static encephalopathy, neuroacanthocytosis (discussed in question 33), Huntington’s disease (discussed in questions 30 and 31), medications, and other causes.
Syndenham’s chorea
Sydenham’s disease is an autoimmune disorder manifesting with chorea that is usually bilateral but often asymmetric, as well as oculomotor abnormalities and behavioral changes following infection with group A Streptococcus. Unlike other features of rheumatic fever, the chorea can present months after the infection or may be the sole manifestation of rheumatic fever. Patients may have elevated antistreptolysin antibodies and antibasal ganglia antibodies but these are neither sensitive nor specific. Treatment of the acute streptococcal infection, as well as subsequent prophylaxis with penicillin in patients who develop rheumatic fever, is essential.
Sydenham’s disease is best treated with antidopaminergic therapies.
Chorea during pregnancy
Chorea occurring during pregnancy does not necessarily imply a genetic etiology; it may signify prior rheumatic fever or an underlying autoimmune disease such as systemic lupus erythematosus. It may also reflect an underlying APLS disorder.
Benign hereditary chorea
Benign hereditary chorea is an autosomal dominant nonprogressive syndrome characterized predominantly by chorea, with mild gait ataxia. It results from a mutation in the thyroid transcription factor gene. Mutations in this gene also lead to a more severe childhood syndrome characterized by mental retardation, hypothyroidism, and lung disease (so-called brain– thyroid–lung syndrome).
Neuroacanthocytosis syndromes
Mixed movement disorder: dystonia and chorea with laboratory findings of acanthocytes (spiculated RBCs) on peripheral blood smear
Include : Chorea-acanthocytosis, Mcleod’s syndrome (an X-linked disorder resulting from mutations in the Kell group antigen), abetalipoproteinemia, and some of the neurodegeneration with brain iron accumulation (NBIA) syndromes
Chorea-acanthocytosis
An autosomal recessive disorder resulting from mutations in the VPS13A gene on chromosome 9 that encodes for the chorein protein.
Onset: 3rd to fourth decade of life
The most prominent clinical features are orolingual dystonias, such as prominent tongue-protrusion dystonia, particularly while eating, self-mutilating behavior, cognitive decline with dementia, dysarthria, ophtophthalmoplegia, parkinsonism, seizures, and behavioral problems. Chorea and athetosis (a slow form of chorea) also occur.
Vs abetalipoproteinemia, which is associated with low serum cholesterol and vitamin E malabsorption, not seen in chorea-acanthocytosis, vs HARP, which is associated with low serum cholesterol but normal vitamin E
_*_HARP (hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa (also seen in abetalipoproteinemia), and pallidal degeneration, also involved with PKAN
Vs Lesch-Nyhan: with chorea-acanthocytosis there is normal serum uric acid and prominent tongue- protrusion dystonia make neuroacanthocytosis more likely.
Dentatorubral-pallidoluysian
Dentatorubral-pallidoluysian atrophy is a neurodegenerative autosomal dominant disorder resulting from expansion of the trinucleotide repeat CAG on chromosome 12. It is more common in people of Asian descent. It typically begins in the fourth decade of life, but earlier onset forms exist. Clinical features include myoclonus, choreoathetosis (a combination of chorea and athetosis), epilepsy, dystonia, tremor, parkinsonism, and cognitive dysfunction.
Bilateral ballistic
Bilateral ballism may be due to bilateral basal ganglia infarcts
Primary generalized dystonia
Primary generalized dystonia (also known as Oppenheim’s dystonia or dystonia musculorum deformans), depicted in question 36, is an autosomal dominant disorder resulting from a mutation in the torsin A gene on chromosome 9, and referred to as DYT1 dystonia. I_t is more common in those of Ashkenazi Jewish descent and has relatively low penetrance. Symptoms typically begin in childhood with action-induced limb dystonia that later spreads to involve the trunk and other limbs, with generalization of the dystonia over a few years. In some patients, the dystonia remains focal._
Response to levodopa is typically poor, and a lack of response obviously does not necessarily imply a psychogenic disorder. Treatment of primary generalized dystonia includes anticholinergics, benzodiazepines, and deep brain stimulation of the globus pallidus interna.
Cervical dystonia
The most common focal dystonia.
Cervical dystonia typically begins in adulthood and manifests with involuntary head posture, neck pain, and in some cases a tremor (dystonic tremor; essential tremor can also lead to head tremor, A sensory trick (geste antagoniste), such as touching the face or head or positioning the head in a specific manner against an object, may partially relieve symptoms. In a proportion of patients with focal dystonia, blepharospasm, or dystonic eyelid movements manifesting as involuntary blinking often followed later by more forceful involuntary eyelid closure occur, often worsened with driving or light exposure. Other forms of dystonia such as oromandibular dystonia (involving the mouth and lips) may occur as well. Therapies including anticholinergics, benzodiazepines, and baclofen may be helpful, but botulinum toxin therapy is the mainstay of treatment. Blepharospasm may be seen as part of Meige’s syndrome, in which oromandibular dystonia occurs as well.
Focal, task-specific dystonia
The most common task-specific dystonia is writer’s cramp, a dystonia occurring during writing. This type of dystonia, occurring only with specific activities, is most often primary, without an underlying secondary cause. It most often occurs after the activity is performed for some time. This type of dystonia can occur during playing of various musical instruments; in horn or woodwind players, embouchure dystonia, or dystonia of the lips, jaw, or tongue can be seen. Treatment may include focal injections of botulinum toxin in a manner that minimizes the dystonia, but also minimizes impact on musical performance.
Although the dystonia may overflow to involve more proximal areas over time during specific activities, it is unlikely to progress to a generalized dystonia.
Cortical myoclonus
The term given to myoclonus resulting from abnormal activity in the sensorimotor cortex.
Lance-Adams Syndrome
Lance–Adams syndrome, depicted in this case, manifests after hypoxic–ischemic brain injury, and may not be evident for months or even years after the insult. The most prominent feature is action myoclonus, and when the myoclonus involves the legs, gait is prominently affected. Spinal cord ischemia is not thought to be directly involved in the pathophysiology of this type of myoclonus. Treatment includes benzodiazepines such as clonazepam, piracetam, levetiracetam, as well as sodium valproate.
Subcortical, brainstem, spinal cord, and peripheral nerve myoclonus
Myoclonus may also have subcortical and brainstem origin, as well as spinal cord origin, the latter resulting in either segmental myoclonus (restricted to a specific limb or area of the trunk) or propriospinal myoclonus (involving axial muscles). Nerve root or peripheral nerve lesions can rarely result in segmental myoclonus as well. Multifocal myoclonus is often seen in the context of a variety of metabolic disorders such as uremia and liver failure; in the latter, negative myoclonus or asterixis is seen.
Physiological myoclonus
Not all myoclonus is pathologic; physiologic myoclonus includes hypnic jerks, which are hypnagogic lower extremity jerks (occurring in the early stages of sleep) and hiccups.
Palatal myoclonus
Characterized by rhythmic palatal movements that may lead to audible clicks due to Eustachian tube contraction (these are not hallucinations). The contractions may also involve other head regions. Palatal contractions as depicted in this case may be essential (without a discernible cause; in some cases thought to be psychogenic) or symptomatic, due to a brainstem lesion such as stroke or tumor. The symptomatic form is one of the few movement disorders that persist during sleep.
When involuntary palatal contractions occur in the context of brainstem lesions, the pathophysiology is thought to result from dysfunction in pathways connecting the dentate nucleus of the cerebellum, the inferior olive, and the red nucleus, all of which make up the Guillain–Mollaret triangle. Hypertrophy of the inferior olive on MRI of the brain may be seen.
Blepharospasm
Blepharospasm typically involves both eyes and does not involve the cheek and mouth
Paroxysmal kinesigenic dyskinesias (PKDs).
There are several categories of paroxysmal dyskinesias, all sharing in common episodes of hyperkinetic abnormal movements (may include dystonia, chorea or choreathetosis, ballism, or dysarthria with intervening normalcy). The abnormal movements may include dystonia, chorea or choreoathetosis, ballism, or dysarthria. These disorders differ in the length of the paroxysm, triggers for the episodes, pharmacologic therapy, and genetics.
PKD is characterized by episodes that last seconds to at most 5 minutes, precipitated by sudden movement as well as by startle and hyperventilation.
Genetics: PRRT2 is implicated in families with both PKD and infantile convulsions with choreoathetosis. Secondary forms of PKD occur in multiple sclerosis, following trauma, in patients with a history of perinatal hypoxic encephalopathy, and in the setting of other underlying neurologic disorders.
The primary form responds well to anticonvulsants such as carbamazepine.
Vs PKND: In paroxysmal nonkinesigenic dyskinesia (PNKD), attacks last 2 minutes to several hours, and there are sometimes no clear precipitants, although episodes can be aggravated by alcohol, caffeine, and fatigue. Episodes are less frequent than in PKD. PNKD does not typically respond to anticonvulsants. Mutations in the myofibrillogenesis regular (MR-1) gene have been reported in some patients with PNKD.
Vs PED: A third form of paroxysmal dyskinesias is referred to as paroxysmal exertional dyskinesias (PED), in which episodes are triggered by prolonged exercise and last typically 5 to 30 minutes but sometimes up to 2 hours. One genetic etiology of PED is mutations in the glucose-1 transporter (GLUT-1) gene. CSF hypoglycorrhachia may be seen in such patients, and treatment with ketogenic diet may help reduce the frequency of episodes.
Paroxysmal kinesigenic dyskinesias (PKDs).
There are several categories of paroxysmal dyskinesias, all sharing in common episodes of hyperkinetic abnormal movements (may include dystonia, chorea or choreathetosis, ballism, or dysarthria with intervening normalcy). The abnormal movements may include dystonia, chorea or choreoathetosis, ballism, or dysarthria. These disorders differ in the length of the paroxysm, triggers for the episodes, pharmacologic therapy, and genetics.
PKD is characterized by episodes that last seconds to at most 5 minutes, precipitated by sudden movement as well as by startle and hyperventilation.
Genetics: PRRT2 is implicated in families with both PKD and infantile convulsions with choreoathetosis. Secondary forms of PKD occur in multiple sclerosis, following trauma, in patients with a history of perinatal hypoxic encephalopathy, and in the setting of other underlying neurologic disorders.
The primary form responds well to anticonvulsants such as carbamazepine.
Vs PNKD: In paroxysmal nonkinesigenic dyskinesia (PNKD), attacks last 2 minutes to several hours, and there are sometimes no clear precipitants, although episodes can be aggravated by alcohol, caffeine, and fatigue. Episodes are less frequent than in PKD. PNKD does not typically respond to anticonvulsants. Mutations in the myofibrillogenesis regular (MR-1) gene have been reported in some patients with PNKD.
Vs PED: A third form of paroxysmal dyskinesias is referred to as paroxysmal exertional dyskinesias (PED), in which episodes are triggered by prolonged exercise and last typically 5 to 30 minutes but sometimes up to 2 hours. One genetic etiology of PED is mutations in the glucose-1 transporter (GLUT-1) gene. CSF hypoglycorrhachia may be seen in such patients, and treatment with ketogenic diet may help reduce the frequency of episodes.
Episodic ataxias
Episodic ataxia type I (EAI): episodes of ataxia with facial twitching that may be myokymia (rippling muscle movements) or neuromyotonia; attacks occur up to several times per day, last seconds to minutes, triggered by startle, movement, or exercise; secondary to KCNA1 mutation on chromosome 12; may respond to AEDs like Tegretol
In EAII: episodes of ataxia with brainstem symptoms such as nystagmus and dysarthria, no facial twitching does not occur; last minutes to hours, can occur daily to monthly; may be triggered by stress and alcohol intake; secondary to CACN1A4 mutation, the same gene mutated in familial hemiplegic migraine, and many patients with EAII have migraines during or outside of the ataxia attacks. EAII episodes may respond to the carbonic anhydrase inhibitor acetazolamide.
Episodic ataxia type III is an autosomal dominant disorder in which the attacks of ataxia are associated with tinnitus and vertigo, and in between attacks myokymia occurs. These attacks respond to acetazolamide.
In episodic ataxia type IV, episodes of ataxia are associated with ocular motion abnormalities, and the attacks maybe triggered by sudden head movement.
The genes for these two types of episodic ataxia (III/IV) have yet to be identified
Stiff person syndrome
Stiff person syndrome is a syndrome that typically begins in the fourth or fifth decade. It is characterized by increased tone affecting predominantly the axial muscles, including the paraspinal muscles, leading to exaggerated lumbar lordosis, in addition to abdominal muscles, leading to a “board-like” abdomen. The limbs later become involved. Superimposed spasms in response to anxiety or excitement occur, as does an exaggerated startle response.
This disorder may be autoimmune, in association with glutamic acid decarboxylase (GAD) antibodies. GAD catalyzes the synthesis of the inhibitory neurotransmitter GABA. In patients with anti-GAD antibodies, insulin-dependent diabetes and other endocrinopathies may occur as well. More focal forms of the disorder, as in stiff leg syndrome, also occur.
Stiff person syndrome may also be paraneoplastic in association with antiamphiphysin antibodies (breast cancer).
The mainstays of therapy for stiff person syndrome are benzodiazepines and baclofen for their GABA effect.
Hypererkplexia
Hyperekplexia, or exaggerated startle, can manifest with sudden brief exaggerated startle reactions (blinking, flexion of the neck and trunk, abduction and flexion of the arms) or more prolonged onic startle spasms. These sometimes occur secondary to minor stimuli and do not habituate.
There are primary familial forms of hyperekplexia in which mutations in the glycine receptor and presynaptic glycine transporter have been identified. _Glycine is the inhibitory neurotransmitter at spinal interneurons including Renshaw cells and Ia inhibitory interneurons, and abnormal spinal Ia inhibitory interneuron reciprocal inhibition is thought to be the cause of startle in these case_s.
Some patients return to benzodiazepine or sodium valproate.
Cerebellar anatomy
Consists of two cerebellar hemispheres, a midline vermis, and several deep gray nuclei interspersed among the cerebellar white matter.
The cerebellar cortex consists of three layers.
- The _molecular laye_r is outermost and consists of inhibitory neurons known as stellate and basket cells.
- Purkinje cells lie in a layer under these neurons, and are the main output of the cerebellum to the deep cerebellar and vestibular nuclei. The main neurotransmitter of Purkinje cells is GABA, an inhibitory neurotransmitter.
- The innermost layer is the granular layer, and consists of g_ranule cells and Golgi_ interneurons. Parallel fibers, axons of the granule cells, travel to synapse with Purkinje cells.
- Granule cells are the only cerebellar cell types that are excitatory.
Inhibitory fibers arise from the Purkinje cells of the cerebellum and project to the deep cerebellar nuclei. Fibers arising from the deep cerebellar nuclei, including the dentate, emboliform, and globose nuclei, are excitatory and are carried through the superior cerebellar peduncle, decussate, and then synapse in the thalamus. The thalamus in turn projects to the cortex, which in turn projects back to the brainstem through the corticobulbar, corticospinal, and other descending pathways. Because the fibers from the cerebellum to the thalamus cross, and motor fibers for the cortex ultimately cross, lesions to one cerebellar hemisphere lead to ipsilateral cerebellar signs and symptoms.
Afferents into the cerebellum are carried through the inferior, middle, and superior cerebellar peduncle (note that the superior cerebellar peduncle carries predominantly cerebellar efferents, though it carries afferents to the cerebellum as well).
- These include axons of the spinocerebellar tract, which are termed mossy fibers, as well as projections from the pons, vestibular nuclei, and reticular nuclei.
- Another main afferent pathway to the cerebellum arises from the inferior olivary nucleus and travels in the form of climbing fibers around Purkinje cells.
Chronic alcoholism and the cerebellum
Alcohol itself is toxic to the cerebellum. It predominantly affects midline structures such as the vermis, and this accounts for the prominent truncal ataxia, though cerebellar hemisphere atrophy leading to limb ataxia can also be seen.
Acquired cerebellar ataxias
There are several causes of acquired cerebellar ataxia.
- Celiac disease can lead to isolated cerebellar dysfunction in the absence of GI symptoms. In a patient with ataxia of unclear etiology, celiac antibodies should be checked as in some cases with gluten enteropathy, a gluten-free diet can improve the ataxia.
- Hypothyroidism can lead to gait ataxia, and checking serum thyroid–stimulating hormone is indicated in an adult presenting with ataxia. Supplementation with thyroid hormone can lead to improvement of the gait disorder.
- Chemotherapeutic agents including 5-fluorouracil and cytarabine can lead to significant cerebellar toxicity. In cytarabine toxicity, Purkinje cell loss and gliosis occur, and there is loss of dentate neurons as well; the cerebellar dysfunction is typically irreversible.
- Metals such as mercury can lead to cerebellar toxicity as well as visual cortex toxicity, leading to a syndrome of ataxia, visual field deficits, and paresthesias.
- Bismuth salicylate can also lead to cerebellar toxicity if ingested in high amounts.
- Other cerebellar toxins include the solvent toluene.
- Chronic intake of phenytoin can lead to cerebellar atrophy due to damage to Purkinje cells. Acute phenytoin toxicity can lead to reversible cerebellar ataxia.
Other causes of acquired cerebellar ataxia include infection (as in HIV infection, Creutzfeldt–Jakob disease, and Whipple’s disease; see Chapter 15) or postinfection (such as is seen after varicella zoster infection in children). The Miller-Fisher variant of Guillain–Barre (discussed in Chapter 9) leads to ataxia in addition to areflexia, ophthalmoplegia, and involvement of other cranial nerves.
Friedreich’s Ataxia
An autosomal recessive hereditary ataxia characterized by cerebellar dysfunction, neuropathy, and upper motor neuron findings. High-arched feet and spinal deformities occur. Cardiac involvement is common, including cardiac conduction abnormalities and hypertrophic cardiomyopathy. It most often presents in young adulthood, but presentation in early childhood or even late adulthood may occur. FA results from an expansion of the trinucleotide repeat GAA in the frataxin gene on chromosome 9. The exact role of frataxin is unclear, but it is thought to be a nuclear-encoded mitochondrial protein.
Idebenone, a synthetic coenzyme Q10 analogue, improves the cardiomyopathy in FA.
Ataxia-telangiectasia (AT)
Ataxia-telangiectasia (AT) is an autosomal recessive disorder that typically presents in childhood with neuropathy, ataxia, and extraocular movement abnormalities, characteristically marked by inability to move the eyes without head thrusting. Telangiectasias are present in the conjunctiva and other areas. These patients are at increased risk of hematologic and other malignancies, and are prone to infections due to immunodeficiency, including hypogammaglobulinemia. This disorder results from a mutation in the ATM gene on chromosome 11. Mutations in this gene result in impaired DNA repair. It is an AR condition.
SCAs
Most commonly AD
Repeat expansions are common to many of them, with the CAG repeat most often expanded, The pathophysiology of the SCAs resulting from repeat expansion is thought to relate to a toxic gain of function, leading to a protein product that is misfolded and abnormally aggregates.
Typically present in the third to fifth decades of life, but can present at any age, with each of the SCAs having a different mean age of onset.
Although clinically heterogeneous, they share in common the occurrence of a progressive truncal and limb ataxia, often with associated spasticity and other upper motor neuron findings. Other abnormalities depending on the subtype include impaired saccades and smooth pursuits, cranial nerve abnormalities, and in some cases neuropathy. In some of the SCAs, epilepsy and cognitive decline occur. In SCA7, there is retinopathy with vision loss.
MRI of the brain shows cerebellar atrophy and in some cases, atrophy of the brainstem and cervical spinal cord.
The most common spinocerebellar ataxia (SCA) is SCA3, also known as Machado–Joseph disease. Like SCA1 and SCA2, age of onset is typically in the third to fourth decades of life, though wide variability again occurs. In addition to ataxia and other cerebellar signs, facial and tongue atrophy and fasciculations occur, and bulbar symptoms such as dysphagia are common. Levodopa- responsive parkinsonism may occur. Neuropathy is a late feature. SCA3 results from expansion of the CAG repeat in the gene ataxin 3 on chromosome 14.
Fragile X tremor–ataxia syndrome,
Fragile X syndrome results from expansion of CGG repeat in the FMR1 gene on chromosome X to more than 200 repeats. In the grandparents of patients with fragile X syndrome, a repeat number of 55 to 200, in the premutation range, may result in clinical manifestations, including tremor, ataxia, parkinsonism, dysautonomia, and cognitive decline. Although the clinical presentation resembles the cerebellar type of multiple-system atrophy (discussed in questions 18 and 19), a family history of mental retardation should prompt consideration of this disorder. Woman may be affected as well, though less commonly and typically with less prominent features. MRI of the brain may show hyperintensities in the cerebellum and inferior cerebellar peduncle on T2-weighted images,
Cerebrotendinous xanthomatosis
An autosomal recessive disorder caused by a defect in the enzyme 27-sterol hydroxylase on chromosome 2, which results in deposition of cholesterol and cholestanol in a variety of tissues, including the brain, lungs, lens of the eye, and tendons. This results in a variety of clinical manifestations in multiple organ systems, including neuropsychiatric symptoms (cognitive decline, personality changes, and psychiatric symptoms), ataxia (in the limbs and trunk), parkinsonism, neuropathy, tendon xanthomas particularly in the Achilles tendon, diarrhea, and cataracts.
Diagnosis is made by measurement of serum cholestanol; serum cholesterol is often not elevated and not helpful in making the diagnosis.
MRI of the brain shows cortical and cerebellar atrophy and white matter abnormalities.
Treatment includes chenodeoxycholic acid as a means of lowering serum cholestanol; long-term therapy may lead to improvement in neurologic signs and symptoms.
Think of this when there is a combo of ataxia, cataracts, and tendon xanthomas
Orthostatic tremor
This type of tremor affects the trunk and thighs. It is characteristically high frequency: surface EMG electrodes on the thighs would show a tremor frequency of 14 to 16 Hz. Symptoms include unsteadiness or shakiness on standing, with improvement when given physical support or with ambulation.
“Halo sign”
Hyperintense lesion on T1 in the cerebra peduncles, seen in beta-propeller protein-associated degeneration (BPAN)
Memory types
Immediate memory is the amount of information someone can keep in conscious awareness without active memorization. Immediate memory can be tested by forward digit span. Normal human beings can retain seven digits in active memory span. Working memory is tested by manipulation of information retained in immediate memory (adding two of the digits repeated in a number series, or reciting a series of numbers backward [digits backward]). Recent memory involves the ability to register and recall specific items after a delay of minutes or hours. It requires the hippocampus and parahippocampal areas of the medial temporal lobe for storage and retrieval, which is why it is usually impaired first in early AD and is evident by impaired word recall (three-word recall). Remote memory is tested by asking about historical life events and long-known information.
Long-term memory anatomy
Language anatomy
Classic aphasias
Broca’s: effortful, disordered grammar, literal paraphasic errors (house → blouse)
Wernicke’s: fluent, empty content, neologisms, semantic paraphasic errors (chair → table)
Conduction: poor repetition, hesitation, decreased auditory short-term memory
Transcortical aphasias
Transcortical motor: echolalia, limited self-generated speech, improves with dopamine agonists
Transcortical sensory: fluent, circumlocutions, poor comprehension but good repetition
Watershed ischemia generally results in transcortical aphasias, leaving repetition intact
Ideomotor apraxia
Best demonstrated with pantomime of transitive actions to command (show me how to cut bread)
Test for “expressive” and “receptive” forms (can patient recognize a pantomimed action?)
Spatial errors:
Postural - body part as tool, incorrect posture
Orientation of movement - fix and free wrong joints
Temporal errors - Loss of usual speed and timing of movements
ideomotor apraxia, which is suggested by use of a body part as an object during pantomime, as well as the unusual movements and postures. Patients with ideomotor apraxia understand the movement that they are supposed to execute, and achieve the general, overall movement, but exhibit abnormal postures and spatial errors. Ideomotor apraxia is seen with lesions in the dominant parietal cortex, in or around the area of the superior marginal and angular gyrus (like Gerstmann’s).
Frontal syndromes
Mesial-frontal = dorsomedial prefrontal cortex
The orbitofrontal cortex is located on the ventral aspect of the frontal lobes. It is involved in judgment, inhibition of socially inappropriate behaviors, as well as emotional and visceral functions. Lesions to this area, which commonly include trauma and olfactory groove or sphenoid wing meningiomas, lead to changes in personality, social disinhibition, facetiousness, inappropriate jocularity (witzelsucht), echopraxia, and utilization behavior (mimicking of use of objects in the environment), as depicted in question 65.
The dorsomedial prefrontal cortex is involved in motor initiation, goal-directed behavior, and motivation. Lesions to this area, and bilateral lesions to the anterior cingulate, which commonly result from anterior cerebral artery infarcts and tumors, lead to apathy, indifference, loss of initiative, amotivation, and abulia, or a reduction (or in severe cases abolition) of movement and communication due to involvement of the supplementary motor area, as depicted in question 66. In extensive bilateral lesions to the dorsomedial prefrontal cortex, the most severe form of this nonparalytic akinesia, akinetic mutism, results. Because the paracentral lobule (the mesial projection of the somatosensory cortex) is involved in voluntary urinary continence, lesions to this area often are associated with urinary incontinence.
The dorsolateral prefrontal cortex is involved in the planning of motor activity and behavior, executive functioning, judgment, and problem solving. Lesions to this area lead to impaired judgment, impaired ability to plan, multitask, and problem solve
Achrompatopsia
V4, V3, V2
Dementia diagnosis
Alzheimer’s disease pathology
Amyloid deposition appears to be an early feature of AD. Amyloid imaging in patients with genetic forms of AD show amyloid deposition in the brain years before clinical symptoms occur. Neuritic plaques and neurofibrillary tangles are the most specific, although granulovacuolar degeneration, amyloid deposition, and Hirano bodies are also commonly seen.
It shows amyloid (neuritic) plaques, which are extracellular collections of amyloid protein deposited on dendrites and axons. They are composed of β-amyloid proteins. Amyloid plaques are a characteristic finding in AD. The other histopathologic findings in AD include intraneuronal neurofibrillary tangles (paired helical filaments made up of abnormally hyperphosphorylated tau protein), granulovacuolar degeneration (neuronal intracytoplasmic granule containing vacuoles), amyloid angiopathy (amyloid deposition in walls of small and medium sized arteries), and Hirano bodies (cytoplasmic inclusions composed mainly of actin and actin-associated proteins).
NFTs - tau
Amyloid plaque - amyloid
FTLD pathology
Pick’s disease is defined pathologically by the presence of silver-staining, spherical aggregations of tau protein in neurons (Pick bodies).
Chromosome 9 is Cr9ORF72
LBD pathology
Neuronal α-synuclein inclusions
Occipital hypometabolism on FDG-PET can be seen but not sensitive or specific enough to use clinically, DAT scan will show decreased DAT uptake in basal ganglia (same as PD or MSA)
MRI typically shows preservation of medial temporal lobe structures
Lewy bodies are cytoplasmic inclusions with anti-ubiquitin and anti-α-synuclein immunohistochemistry.
Reversible causes of dementia
Reversible causes of dementia
According to the American Academy of Neurology (AAN) guidelines, routine dementia screening should include assessment for vitamin B12, complete blood count, electrolytes, glucose, blood urea nitrogen (BUN), creatinine, liver function tests, thyroid function tests, and depression screening.
Further testing including HIV, VDRL, lumbar puncture, and heavy metals are not recommended in routine screening without a specific clinical indication.
Wernicke-Korsakoff
Lewy body in LBD
Amyloid/neuritic plaque - AD
CJD and other prion diseases: vCJD, kuru, Gerstmann-Straussler-Scheinker syndrome (GSS), and fatal familial insomnia (FFI).
These diseases share the neuropathologic features of neuronal loss, glial cell proliferation, absent inflammatory response, and vacuolization of the neuropil, which produces the characteristic spongiform appearance.
NFTs in AD
NFTs are intraneuronal collections of paired helical filaments made up of hyperphosphorylated tau protein.
Figure 12.9 shows granulovacuolar degeneration, associated with Alzheimer’s disease (AD). Granulovacuolar degeneration results from the formation of abnormal neuronal intracytoplasmic granule containing vacuoles.
