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| Genodermatoses and Syndromes |
Tuberous sclerosis (Bourneville’s syndrome) is a multisystem disease that often manifests with cutaneous findings. It is inherited in an autosomal dominant manner and is directly caused by a defect in one of two genes, TSC1 or TSC2, usually due to a spontaneous mutation. TSC1 has been shown to encode the hamartin protein, whereas TSC2 gene encodes the tuberin protein. The skin, central nervous system (CNS), cardiovascular, respiratory, visual, and musculoskeletal systems are affected. This genodermatosis has an extremely variable phenotype. At one extreme is the severely disabled and mentally delayed individual with severe seizure disorders; at the other end of the spectrum is the individual with mild skin disease and unappreciable CNS disease.
Tics and Tourette Syndrome
Tics are sudden, rapid, stereotyped,
repetitive, nonrhythmic
movements or vocalizations affecting discrete muscle groups. Most experts agree
and clinical experience dictates that tics are preceded by a sensory component,
described by patients as an “urge.” When patients are asked to prevent
movements from occurring, an uncomfortable inner sensation builds and an urge
to “release” develops, resulting in expression of the tics.
The
spectrum of tics includes transient tics of childhood when present for
less than 1 year, chronic motor or vocal tics when tics are present for
more than 12 months, and Tourette syndrome, defined by the presence of
both motor and vocal tics for more than 12 months.
Tics
may be classified according to complexity of symptoms as simple motor or
vocal tics when involving only a few muscles or simple sounds, such as eye
blinking, shoulder shrugging, facial grimacing, whistling, grunting, throat
clearing, snorting, chirping, or sniffing. Many such youngsters are initially
mistakenly diagnosed as having chronic rhinitis or “allergies,” or punished
unnecessarily for loud behaviors. Once considered rare, schoolteachers now
easily identify tics and may be the first to call attention to a child’s unique
behavior. In complex motor or vocal tics, multiple muscle groups are
recruited in orchestrated bouts of involuntary movements or utterances of words
and sentences or phrases. Examples include hand gestures, jumping, touching,
pressing, shouting words, or speech blocking. Some individuals may exhibit copropraxia,
the sudden performance of obscene gestures or echopraxia, the
involuntary spontaneous imitation of someone else’s movements.
Tourette
syndrome (TS) is characterized by multiple motor and vocal tics. In many TS
patients, obsessivecompulsive
behaviors and attention deficit disorder, or both, may be present. Anxiety,
depression, and self
injury behaviors may complicate the clinical picture.
Tics
may be primary or “idiopathic” or secondary, in which a definable
cause is found. Primary tics are by far the more common in children and
adolescents, with secondary disorders in that age group being rare. In adults,
trauma, encephalitis, stroke, carbon monoxide poisoning, neurosyphilis,
CreutzfeldtJakob
disease, and central nervous system (CNS) injury from hypoglycemia may result
in tics or Tourettism. Some genetics disorders in which tics have been
described include Huntington disease, neuroacanthocytosis, neuroferritinopathy (HallervordenSpatz disease), dystonia
with tics, tuberous sclerosis complex, and some cases of Duchenne muscular
dystrophy. A few patients with Down syndrome, Asperger/autism spectrum, and
fragile Xtremor syndrome
have also been reportedto have tics. The use of illicit drugs or medications
may result in tics, Tourettism, or punding, particularly the use of cocaine,
amphetamines, and antiepileptic medications (phenobarbital, phenytoin, and
carbamazepine). Less commonly, opioids, lithium, levodopa, and antidepressants
may induce or worsen tics.
The
substrate for tics and Tourette syndrome seems to reside in the basal ganglia
and related structures. Supporting evidence for this concept includes the
clinical observation of tic improvement when patients are treated with dopamineblocking or dopaminedepleting agents. Other
evidence comes from func
tional imaging studies demonstrating volumetric striatal changes and, in some,
increased dopamine synaptic content. Recently, deep brain stimulation has side
effects. Tetrabenazine, a dopamine depletor, may be useful in some cases. A
stimulant such as methylphenidate does not worsen tics as previously thought.
It can therefore be safely used in those with tics and attention deficit
disorder. The serotonin reuptake inhibitors are helpful in treating anxiety, depression,
or obsessivecompulsive
disorder in patients with tics or Tourette syndrome. Botulinum toxin therapy
has proven to be of some value when used in patients with dystonic tics. A
behavioral therapeutic approach using habit reversal therapy at its core has
been shown to be effective in a recent large multicenter study. Thalamic or
pallidal deep brain stimulation is a promising strategy in refractory cases.
Myoclonus
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| Basal Ganglia and Movement Disorders |
Myoclonus is a brief, shocklike muscle jerk, which may be
classified according to origin, (cortical, subcortical, brainstem, and
spinal myoclonus) and distribution (focal, segmental, multifocal, or
generalized). Cortical myoclonus may be epileptic (as in Baltic myoclonus or
progressive myoclonic epilepsy, photosensitive myoclonus, epilepsia partialis
continua) or part of a neurodegenerative disorder (corticobasal degeneration,
Alzheimer dementia, diffuse Lewy body disease, and others). Myoclonus can be
classified according to etiology as
idiopathic/genetic (familial myoclonus, myoclonusdystonia), physiologic (hypnic jerks or diaphragmatic
myoclonus/hiccups) or secondary/symptomatic when a cause for the myoclonus is
clearly identified. Examples of the latter group may include encephalitis,
hypoxia, toxins, storage diseases, and basal ganglia degenerations, as in
Huntington disease, Wilson disease, and certain other disorders). Myoclonus may
be positive due to a brief muscle contraction or negative when
muscle tone is briefly lost, as in asterixis.
Anoxic
brain injuries may result in myoclonus, which, in turn, may be cortical,
diencephalic, or reticular in origin; stimulus sensitive or action
induced; and segmental, generalized, or multifocal in
distribution. This type of myoclonus may be focal, preferentially affecting
the distal limb muscles, or multifocal with spontaneous, reflexive or stimulussensitive jerks accentuated
by movement. Frequently, anoxicinduced
myoclonus is accompanied by secondary seizures, particularly after
cardiopulmonary arrest. Status epilepticus is found in 32% of postanoxic
patients, and in many, multifocal myoclonus alone or in combination with
generalized tonicclonic
seizures is frequently observed. The incidence of myoclonic seizures is
bimodal, with the majority of them occurring within 12 hours after cardiopulmonary
resuscitation and the remaining occurring several days later. Electroencephalography
(EEG) is useful when evaluating these patients, particularly when status
epilepticus is suspected. The most frequent EEG findings include diffuse
slowing with or without spike or polyspike complexes that are sometimes time
locked to the myoclonic jerks. A burstsuppression
EEG pattern, when recorded, has a poor prognostic significance. Magnetic
resonance imaging of the brain may show diffusion restriction in the cortical
and subcortical gray matter between 24 hours and 13 days. Isolated myoclonus
generally does not require treatment unless it interferes with mechanical
ventilation or nursing care. Myoclonus status is refractory to treatment, may
require multiple antiepileptic drugs, and, when accompanied by convul sive status epilepticus,
is best controlled with deep anesthesia.
Electrophysiologically,
myoclonus is characterized by a muscle bursts that are less than 75 msec in
duration. When the cerebral cortex is affected, a “giant” somatosensory evoked
cortical response time locked to the onset of the jerk in backaveraged EEG may be
obtained.
In
1963, James Lance and Raymond D. Adams reported the first series of patients
with the syndrome of intention or action myoclonus as a sequel to hypoxic
encephalopathy. In postanoxic myoclonus, axial and proximal muscle
groups are particularly affected, the myoclonus often occurring when patients
perform an action, such as standing or reaching for an object (action
myoclonus). Limb and truncal ataxia, cerebellar outflow tremor, and dysarthria
are other common accompaniments. The exact substrate of postanoxic myoclonus
generation is not clear. Postanoxic myoclonus may be the result of cortical or
subcortical injury or be due to alterations in brainstem serotonergic pathways.
The serotonergic raphe nuclei have frequently been implicated.
Some
forms of myoclonus, particularly those of subcortical origin, are believed to
arise from the reticular system primarily from the nucleus reticularis
gigantocellularis. This reticular reflex myoclonus is characterized
by a brief electromyographic burst lasting 10 to 30 msec, with generalized
bilateral synchronous activation of muscles following a distribution suggesting
spread up the brainstem and down to the cord.
Essential
myoclonus may be idiopathic or familial, beginning in the first to second decade of
life. In patients with essential myoclonus, the neurologic examination fails to
demonstrate other deficits. In a few families, lower verbal scores have been
reported and occasionally mental retardation. Similar to essential tremor,
alcohol may help to ameliorate the symptoms, but the incidence of alcoholism is
increased. In patients with myoclonus-dystonia, there is an autosomal
pattern of inheritance, men are more affected than women, and there is a higher
incidence of alcoholism and behavioral disturbances.
Also known as hepatolenticular degeneration, Wilson disease is an autosomal recessive disorder that occurs in 1 of 30,000 individuals. The abnormal gene, the ATP7B (adenosine triphosphate) gene, is located on chromosome 13. The defective protein, adenosine triphosphatase (ATPase), is involved in the transport and incorporation of copper into ceruloplasmin and the vesicular compartment near the canalicular membrane for further bile excretion.
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