Movement disorders: Pathology review
AssessmentsMovement disorders: Pathology review
USMLE® Step 1 style questions USMLE
A 12-year-old boy is brought to the pediatrician by his parents due to personality changes, difficulty speaking, and impaired balance over the past year. They describe the patient as a previously bright, cheerful child who enjoyed activities at school and socializing with friends. Over the last several months, he has become very impulsive and irritable and is also having significant trouble completing homework on time. The patient also used to be an avid soccer player but recently dropped out of the team due to poor performance and lack of interest. Vitals are within normal limits. Physical examination of the patient shows significant loss of coordination and dysarthric speech. Slit-lamp examination of the eyes is shown below:
Reproduced from: Wikimedia Commons
Which of the following additional findings is most likely to be found in this patient on further testing?
Content Reviewers:Yifan Xiao, MD
Contributors:Robyn Hughes, MScBMC, Victoria Cumberbatch, Jerry Ferro, Maria Emfietzoglou, MD
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. Movement disorders can be broadly grouped into 2 categories, hypokinetic disorders, which cause slowness of movement, and hyperkinetic disorders, which cause excessive involuntary movement.
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. 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. 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. 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. 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.
On the other hand, chorea involves involuntary, random, rapid, dance-like movements. When they occur together, they’re described as choreoathetosis.
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.
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