Movement disorders: Pathology review

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Case Study0:00–1:06

In the neurology ward, there’s a mother with her child, named Justin, who is 2 years old. Justin’s mother is worried because she palpated a mass in his abdomen while bathing him.
Justin also has been having episodes of rapid, dancing eye movements as well as shocklike, jerky movements of his extremities.
Next, there’s a 42 year old male, named Oliver. For the past few months, Oliver has been acting strangely according to his sister.
He forgets important information and is very aggressive with his family. He also has bursts of wild, dance-like movements of his arms.
His sister is very anxious because their father died at age 50 after having similar symptoms. Okay, now next to Oliver, there’s a 58 year old male, named Ashton.
His wife has noticed that her husband’s face has become inexpressive and he has been having hand tremor at rest for the past few months.
Also, his movements have become slower, and he had frequent falls. His medical history is otherwise insignificant.
Okay, so all of them have movement disorders. The cerebrum, cerebellum, and basal ganglia all help coordinate movements, so movement disorders can be traced back to these structures.

Pathology1:06–1:32

Movement disorders can be broadly grouped into 2 categories, hypokinetic disorders, which cause slowness of movement, and hyperkinetic disorders, which cause excessive involuntary movement.

Parkinsonism 1:32–3:17

Alright, when it comes to hypokinetic disorders, a lot of their symptoms are grouped together under the term “parkinsonism.” This can appear in many conditions including Parkinson’s disease itself, and other syndromes called “parkinson-plus” syndromes.
These cause parkinsonism, plus other clinical features. Some Parkinson-plus syndromes include Lewy body dementia, multiple system atrophy, and progressive supranuclear palsy.
Okay, the four cardinal symptoms of parkinsonism can be remembered with the mnemonic “TRAP”. “T” for tremor, which is classically described as a resting, pill-rolling tremor, because it looks like someone is rolling a pill between their thumb and index finger.
“R” stands for rigidity, which is often described as a cogwheel-like rigidity. This means that when attempting to passively move a limb, there are a series of stops or stalls, kind of like a cog on a wheel.
There’s also lead-pipe rigidity, which is when a limb is rigid throughout the entire passive movement, kind of like trying to move a lead-pipe.
“A” stands for akinesia, which is the absence of movement, and is a severe form of the more common finding of bradykinesia, which is slowness of movement.
This can manifest as a narrow-based shuffling gait or a decreased facial expression, almost to the point where the individual’s face looks like they’re wearing a mask.
“P” stands for postural instability, which causes a stooped posture, problems with balance, and an increased frequency of falls.
Usually, these symptoms are asymmetric, with the exception of medication-induced parkinsonism, which usually causes symmetric symptoms.
Now, Parkinson’s disease is a slowly progressive genetic disorder that primarily affects individuals over 50 years old. Parkinson’s derives from the loss of dopamine-producing, or dopaminergic, neurons in the substantia nigra, which is a part of the basal ganglia.

Parkinson’s disease 3:17–5:44

The substantia nigra can be split into two sub-regions, the pars reticulata, and the pars compacta. The pars compacta sends messages to the striatum via neurons rich in the neurotransmitter dopamine, forming the nigrostriatal pathway, which helps to stimulate the cerebral cortex and initiate movement.
In Parkinson’s the pigmented dopaminergic neurons in the pars compacta gradually disappear and this depigmented region can be seen in an autopsy.
There’s also degeneration in the nigrostriatal pathway which decreases its projections to the cortex, thus causing bradykinesia.
Under a microscope, Lewy bodies are present in the substantia nigra, and these are eosinophilic, round inclusions made of alpha-synuclein protein, that are present in the dopaminergic neurons before they die.
Alright, now normally within the basal ganglia there’s a balance between dopamine, which promotes movement, and acetylcholine, which inhibits movement.
In Parkinson’s disease, the loss of dopaminergic neurons, results in less movement, as well as difficulties in speech and swallowing.
In fact, a common complication in Parkinson’s disease is aspiration pneumonia. Parkinson’s disease also causes cognitive symptoms, like dementia in the later stages of the disease, affective symptoms, like depression, sleep disturbances, and a loss of the ability to smell.
Interestingly, seborrheic dermatitis, an oily skin rash that appears on the scalp, face, chest and axilla has also been associated with Parkinson’s disease.
For treatment, the motor symptoms can be managed by using monoamine oxidase type B inhibitors, amantadine, dopamine agonists, or levodopa.
If these medications don’t work, deep brain stimulation is also an option. Psychosis should be managed with a second generation antipsychotic like clozapine since first generation drugs often worsen the motor symptoms.
Alright, now onto the “parkinson-plus” syndromes. First up is Lewy body dementia, which is distinct from dementia secondary to Parkinson’s disease in that the onset of dementia and motor symptoms are less than one year apart.

Parkinson-plus syndromes5:44–7:36

Also, Lewy body dementia causes very vivid visual hallucinations. There’s also multiple system atrophy which causes parkinsonism plus autonomic system failure, resulting in orthostatic hypotension, impotence, and urinary incontinence or retention.
Another condition is progressive supranuclear palsy which causes parkinsonism plus a disturbance in downward eye gaze, and sometimes a disturbance in upward eye gaze as well.
These individuals often also have cranial nerve palsies, dysphagia, and an increased frequency of falls, especially backwards.
Finally, in individuals predisposed to strokes, multiple small vessel infarcts in the basal ganglia may cause a form of parkinsonism called vascular parkinsonism.
But parkinsonism can also be caused by medications that block dopamine receptors, including typical, or first generation antipsychotics like haloperidol, which blocks dopamine receptors, and metoclopramide, a dopamine antagonist sometimes used to treat vomiting.
This is why these drugs should be avoided in people with parkinsonism. Now, in rare cases, Parkinsonian symptoms may be caused by MPTP, a toxic impurity that can be found in the recreational drug MPPP, or desmethylprodine, which is a synthetic opioid.
Once inside the brain, MPTP is metabolized to the toxic form of MPP+ that can cause damage to the substantia nigra, resulting in parkinsonism.
Okay, moving onto hyperkinetic movement disorders. First up is tremor, which is an involuntary, rhythmic movement of a body part, and is the most common movement disorder.

Tremor7:36–9:34

Tremors can be classified into resting and action tremors. Resting tremors develop when the affected body part is resting, and is gravity-dependent, and they usually disappear when the person begins a voluntary movement.
Action tremors are further grouped into kinetic tremors and postural tremors. Kinetic tremors are simple if they occur uniformly throughout a voluntary movement, intentional, if it worsens as the affected body part approaches the target, and task-specific, if it occurs during a specific task, like writing.
Intention tremors are often associated with a problem with the cerebellum, and can accompany other cerebellar signs like ataxia and dysmetria.
Postural tremors occur when the individual is in a specific position, such as extending their arms out. One very specific type of tremor is called a flapping tremor, or asterixis, and it’s induced when a person fully extends their wrists, which will cause the wrist to flap, like a bird flapping its wings.
It’s a classic sign of hepatic encephalopathy in liver disease, uremic encephalopathy in kidney disease, and carbon dioxide retention in lung disease.A specific and extremely common tremor disorder is essential tremor.
It’s thought to be inherited in an autosomal dominant way, although there can be incomplete penetrance, meaning that some affected individuals may not develop all of the features.
Individuals with essential tremor usually develop a unilateral or bilateral postural and kinetic tremor in their arms, face, and head, including the vocal cords, leading to problems with speaking.
The tremor is often worsened by caffeine, emotional distress, and hunger, while alcohol can relieve the tremor. The treatment is beta blockers like propranolol.
Now, a dystonia consists of an involuntary, sustained contraction of a muscle group that results in abnormal twisting movements or postures.

Dystonia9:34–10:34

Dystonias can occur due to dysfunction of the basal ganglia and can be classified into focal dystonias, involving only a specific muscle group or generalized dystonias, which involve multiple muscle groups.
Examples of focal dystonias include blepharospasm, which is a spasm of the eyelid muscles, causing an increased frequency of blinking.
Another example is cervical dystonia involving the sternocleidomastoid muscle and causing the neck to deviate to one side, and causing torticollis.
Limb dystonias are often brought on by specific tasks, for example writing can cause a “writer’s cramp”, or golfing can cause what’s called “the yips” where the golfer makes sudden involuntary jerks, messing up their putting.
An effective treatment for dystonia is botulinum toxin.Alright, now athetosis is an involuntary, slow, snake-like movement of the limbs.

Athetosis10:34–10:40

On the other hand, chorea involves involuntary, random, rapid, dance-like movements. When they occur together, they’re described as choreoathetosis.

Chorea10:40–13:40

Chorea can be seen in Huntington disease, which is a disease frequently tested on the exams! So, Huntington’s disease is an autosomal dominant neurodegenerative disorder that typically affects individuals around 40 years of age.
It is caused by a mutation in the Huntington disease, or HD, gene on chromosome 4. This gene contains a trinucleotide repeat of CAG sequences, which encode for the amino acid glutamine, The gene encodes for a protein called huntingtin.
The mutated protein aggregates within the neuronal cells of the caudate and the putamen of the basal ganglia, causing neuronal cell death.
The brain regions affected by Huntington disease have decreased GABA and acetylcholine and increased dopamine levels. Over time, if enough neurons die in the caudate and putamen, which together form the dorsal striatum, this can cause actual loss of brain tissue volume in these areas, which can exand to the lateral ventricles.
These areas of the brain play an important role in movement, particularly, inhibiting it, and that’s why Huntington disease causes movement problems like chorea.
But they also have cognitive symptoms, like dementia, and psychiatric symptoms like depression, psychosis or aggressive behavior.
Death usually occurs within 10–20 years of diagnosis, often by aspiration pneumonia, on account of discoordinated swallowing, or by suicide.
Alright, now another high yield concept about Huntington disease is a phenomenon called anticipation, which is where there’s an increased number of trinucleotide repeats in subsequent generations.
This leads to an earlier onset and more severe presentation of the disease. This process of adding more repeats is called repeat expansion.
It happens way more in the production of sperm than eggs, and so anticipation generally occurs when the biological father is the affected parent.
Okay, now, chorea is also a feature of other diseases like acute rheumatic fever, where it’s called Sydenham chorea, and systemic lupus erythematosus.
It can also occur in metabolic conditions like thyrotoxicosis or acute hyperglycemia, or even in pregnancy, in which it would be called chorea gravidarum.
Finally, a severe form of chorea is called hemiballismus. That’s where there are wild, flinging movements of a limb on one side of the body.
For the exams remember that hemiballismus is usually due to a lesion in the contralateral subthalamic nucleus in the basal ganglia.
These lesions are caused by strokes due to long standing hypertension. A myoclonus is an involuntary, brief, rapid, jerky movement.

Myoclonus13:40–15:17

A good example of a myoclonus is that of the diaphragm, which we would call a hiccup. Similar to dystonias, myoclonus can be generalized or focal.
Now, a very important disease associated with myoclonus is Creutzfeldt-Jakob disease. For the exams remember that it is a rare prion-borne illness that results in rapidly progressive dementia and myoclonus.
The myoclonus is usually generalized and can be triggered when the person is startled. It’s caused by accumulation of abnormal prion protein, or PrP and is typically fatal.
Another high yield fact you absolutely have to remember for the exams is opsoclonus-myoclonus syndrome, which is when there’s rapid, erratic, dancing eye movements along with limb myoclonus, and is often also associated with ataxia.
This is classically a paraneoplastic syndrome associated with neuroblastoma which typically develops as an abdominal mass in young children.
Myoclonus can also be a feature of juvenile myoclonic epilepsy, which is a seizure disorder that affects adolescents. Individuals with juvenile myoclonic epilepsy present with myoclonic jerks in the morning followed by generalized tonic-clonic seizures.
Finally, a mitochondrially inherited disorder called myoclonic epilepsy with ragged red fibers, or MERRF, classically causes myoclonus and muscle weakness.

Tics15:17–16:43

Finally, tics are involuntary, brief, purposeless, stereotypical movements that typically involve the head, face, eyes, mouth and neck.
Tics are broadly classified into motor and vocal tics, with each group subclassified into simple and complex. Simple motor tics involve one muscle group, such as twitching of the nose, while complex motor tics involve multiple muscle groups, such as jumping or head banging.
Simple vocal tics tend to manifest as grunting, barking or throat clearing, while complex vocal tics involve words, phrases or sentences.
Motor tics also include echopraxia, which is mimicking the movements of others, or copropraxia, which is expressing inappropriate gestures.
Similarly, interesting vocal tics include echolalia, which is repeating the words or phrases of others, palilalia, which is repeating one’s own words, and coprolalia, which is verbally expressing obscenities.
Now, the most important tic disorder is Tourette syndrome, a genetic disorder that affects boys more than girls and children more than adults.
Interestingly, Tourette syndrome is often associated with psychiatric conditions, like ADHD, OCD, and autism spectrum disorder.
Alright, now restless leg syndrome is characterized by discomfort in the legs when resting or falling asleep, an urge to move the legs, and immediate relief after moving them.

Restless leg syndrome16:43–17:09

Interestingly, restless leg syndrome has been associated with iron-deficiency and chronic kidney disease. It can be treated with dopamine agonists like ropinirole.
Finally, there’s Wilson’s disease which is an autosomal recessive disorder. This is caused by a mutation in hepatocyte copper-transporting ATP-ase which is needed to move copper from the liver into bile for excretion, and it’s also needed to synthesize ceruloplasmin, the copper storage and transport protein in the blood.

Wilson’s disease 17:09–18:22

So the mutation leads to excessive copper buildup in the liver, and low ceruloplasmin level. Eventually, the copper overflows into the blood and deposits in the brain and eyes.
A typical case in your exam will present an individual with cirrhosis and psychiatric changes like personality changes, depression, or psychosis.
Some individuals can also develop a movement disorder, that can be either hypokinetic, like dystonia and parkinsonism, or hyperkinetic like tremor.
And another high yield finding is Kayser- Fleischer ring, which is a dark ring around the iris due to copper deposits in the cornea.
Treatment includes chelation with penicillamine, oral zinc, and in cases where there’s liver failure, a transplant might be needed.Alright, now generally, the diagnosis of movement disorders is based upon the clinical presentation.

Diagnosis18:22–22:23

The diagnosis of Parkinson’s disease requires the presence of bradykinesia in addition to another one of the “TRAP” symptoms, and ruling out other potential causes.
In terms of “parkinson-plus” syndromes, onset of dementia and parkinsonism in less than one year along with vivid visual hallucinations may indicate Lewy body dementia.
Autonomic dysfunction manifesting as orthostatic hypotension or impotence along with parkinsonism may indicate multiple system atrophy.
Downward or upward gaze palsy and an increased frequency of falls along with parkinsonism indicates progressive supranuclear palsy.
Moving onto hyperkinetic disorders. For tremors, the presence of a metabolic disorder, such as hepatic encephalopathy, uremic encephalopathy or lung disease, indicates flapping tremor, while family history of tremor indicates essential tremor.
Now, diagnosis of chorea can be suspected in the presence of acute rheumatic fever or lupus. Also, chorea gravidarum should be suspected in metabolic conditions like thyrotoxicosis or acute hyperglycemia, or even in pregnancy, while hemiballismus occurs due to a lesion in the contralateral subthalamic nucleus in the basal ganglia.
Now, diagnosis of Huntington's disease should be suspected in an individual around 40 years of age with chorea, cognitive and psychiatric symptoms.
Family history of a first-degree relative is also a very important clue. The diagnosis is confirmed using polymerase chain reaction of the HD gene, which shows the CAG repeats.
MRI imaging of the brain characteristically shows atrophy of the caudate and putamen, and enlargement of the lateral ventricles, and that’s something you also have to remember for the exams!
Okay, now presence of myoclonus can indicate Creutzfeldt-Jakob disease, juvenile myoclonic epilepsy or MERRF. In Creutzfeldt-Jakob disease, multiple vacuoles form in neutrophils and neurons of the gray matter and these vacuoles progressively transform into cysts.
These characteristic findings can be seen on MRI and so the disease is also called spongiform encephalopathy. Now, the presence of neuroblastoma, which can be described as an abdominal mass in a child, points towards opsoclonus-myoclonus syndrome.
Alright, now the major difference between tics and any other movement disorder is that although tics are involuntary, the individual can anticipate when the tic is about to happen, and can voluntarily suppress them to a certain degree.
Additionally, tics are accompanied by an irresistible urge to let the tic occur. In fact, the longer the individual holds in the tic, the more intense the outburst will be, a bit like trying to suppress a cough.
To diagnose Tourette syndrome, three criteria must be met. First, the individual should develop at least 2 motor tics and 1 vocal tic.
Second, the onset of symptoms must be before 18 years of age. And third, the individual should have the symptoms for over 1 year.
Now, the diagnosis of restless leg syndrome is primarily based on clinical presentation. However, the presence of iron deficiency anemia or chronic kidney disease can also be a clue.
Finally, any individual less than 40 years of age with a movement disorder like tremor, chorea or dystonia should be evaluated for Wilson’s disease.
This includes performing a slit-lamp ophthalmoscopic examination to look for Kayser-Fleischer rings, and measuring 24-hour urine copper and serum ceruloplasmin levels.
In Wilson’s disease, individuals have a high urine copper level and low serum ceruloplasmin level. All right, as a quick recap!

Review22:23–23:05

Movement disorders can be either hypokinetic, or hyperkinetic. Hypokinetic disorders cause slowness of movement, and include Parkinson's disease and parkinson-plus syndromes, such as Lewy body dementia, multiple system atrophy, and progressive supranuclear palsy.
Hyperkinetic disorders cause excessive involuntary movement, and include tremors, dystonia, athetosis, chorea, tics and restless leg syndrome.
Wilson’s disease can present with either a hypokinetic or hyperkinetic movement disorder. A diagnosis can be made based on the patient’s medical history and clinical presentation.
Now, back to the patients! Justin most probably has opsoclonus-myoclonus syndrome, occurring as a paraneoplastic syndrome.

Summary23:05–23:43

The abdominal mass that his mother palpated is probably a neuroblastoma. Imaging studies and tissue biopsy of the mass must be done to confirm the diagnosis.
Now, due to his age, symptoms, and family history, Oliver most likely has Huntigton disease. PCR of the HD gene can confirm the diagnosis.
Moving onto Ashton. He most probably has Parkinson’s disease due to the bradykinesia, along with the resting tremor,