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.
Striopallidodentate calcinosis, also known as Fahr’s disease.
Calcifications seen most often in the caudate, but also putamen, thalamus, and cerebellum, among other areas.
Striopallidodentate calcinosis can be idiopathic, but can also be seen in both autosomal dominant and recessive familial forms, and a variety of metabolic disorders including secondary hyperparathyroidism as is seen in end-stage renal disease, primary hyperparathyroidism, as well as hypoparathyroidism.
Implicated genes: SCL20A2, PDGFB
Genetic testing for HD
On the other hand, testing of asymptomatic minors should be avoided regardless of family history; genetic testing of asymptomatic children at their parents’ request should not occur, regardless of the parents’ intentions, particularly when the disorder is not treatable and there is no intervention that can be taken to prevent the disease. Testing should occur only after the age of 18, after an informed decision has been made by the patient (after genetic counseling).
REM sleep behavior disorder
RBD is a parasomnia marked by dream enactment and loss of the normal atonia that occurs during REM sleep. It is seen as a “prodromal” state: the majority of individuals with RBD go on to develop a neurodegenerative parkinsonian syndrome that is pathologically grouped among the “synucleinopathies.” These are disorders in which synuclein-containing inclusions are the predominant histopathologic finding in the brain. These include Parkinson’s disease as well as MSA and dementia with Lewy bodies.
How does the DaTscan work?
A commonly used ligand is I123 ioflupane, known in the United States as DaTscan. It is a cocaine analogue and binds to the presynaptic dopamine receptor. This scan therefore assesses presynaptic rather than postsynaptic dopamine transporters (and therefore speaks nothing about the state of the putamen). In the setting of substantia nigra degeneration, there are reduced projections to the striatum and thus less binding of dopamine transporter ligand to presynaptic dopamine transporters in the striatum.
When the diagnosis of PD is straightforward on a clinical basis there is likely little advantage in ordering a dopamine transporter SPECT scan, but in equivocal cases of tremor and/or parkinsonism, this can be helpful. Aside from distinguishing PD from essential tremor, other potentially useful indications for this type of scan include differentiating equivocal cases of idiopathic PD from drug- induced parkinsonism and vascular parkinsonism, among others.
In regards to the utility of other imaging modalities in PD, _fluorodopa PET studies in patients with idiopathic PD show reduced uptake in the putame_n. Given the clearcut findings in Figure 6.5B, a fluorodopa PET scan would not be of use in this case.
How does the DaTscan work?
A commonly used ligand is I123 ioflupane, known in the United States as DaTscan. It is a cocaine analogue and binds to the presynaptic dopamine receptor. This scan therefore assesses presynaptic rather than postsynaptic dopamine transporters (and therefore speaks nothing about the state of the putamen). In the setting of substantia nigra degeneration, there are reduced projections to the striatum and thus less binding of dopamine transporter ligand to presynaptic dopamine transporters in the striatum.
When the diagnosis of PD is straightforward on a clinical basis there is likely little advantage in ordering a dopamine transporter SPECT scan, but in equivocal cases of tremor and/or parkinsonism, this can be helpful. Aside from distinguishing PD from essential tremor, other potentially useful indications for this type of scan include differentiating equivocal cases of idiopathic PD from drug- induced parkinsonism and vascular parkinsonism, among others.
In regards to the utility of other imaging modalities in PD, fluorodopa PET studies in patients with idiopathic PD show reduced uptake in the putamen. Given the clearcut findings in Figure 6.5B, a fluorodopa PET scan would not be of use in this case.
NBIA
This patient’s history and imaging finding suggest that he has neurodegeneration with brain iron accumulation (NBIA). The NBIAs encompass several disorders that can present with or manifest various movement disorders including parkinsonism (which may be partially levodopa responsive, but with early and at times severe dyskinesias), dystonia, and choreoathetosis. Developmental delay may be present, but not in all cases. Other neurologic manifestations include spasticity, ataxia, and seizures. While they usually present in infancy or childhood, adult-onset cases occur as well. Iron deposition is seen in the globus pallidus as well as other regions (depending on the specific type of NBIA) as detailed below. I_ron deposition is best seen on T2*-weighted (gradient-echo [GRE]) and susceptibility weighted images (an example is shown in_ Fig. 6.7__). Iron deposition occurs in the globus pallidus with increasing age but age-related iron deposition would not be present in a 13-year-old boy. The differential diagnosis of hypointensity on T2*-weighted imaging includes hemosiderin and calcium.
Genetic mutations → NBIA
Associated with lipid/Fe metabolism
- Pantothenate-kinase–associated neurodegeneration (PKAN): this is the most common NBIA. Due to mutations in the pantothenate kinase 2 gene. Imaging findings include hypointensity of the globus pallidus with a central hyperintensity (so-called eye-of-the-tiger sign, which is suggestive but not pathognomonic), as well as, in some cases, hypointensity of the substantia nigra and dentate nucleus of the cerebellum. Iron deposition may be absent or subtle particularly in adult-onset cases.
- PLA2G6–associated neurodegeneration (PLAN): due to mutations in a phospholipase gene, PLA2G6, which is also the causative gene for infantile neuroaxonal dystrophy. Cerebellar atrophy on MRI is prominent in this disorder.
- Mitochondrial membrane protein–associated neurodegeneration (MPAN): due to mutations in chromosome 9 open reading frame 12 (C19orf12). On MRI, in addition to iron deposition evident on GRE in the globus pallidus, iron deposition in the substantia nigra may be prominent, and there may be a hyperintense streak-like appearance within the globus pallidus on conventional T2.
- Beta-propeller protein–associated neurodegeneration (BPAN) due to mutations in WD repeat domain 45 (WDR45) gene. A T1 halo of hyperintensity surrounding the substantia nigra on T1- weighted imaging suggests this disorder. Psychomotor regression followed by static encephalopathy in childhood, with subsequent relatively abrupt onset of dystonia or other abnormal movements later (in early adulthood) may be seen with BPAN
- Neuroferritinopathy: due to mutations in ferritin light chain. Serum ferritin may be low in some but not all cases. Iron deposition is widespread involving not only the globus pallidus but also cortex, caudate, and putamen. Among the NBIAs, neuroferritinopathy (along with aceruloplasminemia) is more likely than some of the others to present in adulthood.
- Aceruloplasminemia: an autosomal recessive disorder due to mutations in the ceruloplasmin gene. Caudate, putamen, red nucleus, and thalamic involvement with iron deposition is seen on MRI. Along with neuroferritinopathy, it has a higheraverage age of onset compared to the other NBIAs.
- Fatty-acid hydroxylase–associated neurodegeneration (FAHN): due to mutations in the fatty-acid hydroxylase gene. In addition to iron deposition, white matter changes maybeprominent on MRI in this disorder.
- Kufor-Rakeb syndrome: due to mutations in ATP13A2. Inaddition to the many manifestations of NBIAs described above, oculogyric dystonic spasms and facial-faucial finger mini- myoclonus may be seen, and these findings would suggest this as a potential etiology in the evaluation of a patient with a presumed NBIA.
- CoA synthase protein–associated neurodegeneration (CoPAN).
Nonketotic hyperglycemia causing chorea
The history and examination, combined with MRI findings and serum glucose value, suggest the most likely diagnosis is nonketotic hyperglycemia. This may occur in patients with already- diagnosed diabetes or may be the presenting features of diabetes. The chorea is usually unilateral but bilateral cases have been rarely reported. Unilateral hyperintensity of the striatum on T1-weighted imaging suggests this disorder in the right clinical context. (Note that streak artifact is seen in the right frontal region on this MRI and this should be disregarded).
When severe, treatment with a dopamine-receptor antagonist is indicated and is usually effective. The prognosis is variable, with chorea resolving entirely in some cases and persisting in others.
Other metabolic etiologies of chorea include (but are not limited to) hypoglycemia and uremia.
Direct pathway
Excitatory: increases thalamic excitation of cortex
Indirect pathway
Inhibitory: decreases thalamic excitation of cortex
Hyperkinetic movement
Reduced activity of indirect pathway
Hypokinetic movement disorders
Reduced activity of direct pathway
Sites involved in indirect pathway
Caudate/putamen (striatum), GPe, STN, GPi, SNr, and thalamus
Sites involved in the direct pathway
Caudate/putamen (striatum), GPi, SNr, and thalamus
MOA ropinirole and pramipexole
Dopamine agonists at D2 and D3
MOA entacapone
COMT inhibitor
MOA levodopa
Dopamine precursor, covered into dopamine by agonist of dopa-decarboxylase (same enzyme that carbo-dopa inhibits in the periphery)
Parkinson’s disease therapy→impulse control problems
Dopamine agonists
MC gene mutated in hereditary Parkinson’s disease
Leucine-rich repeat kinase 2 (LRRK 2)
Tongue-protrusion dystonia, chorea, acanthocytes on wet mount peripheral smear
Neuroacanthocytosis
Huntington’s disease: chromosome, mode of inheritance, protein, genetic abnormality
Chromsome 4, AD, Huntington, CAG trinucleotide expansion
Torsin A mutation
Primary generalized dystonia, AD, chromosome 9, DYT1 dystonia
Filipino with dystonia and Parkinsonism
DYT3, Lubag, X-linked dystonia-parkinsonism
Dystonia in a young girl with diurnal variation and Parkinsonism on examination
Dopa-responsive dystonia, AD, GTP cyclohydrolase 1 (GCH 1) on chromosome 14
Episodes of ataxia with facial twitching
Episodic ataxic type I
Gene: KCN1A
Triggers: Exercise, startle
Treatment: AEDs like carbamazepine
Episodes of ataxia with nystagmus and dysarthria
Episodic ataxic II
Gene: CACN1A4
Triggers: Alcohol, fatigue, stress
Treatment: acetazolamide
Neurotransmitter implicated in familial hyperekplexia (exaggerated startle syndrome)
Glycine
Antibodies in stiff person syndrome
Autoimmune: antiglutamic acid decarboxylase (GAD)
Paraneoplastic: amtiamphiphysin
High-arched feet, scoliosis, neuropathy, ataxia, cardiomyopathy
Friedrichs ataxia, GAA expansion in frataxin gene on chromosome 9, AR
Telangiectasia, ataxia, oculomotor abnormalities, immunodeficiency, hematologic malignancy
Ataxia-telangiectasia, AR, ATM gene on chromosome 11, results in impaired DNA repair
Ataxia with high serum alpha-fetaoproten
Ataxia-telangiectasia and ataxia with oculomotor apraxia type 2
Cause and mode of inheritance of SCA type 3 (Machado-Joseph disease), clinical presentation
CAG repeat expansion, AD. Ataxia, spasticity, neuropathy
Ataxia, parkinsonisms in the grandfather of a boy with fragile X syndrome.
Fragile X tremor-ataxia syndrome (FXTAS) from permutation (55-200 repeats) in CGG in FMR1 gene on chromosome X. T2 hyper intensities in cerebellum and inferior cerebellar peduncle.
Ataxia, cataracts, tendon xanthomas
Cerebrotendinous xanthomatosis, serum cholestanol
“Eye of the tiger”
Hyperintensity surrounded by hypo intensity in the basal ganglia, seen in PKAN
Mediation that improves outcome of cardiomyopathy in Friedreich’s ataxia
Idebenone, a coenzyme Q10 analogue
“Halo sign”
Hyperintense lesion on T1 in the cerebra peduncles, seen in beta-propeller protein-associated degeneration (BPAN)
Big picture cognition
Left - language, praxis/Right - prosody, spatial representation, attention
Anterior - action/Posterior - perception
Dorsal - where/Ventral - what
In general, though there are exceptions, lesions of the dorsal visual pathways that pass through the parieto-occipital regions can be thought of as leading to an abnormality in detecting “where”: where an object is in space, how to reach that object while looking at it. Lesions of the ventral, temporo-occipital pathways lead to an abnormality of detecting “what”: what an object is.
Short-term memory
Aka working and immediate memory
Ability to hold information across an undistracted delay
Not really localized (answer pre-frontal cortex if forced)
Long-term memory
Memory of thing not lost by distraction
Hippocampus, basal forebrain, Papez circuit
Remote memory
Memory of events many months ago
Distributed in neo-cortex, no longer requires hippocampus for retrieval
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
Hippocampal amnesias
Antereograde amnesia (unable to form new memories)
Temporally graded retrograde amnesia (memories of events > 6 months before injury intact), intact working-memory
Occurs in bilateral hippocampal damage (sx, anoxia, HSV, limbic encephalitis)
Korsakoff’s amnesia
Similar to hippocampal amnesia with marked confabulation
Chronic thiamine (B1) deficiency, paraventricular hemorrhages, particularly in mamillary bodies and medial dorsolateral thalamus
Transient global amnesia
Sudden onset antereograde amnesia of several hours duration, monophasic
Believed to be due to spreading depression in mesial-temporal lobes
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
Pure word deafness
A selective impairment in understanding spoken language (intact reading and language production). Caused by bilateral damage to the superior temporal lobes
Pure word deafness, or verbal auditory agnosia, is marked by impaired auditory comprehension of language, though hearing per se (of tones and other nonverbal sounds) is intact; audiogram is normal in these patients. There is normal comprehension of written language, distinguishing it from Wernicke’s (sensory) aphasia; Wernicke’s aphasia is characterized by inability to comprehend, read, or repeat, with fluent, nonsensical speech. The lesion causing pure word deafness is most often in the bilateral middle portion of the superior temporal gyri, sparing Wernicke’s area, but disrupting its connections with the primary auditory cortex (Heschl’s gyrus) and temporal lobe association cortices. Cases have been reported with unilateral dominant hemisphere temporal lobe lesions. This may be associated with amusia, or agnosia for music.
Anomic aphasia
Isolated impairment in word finding. Not associated with a focal lesion, but instead is a feature of dementing illnesses (e.g., logopenic Alzheimer’s Disease)
Aphemia
Aphemia (mutism) can result from a lesion that undercuts the white matter of Broca’s area. Ability to write is spared.
Aphemia, or pure word mutism, also referred to as verbal apraxia, is marked by an inability to speak fluently, impaired repetition, and intact auditory comprehension. A pure Broca’s (expressive) aphasia is characterized by inability to speak, write, name, or repeat, but intact comprehension. In aphemia, there is retained ability to write and comprehend written language. The lesion is in the dominant frontal operculum, anterior and superior to Broca’s area (posterior inferior frontal gyrus).
Counterpart to pure word deafness
Impairments in prosody
Impairments in prosody (rhythm and inflection of speech) may accompany homologous lesions in the right tempero-parietal and frontal lobes (receptive and expressive prosody, respectively
Alexia without agraphia
Impaired word reading with intact writing (letter reading may be OK), Associated with RHH, color anomia.
Disconnection of right hemisphere visual areas from left hemisphere language areas. Left PCA including forceps major of CC.
Gerstmann’s syndrome
Features: - Agraphia (± alexia), acalculia, finger agnosia, R/L confusion - A more general “body schema disturbance” can be seen (autopagnosia) - Apractic agraphia can be seen (cannot write; can type)
Left (dominant) angular gyrus (inferior parietal)
This man exhibits the features of Gerstmann’s syndrome, which is characterized by the tetrad of finger agnosia (inability to identify fingers bilaterally), right–left confusion, dyscalculia (inability to carry out calculations), and dysgraphia (inability to write). It localizes to the dominant inferior parietal lobule, particularly the dominant angular gyrus. A common cause is infarction of the inferior division of the middle cerebral artery, in which case there may be associated contralateral visual field deficits. Features may occur individually.
Apraxia
An acquired deficit in learned or skilled movements in the presence of intact strength and sensation
Most cases of apraxia, even when the left hand is clumsy, result from left hemisphere lesions
Can be seen after focal lesions, but also degenerative disorders, particularly cortico-basilar ganglionic degeneration (CBGD)
There are other varieties of apraxia, but ideomotor is the form most commonly encountered and described
Conduction apraxia
The dominant feature of conduction apraxia is impairment in imitation of movements. The localization of conduction apraxia is not well defined.
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).
Limb-kinetic apraxia
Difficulty with precise, independent finger movements secondary to lesion in sensori-motor cortex (usually left)
The pyramidal tract is largely dedicated to fine finger movements
Left hemisphere chiefly responsible (left pyramidal tract lesions cause some clumsiness in left hand as well)
Demonstrated best by tests of finger opposition or coin manipulation
Abstract apraxias
Occur secondary to diffuse left-hemisphere lesions damaging the concept of action purpose and sequence
ideational apraxia: Impaired action sequence (fold letter, close envelope, add stamp) - can’t come up with a plan for action
Ideational apraxia is characterized by impairment in the sequence of motions needed to carry out a specific movement. When asked to pantomime pouring a glass of water and drinking from it, patients with ideational apraxia will, for example, drink from the cup before pouring water into it. Ideational apraxia is seen in patients with bifrontal or biparietal dysfunction, as occurs in neurodegenerative disorders.
Conceptual apraxia: Loss of knowledge of the purpose of tools and the mechanical advantage they provide
Conceptual apraxia is characterized by misconception of the function of objects in the environment. For example, a patient with conceptual apraxia might use a fork to eat soup, or may pretend to use a screwdriver when asked to pantomime hammering a nail into a wall. Conceptual apraxia is seen with diffuse neurodegenerative processes, as well as with lesions in the nondominant hemisphere.
Dissociation apraxia
Disassociation apraxia is characterized by inability to execute a movement on command, but with normal ability to imitate (opposite of conduction). It has most commonly been reported to occur in the left hand in left hemispheric language dominant patients who have left MCA territory lesions.
Focal apraxias
Gaze apraxia - Disordered eye movements seen in Balint’s syndrome
Apraxia of eyelid opening - Difficulty opening the eyes despite normal consciousness and strength. Associated with right parietal lesions.
Bucco-facial - Impaired tongue / lip actions (whistle, blow out match, kiss). Often accompanies Broca’s aphasia. Seen in left inferior-frontal region (area 44).
Pseudo-apraxias
Gait “apraxia” (Brun’s ataxia) - Magnetic gait of normal pressure hydrocephalus
Constructional “apraxia” - Disorganized copying complex figures (intersecting pentagons, Rey-Osterreith) from frontal or parietal lesions
Dressing “apraxia” - Difficulty with spatial arrangement of limbs and clothing. Localizes to right parietal region
Two types of alien limb
Two types of alien limb…
Alien hand syndrome (disconnection) -
• limb (usually left hand) engages in purposeful movement the patient does not will
• Follows anterior callosal lesion
Alien hand syndrome (CBGD) -
• limb assumes postures and positions without the patient’s awareness
• usually seen in right parietal disease
The phenomenon of alien limb is marked by movement of a limb, sometimes seemingly purposefully, but not under voluntary control. Seen in CBS and PSP. Alien limb syndrome also occurs with lesions to the contralateral anterior cerebral artery territory, involving the corpus callosum or supplementary motor area
Attentional neglect
Decreased awareness of stimuli contralateral to lesion
Degree of extinction related to stimulus salience, modality, proximal vs. distal, and location in hemispace
Seen in right inferior parietal (pulvinar, basal ganglia, cingulate)
Intentional neglect
Decreased tendency to at towards stimuli or hemispace contralateral to lesion
Right dorsolateral frontal
Balint’s syndrome
Features: - Simultagnosia (can’t see forest for trees) - Optic ataxia (can’t reach for visual targets) - Ocular apraxia (can’t direct gaze)
Bilateral parietal (AD, CBGD, CJD, sagittal sinus thrombosis)
Other right parietal syndromes
Impaired sarcasm - related to loss of prosody
Topographagnosia - difficulty finding way in locomotor environment
- Dressing apraxia - not a true apraxia, but difficulty orienting limbs to clothing*
- Eyelid apraxia*
Attentional neglect
Alien limb with postures
Visual form agnosia (apperceptive)
A form of apperceptive agnosia
- Associated with diffuse damage (frequently CO poisoning) - diffuse infero-temporal damage
- Potentially intact visual fields, color, motion perception
• Unable to copy figures
Deficit of intermediate vision: difficulty segregating foreground from background or grouping objects, tend to engage in a teaching strategy to try and obtain form frommotion
Color anomia
Loss of language for color
Unable to name presented colors, but can still sort and match by color
Can accompany pure alexia (left occipital lesion)
Categorical agnosia (associative)
Prosopagnosia (FFA) • unable to process internal facial features • patient can usually discern age, gender, emotion, gaze direction • usually bilateral lesions, always right
General object agnosia (LOC) • an impairment in object recognition that FFA can spare face perception • usually bilateral lesions LOC
- *Landmark agnosia (PPA) • inability to recognize familiar environmental landmarks**
- *• uses non-salient cues for navigation (park bench, mailbox) • unilateral right lesions sufficien**
Anton’s syndrome
Cortical blindness with denial of blindness (bilateral occipital pole lesions)
This syndrome results from bilateral lesions of the medial occipital lobes (primary visual and visual association cortices).
Palinopsia
Persistence of visual sensations
Caused by occipito-temporal seizures and migraines
Release hallucinations
Caused by loss of visual input (either ocular disease or V1 lesion)
Extra-striate, categorical visual areas (for face, place, and object perception) interpret input noise as people, animals, and landscapes.
Typically non-threatening, with intact insight
In elderly people with ocular disease, this is Charles Bonnet syndrome
“Hemianopic hallucinations” within the blind field following a V1 lesion
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
Pseudo-bulbar affect (PBA)
Symptoms - • Exaggerated emotional responses (laughter, crying) with lability • Incongruous mood and affect • Upsetting to the patient, who is aware of the loss of control
Causes - • Common feature of many degenerative disorders (ALS, Alzheimer’s, Parkinson’s, multiple sclerosis) • The cerebellum seems to modulate emotional displays, and PBA results from disruption of corticopontine—cerebellar pathway
Treatment - • dextromethorphan / quinidine sulfate 20/10 mg (Nuedexta®) BID - Reduced episodes by half in patients with ALS and MS
Geschwind-Waxman syndrome
Hyposexuality, hypergraphia, hyperreligiosity
Interictal phenomenon with temporal lobe epilepsy
Kluver-Bucy syndrome
Hypersexuality, emotional placidity, hyperorality • bilateral amygdala lesions
Kluver–Bucy syndrome is caused by lesions to bilateral anterior temporal lobes/amygdala and is characterized by hyperorality (tendency to explore objects with mouth), hypermetamorphosis (preoccupied with minute environmental stimuli), blunted emotional affect, hypersexuality, and visual agnosia.
Pick’s disease has been associated with Kluver–Bucy syndrome.
This man exhibits features of Klüver–Bucy syndrome, which is seen with bilateral medial temporal lobe lesions, involving the amygdala. Clinical features may include hyperorality, visual agnosia, hypersexuality, blunted emotional affect (docility), hypokinesia, and hypermetamorphosis (over-attention to minute stimuli in the environment). It is seen following herpes simplex encephalitis, with neurodegenerative disorders such as frontotemporal dementia, following anoxic–ischemic injury to the temporal lobes, and after bilateral temporal lobectomy (a historical procedure).
Achrompatopsia
V4, V3, V2
Cognitive changes with normal aging
“Tip-of-the-tongue phenomenon”
Effortful recall that patient is aware off, but usually successful
SLOWING
This affects everything (and why older adults do worse on many tasks on time-dependent neuropsychiatric tests)Cog
Vocabulary gets better with age
Why your attendings know more words to describe things
What protects you from effects of cognitive aging (i.e. Cognitive Reserve)?
- More education
- Regular aerobic exercise before age 50 (RITE 2021)
Changes with aging
- Eye movements have mild disruptions •Restricted up-gaze after age 60 •Decreased smooth pursuits •Smaller pupils
- More physiologic tremor
- Decrease in high-frequency hearing (presbycusis)
MCI
Criteria: 1.Cognitive complaint 2.Objective impairment in one or more cognitive domains: attention, memory, language, executive, or visuospatial function.•Specific neuropsychological tests much more sensitive than MOCA/MMSE 3.Normal ADLs•can be slower and make small errors in things like paying bills, shopping, etc but still able to be independent 4.Not demented
Progression to dementia: •~15% over 2 years (95% CI 11.6-19.1%) with roughly annual 10-15% conversion rate, RR at 2-5 years of dementia compared to normal controls is 3.3 (2.5-4.5) •Approximately 14-33% will revert back to cognitively normal •Around 65% ultimately will develop dementia
What is going on during this phase? •Accumulation of neuropathology •Markers of pathology in CSF or on PET imaging •Some changes may be seen on MRI
MCI is classified as amnestic MCI (primarily memory), nonamnestic MCI (cognitive domain other than memory, such as language), or multiple domain MCI (more than one cognitive domains are affected).
Dementia diagnosis
Alzheimer’s disease
Most common pathology leading to dementia (10% over 65, 40% over 85)
Neurodegeneration starts in medial temporal lobe prior to spread posteriorly and then frontally (classically), which helps explain clinical course
Early signs: Repeat self in conversation, confusion around day/date, poor insight to deficits
Next stages: Subtle apraxia, paucity of speech content (similar to transcortical sensory aphasia), anomia w/ circumlocutions, paranoid/delusional behaviors (50%)
Late features: Nocturnal wandering, pseudobulbar affect, myoclonus, hallucinations, Balint’s syndrome (bilateral parietal atrophy)
Memory impairment is the essential and earliest clinical feature of AD. Declarative memory (facts and events) is significantly affected in AD. Of declarative memory, episodic memory (specific events and contexts) is the most impaired in early AD. Within episodic memory, memory for recent events is more prominently impaired in early AD compared with immediate or remote memory. Loss of visuospatial skills is also often an early feature of AD which manifests as navigational difficulty in unfamiliar and later familiar areas and misplacement of items.
Memory for facts such as vocabulary and concepts (semantic memory) is spared until later. Likewise, procedural memory and motor learning are also spared until later.
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
Alzheimer’s disease genetics
Familial AD is rare: 5% of all cases, they are younger at onset, autosomal dominant inheritance
APP on c21 is uncommon source of mutation (10%) but T21 is associated with premature AD pathology, possibly due to dosage
Presenilin is cofactor for γ-secretase and mutations may increase activity •Presenilin 1 (c14) mutation accounts for ~50% of familial early-onset AD •Presenilin 2 (c1) mutation accounts for ~1% of familial aggressive early-onset AD
Variation in ApoE (c19) accounts for 50% of sporadic, late-onset AD•ε4 allele increases risk in dose-dependent manner (90% risk in homozygotes by age 85)•ε2 allele protective, but increases risk for CAA
Alzheimer’s disease diagnostic study
Diagnosis is clinical, so these tests are for research purposes (although FDG PET is FDA approved for distinguishing between AD and FTD)
PET imaging:•Amyloid PET (Pittsburgh compound B (PiB), Florbetapir, Florbetapen)•Tau PET (AV-1451, aka flortaucipir)•FDG PET: temporal and parietal hypometabolism
CSF analysis: low Aβ42 and high tau (RITE 2021)•Due to poor clearance of Aβ42 so stuck in brain, not in CSF
MRI: early mesial temporal atrophy, parietal atrophy, other association cortices
Psychometric tests: impaired list learning, Boston-naming task, praxis
Alzheimer’s disease treatments
Patients with AD have reduced cerebral production of choline acetyl transferase, which leads to a decrease in acetylcholine synthesis and impaired cortical cholinergic function.
Acetylcholinesterase inhibitors: mainstay of treatment for over two decades•Data demonstrates a slowing of loss of functional independence but does not impact disease directly•Mechanism is to increase acetylcholine levels, as this is the main neurotransmitter reduced in AD
Donepezil: pure acetylcholinesterase inhibitor, only approved in mild to moderate AD (not MCI or other dementias)
Rivastigmine: a combined acetylcholinesterase and butyrylcholinesterase antagonist, approved for AD and PDD/DLB, also comes in transdermal form
Galantamine: combined acetylcholinesterase inhibitor and allosteric nicotinic modulator, approved for mild to moderate AD•Common side effects: GI upset, insomnia, vivid dreams (or nightmares)•Less common but tested: bradycardiaàorthostasis, muscle cramps (RITE 2021)•NMDA receptor antagonist
Memantine: low-to-moderate affinity noncompetitive NMDA receptor antagonist for moderate–severe dementia in Alzheimer’s disease (AD). •Generally well tolerated (but in case RITE asks: headache, constipation, sleepiness, and dizziness)
Mood/psychotic treatment in Alzheimer’s disease
- Antipsychotics can be used for confusion and aggression in dementia•Note that all antipsychotics carry black box warning for increased risk of death in dementia
- Olanzapine, Risperidone, and Aripiprazole have lowest QT-prolongation so preferred in AD•Olanzapine causes hyperglycemia and weight gain so do not use in diabetes (RITE 2021)
SSRIs are preferred antidepressants; avoid TCAs due to anticholinergic side-effects (RITE 2021)•Use mirtazapine if also have sleep issues (RITE 2021)
Control vascular risk factors to help prevent concomitant vascular dementia•SPRINT MIND trial found that aggressive BP goal (SBP < 120) in adults over age 50 led to reduction of combined rate of MCI/dementia (HR 0.85, 95% CI 0.74-0.97) compared to standard treatment (SBP < 140)
FTLD
Onset in 50s: Earliest symptoms are personality changes with relatively preserved memory
Typical MRI with temporal or anterior temporal atrophy (70% are unilateral)
Most common personality changes: Disinhibition, stereotyped behaviors, “grammaphone” (catch-phrase) syndrome, preference for sweet foods, item hoarding
FTLD three clinical variants
Three classical subtypes: 1) Behavioral variant: apathy, disinhibition, poor hygiene 2) Primary Progressive Aphasia: effortful, non-fluent speech 3) Semantic dementia: poor comprehension, anomia, associative agnosia
In FTD, mean age of symptom onset is between 55 and 60 years.
There are three major distinct clinical phenotypes of FTD. The behavioral variant FTD is the most common phenotype and symptoms include personality change, abulia, apathy, social withdrawal, social disinhibition, impulsivity, lack of insight, poor personal hygiene, stereotyped or ritual behaviors, hyperphagia, suddenly new artistic abilities or hobbies, emotional blunting, loss of empathy, mental rigidity, distractibility, impersistence, perseverative behavior, impaired organizational and executive skills.
The second phenotype, progressive nonfluent aphasia, is characterized in early stages by anomia, word-finding difficulty, impaired object naming, and effortful speech with preserved comprehension. Spontaneous speech becomes increasingly dysfluent and speech errors become frequent. Behavior and social interaction remain unaffected until late in the disease at which point the patient becomes globally aphasic.
The third phenotype is semantic dementia, also called progressive fluent aphasia, or the temporal variant of FTD. It is characterized by a progressive speech disturbance with normal fluency, b_ut impaired comprehension, anomia, and semantic paraphasias. It may clinically resemble a transcortical sensory aphasia. There is typically a predominance of left temporal dysfunction, and/or in face and object recognition, reflecting right temporal dysfunction._
In addition, some patients with FTD may develop variant syndromes of motor impairment including motor neuron disease, progressive supranuclear palsy, and corticobasal degeneration.
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
FTLD treatment
Antipsychotics can be used for aggression or agitation as described in earlier slides
Treatments for Alzheimer’s are ineffective or worsen disease: Acetylcholinesterase inhibitors should not be used in FTLD as they can worsen disease. No evidence for memantine in FTLD
Lewy body dementia
Characterized by Parkinsonism, fluctuations in attention and cognition, and visual hallucinations (typically well formed)•May have history of prior REM sleep behavior disorder
Two varieties that are highly overlapping: Dementia with Lewy Bodies—dementia with features described above and Parkinsonism starting with or after dementia diagnosis
Parkinson’s disease dementia—dementia in context of established diagnosis of PD•25-30% of patients with PD and >80% of patients will have some form of cognitive impairment (MCI or dementia) at 15 years with disease
Accounts for 3.8% of new dementia diagnoses, 4.2% of all dementia in community vs 7.5% in secondary care (likely often misdiagnosed as AD—some estimates suggest 1 in 3 cases missed).
Parkinsonism, fluctuating cognitive impairment, and visual hallucinations make up the classic triad of dementia with Lewy bodies (DLB). In addition to dementia, other clinical features may include dysautonomia, REM sleep behavior disorder, and neuroleptic sensitivity.
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.
LBD treatment
Acetylcholinesterase inhibitors approved for LBD (technically only rivastigmine) •Only approved for AD and LBD (RITE 2021)
Antipsychotics—all carry a black box warning of increased risk of death in dementia
Pimavanserin is only FDA-approved antipsychotic for treatment in LBD (specifically for PD psychosis) (RITE 2021)•5-HT2A antagonist (no dopaminergic effect)
Otherwise quetiapine and clozapine are preferred as they have they fewest extra-pyramidal side effects. Parkinsonism usually treated with levodopa therapy but typically less effective in DLB.
Acetylcholinesterase inhibitors may be of benefit. Levodopa may worsen hallucinations and high doses should be avoided in DLB. Neuroleptics have been associated with increased risk of mortality when used in older adults with dementia, but in some cases, putative benefits outweigh risks of use. Typical neuroleptics are generally avoided due to significant sensitivity, with reactions such as neuroleptic malignant syndrome, worsening parkinsonism, confusion, or autonomic dysfunction. If absolutely necessary, especially for agitated psychotic symptoms, atypical neuroleptics should be tried cautiously in low doses. Of the choices in question 11, quetiapine is the only atypical antipsychotic. Clozapine might be used as well, but the risk of neutropenia and complexity of use and follow-up make it less desirable.
Corticobasal degeneration
Most pronounced features are unilateral limb apraxia, parkinsonism, and dementia. Imaging will often show asymmetric parietal atrophy (although sometimes just asymmetric atrophy).
Trouble with numbers, spatial tasks and can cause Balint’s syndrome
Often causes “Alien-hand syndrome” where hand will behave on its own (but not that patient does not recognize as their hand)
Most often caused by 4R tau—astrocytic plaques (not neuronal) (MSA is also glial inclusions)
Vascular dementia
Heterogenous presentation but on population level tend to have more executive dysfunction and cognitive slowing
Up to 40% of cases have gradual decline that makes it difficult to differentiate from other causes of dementia•Step-wise decline and history of stroke make it more likely etiology
Often seen as co-pathology rather than pure dementia
Hachinski ischemic score has 89% sensitivity/specificity to distinguish AD•1-2 pts each: Abrupt onset, Fluctuating course, history strokes, focal symptoms, focal signs•1 pt each: stepwise deterioration, nocturnal confusion, preservation personality, depression/somatic complaints, emotional incontinence, HTN/atherosclerotic dz•If ≥ 7 points—most likely vascular dementia; ≤ 4 unlikely vascular
Vascular dementia treatment
Treatment: Acetylcholinesterase inhibitors are effective (although do not carry FDA approval) - donepezil and galantamine both with data to support efficacy
Teating vascular risk factors is paramount to prevent further accumulation of pathology: Hypertension, cholesterol management, ASA/AC for secondary stroke prevention when indicated, SPRINT MIND trial as discussed earlier
Neurostimulants can be used in patients with significant abulia or apathy: ritalin, bromocriptine, modafinil
Normal pressure hydrocephalus
Triad of gait instability, urinary incontinence, and dementia. Gait dysfunction should before or with urinary incontinence and dementia.
Most commonly presents with subcortical dementia (also seen in MS, VCID): psychomotor slowing, impaired concentration, impaired reading, forgetfulness, lack of aphasia, agnosia, apraxia. Gait is typically short and shuffling but with upright posture (magnetic gait).
Test whether shunt will be beneficial with large-volume tap (50-60% improve)
Imaging findings: Evan’s index > 30, tight high convexity, enlarged subarachnoid spaces (DESH)
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.
CJD
CJD causes rapidly progressive dementia, often with myoclonic jerks
14-3-3 and RT-Quic positive in CSF
MRI can show increased signal in caudate and thalamus, cortical ribboning on diffusion-weighted imaging (most likely sequence to show abnormality)—higher sensitivity than EEG and 14-3-3 (RITE 2021)
EEG with period sharp-wave complexes•Most commonly sporadic; variant form caused by ingestion causes more psychiatric presentation (RITE 2021)
Wernicke-Korsakoff
Chronic traumatic encephalopathy
Associated with repeated trauma
Tau in perivascular spaces and cerebral sulci (RITE 2021)
Capgras delusions
Belief that those around you replaced by imposters, localizes to temporal lobe
Fregoli syndrome
Belief that strangers are familiar, does not localize
Deep dyslexia
Semantic paraphasic errors, better with concrete than abstract, due to left hemisphere damage
Deep dyslexia is an acquired form of dyslexia, meaning it does not typically result from genetic, hereditary (developmental) causes. It represents a loss of existing capacity to read, often because of head trauma or stroke that affects the left side of the brain. It is distinguished by two things:semantic errors and difficulty reading non-words.
A paraphasia has two essential features: (1) It is an error of selection resulting in the substitution of a word or part of a word with a frequently incorrect or inappropriate alternative, and (2) it is unintended.
Surface dyslexia
Common in semantic dementia and does not localize
Regularize irregular words (sew read as “sue”)
A type of dyslexia characterized by difficulty with whole word recognition and spelling, especially when the words have irregular spelling-sound correspondences.”
Balint’s syndrome location
Balint’s syndrome: simultagnosia, optic ataxia, ocular apraxia
Bilateral parietal damage (AD, CBD, CJD) (RITE 2021)
Circuit of Papez
The circuit of Papez is: [entorhinal cortex → hippocampus → fornix → mammillary bodies → anterior nucleus of thalamus → cingulate gyrus] → entorhinal cortex → hippocampus.
The mediodorsal nucleus of the thalamus is not part of the circuit of Papez.
FDG-PET scan in different types of dementia
FDG- PET scanning may reveal decreased glucose metabolism in parietotemporal regions in AD, in the frontal and anterior temporal regions in frontotemporal dementia, in the head of the caudate in Huntington’s disease, and in the occipital regions in diffuse Lewy body disease. Progressive supranuclear palsy is associated with global metabolic reduction in regions including the anterior cingulate, basal ganglia (especially caudate and putamen), thalamus, and upper brainstem.FDG-PET scanning in Parkinson’s disease usually does not show a decrease in metabolism.
Alzheimer’s type II astrocytes
Alzheimer’s type II astrocytes are seen in hepatic encephalopathy, not in AD.
Acetylcholine in AD
In AD, along with loss of cholinergic neurons in the nucleus basalis of Meynert, there is loss of acetyltransferase activity throughout the cortex which correlates with the severity of memory loss.
Locus coeruleus
Norepinephrine (noradrenaline)
Locus coeruleus
Norepinephrine (noradrenaline)
Median and dorsal raphe nuclei
Serotonergic
FTLD genetics
In familial frontotemporal dementia (FTD), the most common linkage is to chromosome 17q21, although chromosomes 3 and 9 have also been implicated in autosomal dominant inheritance of this condition. Most sporadic cases of frontotemporal dementia have not been linked to specific chromosomal sites.
Temporal lobe lesions
Thalamic lesions and cognition
The dorsomedial nucleus has projections to dorsolateral prefrontal, orbitofrontal, anterior cingulate gyrus, and temporal lobe/amygdala. Dysfunction of this nucleus can result abulia, anterograde amnesia, social disinhibition, and motivation loss.
The anterior nucleus is mostly involved in limbic relay and memory formation (part of Papez circuit).
The pulvinar is involved in processing visual info and sensory integration. The ventral posterolateral (VPL) nucleus is involved in sensory relay from the body, while the ventral posteromedial (VPM) nucleus is involved in sensory relay from the face, both of which project to the somatosensory cortex.
Akinetic mutism
Bilateral globus pallidus interna lesions can cause akinetic mutism. In akinetic mutism, the patient generally has preserved awareness with open eyes, but remains immobile, mute, and does not respond to commands. The globus pallidus interna is part of the anterior cingulate–frontal–subcortical circuit. Recall that bilateral ACA infarcts to the frontal lobes and other lesions to the medial frontal lobes are other causes of akinetic mutism
TBI and recovery
Disorders of higher cortical function often confer more disability than focal neurologic deficits after traumatic brain injury (TBI) and interfere with rehabilitation. Of these, alterations in personality usually interfere with rehabilitation the most.
TGA
In transient global amnesia (TGA), recent memory is impaired. The pathophysiology of TGA is not well understood, but in at least some cases it is thought to result from functional alterations in the bilateral medial temporal lobes. It has been associated with migraine, hypertension, medical procedures, and stressful events, among others. It typically lasts 12 to 24 hours and usually resolves without deficit. Clinically the patients may ask the same questions over and over each time the examiners come into the room. They often forget meeting the examiner if the examiner leaves the room briefly and then returns. Immediate memory is usually spared and can be tested by digit span. Remote and procedural memory and personal identity are also retained. The primary clinical impairment in TGA is in recent (short-term) memory.
Psychogenic amnesia
Psychogenic amnesia has the characteristic finding of loss of autobiographical memory, sometimes with preserved ability for new learning.
Psychogenic amnesia
Psychogenic amnesia has the characteristic finding of loss of autobiographical memory, sometimes with preserved ability for new learning.
Wernicke’s/Korsakoff
Wernicke’s encephalopathy, which results from deficiency in thiamine (vitamin B1), as occurs in malnourishment such as in alcoholism, is defined by the triad of confusion, ataxia, and ophthalmoplegia. Korsakoff’s disease is the chronic phase of thiamine deficiency and presents with anterograde and retrograde amnesia, and is classically associated with confabulation as a result of the poor memory
Synucleinopathies and tauopathies
The synucleinopathies (also discussed in Chapter 6) are a family of proteins that includes α-synuclein, β-synuclein, and γ-synuclein. Abnormal accumulation of these proteins results in the synucleinopathies which include Parkinson’s disease, dementia with Lewy bodies, multiple system atrophy, and neuroaxonal dystrophies. The tauopathies are associated with the microtubule-associated protein, tau. Tau promotes microtubule polymerization and Accumulation of this protein results in the tauopathies.
Anomia
Anomia is inability to name objects with otherwise relative preservation of language expression and comprehension. Patients are able to recognize the objects but cannot name them. Anomia usually occurs in association with other features of Broca’s (expressive) aphasia (see question 54), though it may occur in isolation, particularly during recovery of a Broca’s (expressive) aphasia. Anomia may occur with a variety of lesions, including dominant hemisphere posterior inferior frontal gyrus and temporal lesions. It has also been reported to occur in angular gyrus syndrome, due to lesions of the dominant angular gyrus, in association with Gertsmann’s syndrome (discussed in question 70) and constructional difficulties.
CJD and prion day
This histopathology is consistent with Creutzfeldt–Jakob disease (CJD). The five human prion diseases are kuru, CJD, variant Creutzfeldt–Jakob disease (vCJD) (“mad cow disease”), Gerstmann–Straüssler–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.
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.
Sporadic CJD
CJD is a rapidly progressive dementia associated with variable extrapyramidal/pyramidal tract signs, myoclonus, and ataxia, and death typically ensues within 1 year.
Neuroimaging of CJD includes cortical ribbon sign (restricted diffusion in the cortex), and increased T2 signal in the caudate, putamen, and pulvinar of the thalamus.
Sporadic CJD occurs at a rate of approximately 1 per 1,000,000 population per year.
Sporadic cases account for 85% to 95%, while 5% to 15% are familial, with an autosomal dominant pattern of inheritance. The pathology occurs when the normal prion protein (PrP), which is primarily an α-helical structure, converts into an abnormal form containing a higher percentage of β-pleated sheets. The abnormal form is insoluble, polymerizes, and accumulates intracellularly and is resistant to proteolysis. The prion protein gene (PRNP) coding for PrP is located on chromosome 20p. The other chromosomes listed all relate to Alzheimer’s disease. Polymorphism at codon 129 of the PRNP is believed to determine susceptibility for CJD, and homozygosity for either methionine or valine at codon 129 has a strong correlation with the various forms of CJD including sporadic, iatrogenic, variant (“mad cow disease”), and familial forms.
Genetics of CJD
Chromsome 20
5% to 15% are familial, with an autosomal dominant pattern of inheritance. The pathology occurs when the normal prion protein (PrP), which is primarily an α-helical structure, converts into an abnormal form containing a higher percentage of β-pleated sheets. The abnormal form is insoluble, polymerizes, and accumulates intracellularly and is resistant to proteolysis. The prion protein gene (PRNP) coding for PrP is located on chromosome 20p.
NFTs in AD
NFTs are intraneuronal collections of paired helical filaments made up of hyperphosphorylated tau protein.
Risk factors for AD
The major risk factor for AD aging. Gender has also been associated with increased risk, with female gender conferring a greater risk than male gender. Apolipoprotein E4 genotype is also associated with increased risk of AD. Low level of education, repeated head trauma, family history of dementia, smoking, and vascular risk factors have also been associated with increased risk of AD.
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.
Agnosia
Agnosia is loss of ability to recognize previously known stimuli, while the specific sense to detect the stimuli is not impaired.
Prosopagnosia is the inability to recognize faces. Ability to recognize people using other cues is often preserved. Face recognition is thought to be a function of the right hemisphere, but prosopagnosia most commonly occurs with bilateral lesions of the emporo-occipital regions (bilateral fusiform gyri), as occurs with bilateral posterior cerebral artery infarction. It can also be seen as part of more diffuse processes that preferentially affect the temporal lobes, such as Alzheimer’s disease. Associated features may include achromatopsia (a disorder of color perception) and visual field deficits.
Topographagnosia, a defect in spatial orientation, is marked by inability to navigate in familiar places, read maps, draw floor maps of familiar places, and perform similar functions. It localizes to the nondominant posterior parahippocampal region, infracalcarine cortex, or nondominant parietal lobe.
Asomatognosia is marked by an indifferent inability to recognize one’s own body part. It most often localizes to the contralateral (usually nondominant) superior parietal lobule, the supramarginal gyrus, and/or its connections. In somatoparaphrenia, a form of asomatognosia, the patient denies ownership of a limb or limbs and claims the limb is missing, or has been stolen.
Misoplegia is severe hatred of a limb, a rare form of agnosia seen in hemiparetic or hemiplegic patients following stroke. The patient may attempt to cut off the limb or otherwise damage it.
Alexia without agraphia
This patient exhibits the syndrome of alexia without agraphia, or pure word blindness. Alexia is a loss of reading comprehension despite normal visual acuity. Ability to read individual letters of a word is often retained. Writing and language comprehension are normal in alexia without agraphia. It is a disconnection syndrome, due to lesions in the dominant (usually left) posterior cerebral artery territory, commonly involving the medial and inferior occipitotemporal region and splenium of the corpus callosum. The patient has a contralateral (usually right) homonymous hemianopia. While the ipsilateral visual field is intact, words that are seen cannot be effectively read, as the lesion in the splenium of the corpus callosum prevents them from being transmitted to Broca’s area.
Nonverbal auditory agnosia
In nonverbal auditory agnosia, there is agnosia to sounds, such as the sounds animals make or environmental sounds. This most often occurs with bilateral anterior temporal lesions, though nondominant temporal lobe lesions can lead to this as well.
Foix–Chavany–Marie syndrome
Foix–Chavany–Marie syndrome, also known as anterior opercular syndrome, is characterized by severe dysarthria, bilateral voluntary paralysis of the lower cranial nerves with preserved involuntary and emotional innervation. This syndrome is associated with bilateral anterior opercular lesions, frequently in the setting of multiple infarcts.
Amelodia
Amelodia or affective motor aprosodia localizes to the nondominant posterior inferior frontal gyrus, the nondominant hemisphere’s analog to Broca’s area. Similarly, the inability to perceive and understand the emotional content of others’ speech, sensory or receptive aprosodia, localizes to the nondominant posterior superior temporal gyrus, the nondominant hemisphere’s analog to Wernicke’s area.
Pseudobulbar affect
The pathophysiology of pseudobulbar affect is complex, but it most often occurs in patients with bilateral lesions that disconnect the corticobulbar tracts from the brainstem cranial nerve nuclei. It is commonly seen in patients with diffuse subcortical dysfunction, as occurs with amyotrophic lateral sclerosis, multiple sclerosis, and following traumatic brain injury but has also been reported in patients with focal mass lesions or acute infarctions.
Wiscosin Card Sorting Test
The Wisconsin Card Sorting Test can be used as a measure of prefrontal cortical function. It requires the patient to arrange cards based on a specific concept. It is a test of frontal lobe function, and assesses visual conceptualization and set shifting.
The Grooved Pegboard Test
The Grooved Pegboard Test evaluates finger dexterity. The patient is timed as he/she places pegs into small grooved holes in a board. The grooves are oriented in different directions, requiring the patient to rotate the peg in their fingers, which increases the demands for distal dexterity. Right and left hands are performed separately, and the patient’s time is compared to normative data.
The Trail Making Test Part A
The Trail Making Test Part A times the patient as he/she connects numbers on a page, and is a test of simple speed of processing, visual search, and attention. The Trail Making Test Part B requires the patient to connect consecutive numbers and letters, and tests set shifting (shifting between numbers and letters) and working memory (maintaining the correct sequence), in addition to the demands of Trails A.
The Random Cancellation Test,
A measure of visual attention and processing speed, assesses the ability to visually scan and identify specific targets in a large array of similar items.
The Clock-Drawing Test,
In the Clock-Drawing Test, a test of visuospatial function but also auditory comprehension, attention, and executive function, the patient is asked to draw a clock (including the numbers) with the hands set at a specific time.
Reduplicative paramnesia
Which overlaps significantly with Capgras’, but there is a delusion that there are identical places/objects rather than just people
Cotard’s delusion
A person’s belief that they are dead or dying
Pseudocyesis
Pseudocyesis is not classified under the delusional misidentification disorders but is a delusion that a person is pregnant when they are in fact not; the patient may manifest the signs and symptoms of pregnancy. It is more common in females but has been reported in males.
Anosognosia
A lack of awareness of an acquired neurologic deficit, and hemispatial neglect syndrome, consistent with a lesion in the nondominant hemisphere involving the primary somatosensory cortex (area SI). A lesion in the thalamus can also lead to a neglect syndrome.
Thalamic pain syndrome
Damage to the posterolateral thalamus gives rise to Dejerine– Roussy syndrome, or thalamic pain syndrome, which is characterized by initial contralateral hemianesthesia followed weeks later by pain, hyperesthesia, and allodynia. A similar delayed central pain syndrome can occur with a lesion to the medial lemniscus, dorsal columns, or with lesions to the parietal operculum (the latter is also termed pseudothalamic syndrome). The spinothalamic tract projects to the ventral posterolateral nucleus of the thalamus, which in turn projects to the secondary somatosensory cortex (area SII).
Loss of declarative memory vs nondeclarative memory
Declarative, or explicit memory, involves memory for facts or experiences. Declarative memory includes semantic knowledge, or knowledge for facts and objectives, and episodic knowledge, or knowledge of events. Nondeclarative, or implicit memory, involves memory of skills and other acquired behaviors, such as ability to drive a car or ride a bicycle. Lesions to the bilateral medial temporal lobes leads to loss of predominantly declarative (explicit) memory, leading to an anterograde amnesia with a retrograde amnesia involving a specific period prior to injury, but usually with preservation of more remotely formed memories. On the other hand, there is not a specific lesion that would lead to loss of nondeclarative memory in general.
Consciousness
Consciousness is maintained by a variety of structures, including the reticular activating system in the brainstem, the thalamus (particularly the intralaminar nuclei), and the frontal lobes, particularly the medial aspect. In order to significantly affect consciousness, these areas must be involved.
CSF findings in AD
CSF findings in AD include reduced CSF beta-amyoid1–42 and increased total and phosphorylated CSF tau.
Phases of AD
The concept of Alzheimer’s disease (AD) has been reframed to incorporate the presymptomatic phase of the disease. Three phases of AD have been defined: preclinical (where there are no clinical symptoms but there are biomarker changes such as amyloid deposition seen on amyloid imaging), prodromal (where patients have biomarkers positive and early symptoms but not affecting function), and Alzheimer’s dementia (where patients have biomarkers and express functional deficits). T
The preclinical phase is thought to predate the onset of Alzheimer’s dementia by years. Imaging studies with amyloid PET imaging have shown amyloid deposition years prior to clinical symptoms, consistent with a prolonged asymptomatic period for this disease.
Chromosome 1
Presenlin 2 (AD)
Chromosome 14
Presenlin 1 (AD)
Chromosome 19
Apolipoprotein E4 (AD)
Chromosome 21
Amyloid precursor protein (AD)
Neuritic plaques, amyloid plaques, amyloid antipathy, neurofibrillary tangles, granulocvacuolar degeneration, Hirano bodies
AD
Lewy bodies
Dementia with Lewy bodies
Fluctuating cognition, visual hallucinations, Parkinsonism
Dementia with Lewy bodies
CAG repeat on chromosome 4, AD
Huntington’s disease
Waxing and waning mental status
Delirium
Synucleinopathy
MSA, PD, dementia with Lewy bodies, neuroaxonal dystrophy
Tauopathy
AD, CB(G)D, PSP, FTD
Globose NFTs and tufted astrocytes
PSP
Spongiform encephalopathy
CJD
Cognitive dysfunction, gait impairment, urinary incontinence
NPH
Gerstmann’s syndrome
Finger agnosia, R//L confusion, dysgraphia, dyscalculia, Localization: dominant inferior parietal lobule (angular gyrus)
Where?
Parieto-occipital pathways
What?
Parieto-temporal pathways
Balint’s syndrome
Optic ataxia, oculomotor apraxia, and simultagnosia. Localization: bilateral parieto-occipital cortices.
Anton’s syndrome
Denial of cortical blindness, bilateral medical occipital lesions
Kluver-bucy syndrome
Hyperorality, visual agnosia, hyper sexuality, blunted emotional affect (docility), hypokinesia, and hypermatamorphosis. Localization - bilateral medial temporal lobe lesions, involving amygdala.
Dressing apraxia
Nondominant parietal cortex
Hemisensory neglect
Nondominant parietal cortex
Conjugate gaze deviation in direction contralateral to the hemiparesis
Lesion in FEF
Expressive aphasia but with intact repetition
Transcortical motor aphasia, MCA-ACA watershed territory, disconnecting SMA from Broca’s area
Receptive aphasia but with intact repetition
Transcortical sensory aphasia, MCA-PCA watershed territory or thalamic infarct
Ideomotor apraxia
P_atient understands the movement to be executed but has difficulty with postural and spatial orientation. Dominant parietal cortex (superior marginal/angular gyrus)_
Ideational apraxia
Patient struggles with temporal sequence of events need to execute a movement. Bifrontal or biparietal cortex.
