All posts by Rob Davis

Seizure Disorders

Definitions

Seizure – (Schomer) state of pathologic hypersynchronous behavior of large number of neurons associated with an altered neurologic function

  • text defines it as – an episode of abnormally synchronized and high-frequency firing of neurons that results in abnormal behavior or experience of the individual

Epilepsy – a condition in which there is a tendency to have recurrent unprovoked seizures (about a 1- 2% incidence)

  • Lifetime risk of having a single seizure is higher, estimates ranging from 10 – 15% of population
  • 4th most common neurological disorder; most common neurological condition in childhood (4.3-9.3/1000)
  • Onset most often during childhood and adolescence
  • High incidence in prisons (4x general population): impulse control + lower SES + criminal behavior

Kindling – may account for susceptibility to electrophysiologic dysfunction in area opposite hemisphere homologous to original site of discharge

Aura – brief, simple partial seizures of any type experienced by a patient with no outward behavioral manifestations. They may occur in isolation, or they may serve as a warning for a larger seizure, when patients have seizures that typically begin in one region of the brain before spreading.

  • Patients with seizures arising from medial temporal limbic structures often report a visceral sensation of rising in the epigastric area, a feeling of déjà vu, strange unpleasant odors, or feelings of extreme fear and panic (smell, emotion, memory)
  • Odors and panic are thought to arise from the amygdala and nearby cortex, rather than the hippocampus

EEG (Electroencephlogram)

Alpha

8-13 CPS/hertz; the normal dominant/background activity; occurs over occipital region

  • Reflects an anxiety free state; used as guideline in biofeedback
  • Lost with eye opening, falling asleep, medication that affects mental function
  • Slows in elderly and in nearly every brain-based neurological illness
  • Slows in early stage Alzheimer Disease, but remains in normal range

Beta

>13 hertz; read over frontal lobes

  • Prominent with concentration, anxiety, under effects of minor tranquilizers

Theta and Delta

4-7 hertz and 1-3 hertz

  • Detected in children and everyone entering deep sleep; generally absent in healthy, alert adults
  • Presence may indicate a degenerative illness or metabolic derangement
  • Focal presence may suggest a lesion in that region

EEG in other differential diagnoses

  • triphasic waves present in metabolic/toxic encephalopathy and hepatic/renal failure delirium;
  • periodic complexes present (seen as myoclonic jerks) in subacute sclerosing parencephalitis (SSPE) and Creutzfeld-Jakob disease;
  • can differentiate between locked-in syndrome and persistent vegetative state (slow and disorganized)
    • EEG is not useful to detect or exclude structural lesions
    • EEG after ECT looks post-ictal (similar to GTC sz), and slow wave activity may continue for 3 months

Seizure Activity

  • Ictally, EEG reveals paroxysmal activity consisting of bursts of spikes, slow waves, or complexes of spikes and waves or poly-spikes and waves.
  • Post ictally, EEG shows low voltage activity (“postictal depression”) followed by diffuse high voltage slowing
  • Interictally, EEG often contains specific abnormalities supporting a diagnosis in 80% of epilepsy patients (20% have normal interictal EEGs). To evoke abnormalities, may try hyperventilation, strobe, sleep deprivation
  • 15% of population has nonspecific EEG changes (e.g., background slowing) – 1-2% have slow wave or spikes but no ictal events
  • Up to 60% of individuals with known epileptic disorders will not show abnormalities on the typical in office brief EEG!

Taxonomy

Partial Seizures (a.k.a. “focal”)

Begin in focal region of brain and semiology reflects this focus; may or may not spread; aura may be present. Typically last 5-10 seconds, but longer periods not uncommon

Simple Partial

  • No post-ictal deficits unless seizures are prolonged or recurrent as in Todd’s hemiparesis (see below)
  • Consciousness not impaired; one mode of expression
  • Motor (Jacksonian march – spreads along motor cortex. Todd’s mono or hemiparesis – accompanying post-ictal muscle weakness)
  • Seizures in frontal motor association cortex can include “fencing posture”, bilateral leg cycling movements, turning of eyes, head or body
  • Sensory (unformed hallucinations in any sensory modality)
  • Can have positive symptoms (e.g., hand twitching), or negative symptoms (e.g., impaired language abilities)

Complex Partial (i.e., “psychomotor seizures”)

  • Typical duration 30 seconds – 2 minutes
  • Consciousness is impaired
  • May have complete impairment or may only be “mild” – sometimes making the distinction between simple partial seizures difficult
  • Can have simple partial onset followed by impairment of consciousness – or consciousness can be affected at onset
  • complex symptoms including automatisms, subjective feelings, postural changes
  • postictal – confusion (including aphasia w/dominant hemisphere involvement), amnesia, fatigue, agitation, aggression, and headache
  • Most originate in temporal lobe
    • Medial temporal lobe-onset complex partial seizures often begin with an aura of unusual, indescribable sensation, or with epigastric, emotional, or olfactory phenomena.
  • Initial symptoms are followed by unresponsiveness and loss of awareness, during which patient may have automatisms (e.g., lip smacking, swallowing, or stereotyped hand or leg movements)
  • Often, basal ganglia are involved – leading to contralateral dystonia/immobility. Thus, automatisms occur in the ipsilateral extremity — can lead to inaccurate localizing to the “unpracticed eye”
  • Usually begin in late childhood and early thirties
  • Most common type of seizure (65% of all epilepsy pts)
  • Difficult to recognize and interpret due to almost limitless variety of clinical findings; often mimic other disorders, especially psychiatric ones
  • Intellectual symptomatology (aphasia, memory distortion – déjà vu [already seen], jamais vu [feeling of not having seen that which is familiar], deja entendu, jamais entendu, deja pensee, cognitive alterations – dreamy state, depersonalization, forced thinking, thought blocking)
  • Affective symptomatology (fear, depression, pleasant/unpleasant experience, anxiety, embarrassment, anger, compulsions)
  • Psychosensory symptomatology (illusions – metamorphosia [sudden distortion of a common object or person], micropsia [objects have become smaller, further away, or suddenly out of reach], macropsia [objects have become larger, closer to or “towering over” the patient], hallucinations – olfactory, gustatory, auditory)
  • Psychomotor symptomatology (automatisms – simple, speech, affective, complex; present in 80% of complex partial seizure pts)

Partial Seizures evolving to secondarily generalized seizures

  • From simple or complex; spreads across corpus callosum to entire cortex
  • Epilepsia partialis continua (a.k.a. focal status epilepticus) – partial seizures continue for hours/ days

Generalized Seizures

  • Synchronized bilateral electrical discharge involving whole cortex.
  • No aura, no focal semiology, no lateralized findings, no focal EEG abnormalities.
  • Immediate LOC.
  • May be nonconvulsive (e.g., absence) or convulsive (e.g., tonic-clonic).
  • Rarely result from tumors, infarctions, or structural lesions.
  • Postictal amnesia, confusion, fatigue, unresponsiveness

Absence (petit mal)

  • Onset usually 4-10 years of age, disappear in adulthood in about 40% of cases
  • 40% – absence replaced by GTC seizures
  • characteristics: 1-10 second lapse of attention (staring) with automatisms and subtle clonic limb movements; maintain tone and bladder control; no significant postictal symptoms
  • easily confused with inattention, dullness, or complex partial seizures (but differential diagnosis critical due to variable treatment)
  • inherited autosomal dominant pattern
  • 3/second spike and wave
  • often can be provoked by hyperventilation, strobe lights, or sleep deprivation

Atypical Absence

  • Usually begin in early childhood
  • Frequently accompanied by other generalized seizure
  • Difficult to control

Myoclonic

  • Brief, single symmetrical jerks of head and upper extremities; in series or clusters, common after waking
  • No LOC (duration of generalized polyspike-wave burst usually <1 second)

Clonic

Tonic

Tonic-clonic (grand mal)

  • Begin at any age after infancy and persist into adulthood
  • Massive motor activity (tonic stiffening of trunk followed by clonic rhythmic jerking of extremities) lasting less than 5 minutes, profound postictal residua
  • Inherited autosomal dominant trait
  • Incontinence or tongue biting is common
  • Immediately postictally, patients lie immobile, flaccid, and unresponsive, with eyes closed, breathing deeply to compensate for the mixed metabolic and respiratory acidosis produced by seizures
  • Post-ictal deficits last from minutes to hours and include profound tiredness, confusion, amnesia, headache, and other deficits related to location of seizure onset

Atonic (“drop seizures”)

Abrupt loss of muscle tone that produces a sudden fall

Generalized status epilepticus

May persist for many hours and become life threatening.

Reflex epilepsy

Seizures in response to specific stimulus (e.g., light, television, music)

Febrile seizures

Occur in 2-4% of all children; recur in 1/3 of them. Tx is fever prophylaxis or oral diazepam with fever onset

Staring Spells: Complex Partial Seizures vs. Absence Seizures

Features Typical absence Seizure Typical medial temporal complex seizure
Aura None May be present
Duration less than 10 sec. 30-120 secs
Automatisms None aside from minor mvmt of mouth / eyelids May be present
Post-ictal deficits None May be present
Frequency Multiple events daily 3-4 monthly
Ictal EEG Generalized 3-4 hz spike-wave Unilateral or assymetric 5-8 hx over temporal lobe

Epilepsy Syndromes

West Syndrome (infantile spasms)

  • Clusters of myoclonic seizures
  • Myoclonic seizures cease between 2-4 years old, but give rise to other seizure types in 25-60% of cases

Lennox-Gastaut

  • Mixed seizure disorder – includes atypical absence, atonic, myoclonic
  • Onset ages 2-8
  • EEG – background slowing and slow spike and wave
  • Seizures difficult to control and status is common

Benign Focal Epilepsy of Childhood

  • Most common type of partial seizure
  • centrotemporal spikes
  • Rolandic Epilepsy (nocturnal seizures)
    • believed to have autosomal dominance with incomplete penetrance
    • EEG has characteristic centrotemporal spikes
    • onset b/t 3 and 13; remission nearly always complete by age 15
    • Characteristics: unilateral parasthesias, speech arrest, T-C seizures occurring mostly at night
  • Benign Occipital Epilepsy (visual symptoms)
    • Onset between ages 3-10, more common in boys, often remits by puberty; inherited
    • Responsive to AEDs

Childhood Absence Epilepsy

  • Onset between 4 and 8 (second peak of onset at puberty known as juvenile absence epilepsy)
  • Easy to treat and spontaneous remission in 80%
  • Onset in adolescence more likely to experience generalized seizures and persist into adulthood

Juvenile Myoclonic Epilepsy

  • Onset late childhood, early adolescence
  • Involves myoclonic jerks of upper extremities generally associated with morning waking. No associated LOC, BUT 90-95% have generalized tonic-clonic seizures
  • Responds to AED’s but resolution is infrequent
  • Accounts for 10% of all epilepsies; genetically inherited (autosomal dominant)
  • IQ usually ok

Landau-Kleffner

  • “Acquired aphasia with convulsive disorder”
  • need abnormal EEG (usually over temporal areas) but no actual seizures are necessary for diagnosis
  • Age of onset b/t 2 and 11; follows a period of normal development
  • Characterized by sudden or gradual onset of auditory agnosia; may involve total unresponsiveness to language or progressive deterioration of expressive speech
  • Usually associated with behavioral difficulties as well
  • Seizure type varies, but most common is generalized motor seizures
  • Seizures and language deficits unresponsive to AED’s (current: steroid tx)
  • Earlier onset is related to poorer prognosis

Continuous spike-wave discharges during sleep (CSWS)

  • Continuous activity during >85% of non-REM sleep
  • Neuropsychological regression associated
  • Partial motor seizures, absence seizures

Etiology

  • Diagnosis = more than 1 unprovoked seizure
  • Symptomatic epilepsy – origin of seizure is identified (only 30% of cases; harder to control with AEDs)
  • Idiopathic – unknown seizure origin
  • Risk of new onset seizures is high in infancy and childhood, declines in adulthood, and then rises again in elderly
    • Most common cause in infancy and childhood are febrile seizures, congenital disorders, and perinatal injury
    • Most common cause in patients > 60 – cerebrovascular disease, brain tumors and neurodegenerative conditions
  • Febrile seizures – occur in 3-4% of all children, usually between ages of 6 months and 5 years; usually are brief, generalized tonic-clonic seizures (called simple febrile seizures).
    • Increased risk of subsequent epilepsy in children with complex febrile seizures – seizures lasting more than 15 minutes, or occurring more than once in 24 hours – some of these kids may have an underlying cause for epilepsy which is triggered by the fever
  • Metabolic factors – hypoglycemia, hypocalcemia, electrolyte imbalance, uremia, hepatic failure, hypoxia
  • Drug withdrawal – EtOH, barbiturates
  • Post-traumatic – CHI, SDH, EtOH w/ multiple falls. 50% of people who develop seizure disorders will do so in first year post-injury; 80% within four years
  • Birth injury – congenital malformations, infection, trauma, idiopathic
  • Relative to age of onset:
    • Perinatal – toxemia, infection, congenital defects, difficult birth
    • Young children – congenital abnormality, neonatal meningitis, neurocutaneous disorders
    • Adolescent – idiopathic, trauma, drug-related
    • Young adult – trauma, EtOH, neoplasm, drug-related, AVM, AIDS (cerebral toxoplasmosis)
    • Middle age – neoplasm, EtOH, vascular disorder, trauma
    • Late life – vascular disorder, neoplasm, degenerative, cysticercosis; CVA most common after age 65
  • Risk Factors:
    • Genetic predisposition
    • Cerebral insult
    • Precipitating conditions (e.g., EtOH, physical debilitation, emotional stress, video games/TV)

Differential Diagnosis

  • CT usually normal
  • Normal EEG does not rule out seizure disorder; sleep EEG more sensitive than waking
  • PET/SPECT: hyperperfused ictal foci; hypoperfused post-ictally; better at detecting foci than MRI/ CT

Pseudoseizures

Non-epileptogenic events, psychogenic seizures

  • Resembles an epileptic seizure but is not caused by neuronal discharge
  • Is not “voluntary”; etiology is emotional or psychological

•Possible distinguishing semiology: acute emotional disturbance may initiate, rare when sleeping or alone, gradual onset, crying during ictus, occasional talking, movements may be asynchronous, thrashing and may include side-to-side movements and pelvic thrusting, personal injury fairly rare, directed violence not unusual, react to avoidance testing, infrequent micturition and defecation, may be quite long, NO ictal epileptiform EEG abnormality

  • More prevalent in women, children, and adolescents
  • Risk Factors:
    • h/o sexual abuse,
    • epilepsy,
    • psychiatric disorder (esp. depression/anxiety),
    • or head injury/ PCS;
    • model for seizure disorder (family/friend),
    • traumatic life course, family discord/academic stress
  • Important: 50% also have “real” (i.e., electrical) seizures

Other conditions that mimic seizures

  • Episodic dyscontrol syndrome (i.e., recurrent rage attacks)
  • Cerebrovascular disturbance (e.g., syncope, cardiac arrhythmias, TIA, transient global amnesia)
  • Panic disorder
  • Breath holding spells in infants
  • Sleep disorders (e.g., narcolepsy, cataplexy)
  • Migraine
  • Metabolic disturbances (e.g., med reactions, hyperventilation, hypoglycemia)

Management

  1. Anti-epileptic drugs
    1. Use AED’s when seizures are prolonged or recurrent
    2. Seizure control can be established in up to 80% of pediatric population
  2. Surgery
    1. Focal resection – usually for partial complex
      1. In temporal lobectomies — 80% are seizure free or have significantly reduced seizures
      2. improvements in behavior and psychosocial functioning have been suggested
    2. Corpus callosotomy
      1. Used to control generalized seizures by preventing their spread across the hemispheres
      2. Tends to decrease frequency — but does not resolve disorder
    3. Functional hemispherectomy
  3. Vagus Nerve Stimulator
    1. VNS generator is implanted in left side of chest – stimulating lead is attached to left vagus nerve in carotid sheath
    2. Stimulus given off in cycles of 3 seconds on and 5 minutes off
  4. Ketogenic Diet
    1. 1/3 experience complete control of seizures
    2. adherence issues
  5. Multiple subpial transection – used when seizure site is inoperable (e.g., if in motor or language cortex). Involves inserting a sharpened probe under the pia to sever the cortical-cortical connections…essentially disconnecting the epileptogenic cortex) Can cause aphasia if dominant temporal lobe is transected

NP Effects of Anticonvulsants

  • May cause problems with attention, motor speed, memory, and processing speed – even when AED’s are within therapeutic range; *they may compound the cognitive difficulties and behavioral problems seen in people with epilepsy

Carbamazepine (Tegretol)

  • Few cognitive side effects
  • May improve speed of information processing, psychomotor speed and problem solving; may also decrease aggression and emotional lability
  • Interferes with BCPs

Valproic Acid (Depakote)

  • Minimal cognitive effects
  • May improve alertness
  • Few behavioral effects

Phenytoin (Dilantin)

  • Highest rate of side effects
  • Adverse effects on psychomotor speed, memory, and problem-solving
  • May result in progressive encephalopathy w/deterioration of intellection functioning, especially in children with MR or neuro problems
  • Dilantin (phenytoin) intoxication: nystagmus, ataxia, dysarthria
  • Due for frequent overgrowth of gum tissue (which can result in dental disease and heart issues), patients should have teeth cleaned 2X/year minimum

Phenobarbital

  • Inconsistent cognitive findings
  • Consistently related to hyperactivity, irritability and sleep disruption; may exacerbate premorbid problems

Polytherapy treatment

  • More negative impact on cognition and mood than monotherapy

Neuropsychological Findings in Epilepsy

  • IQ
    • In general, not associated with intellectual decline (except in syndromes such as tuberous sclerosis, Rett syndrome, chromosomal disorders, etc.) – when decline is noted, often associated with AED toxicity or status epilepticus
    • Co-occurs with MR (9-31%), autism (11-35%), and CP (18-35%)
  • Language
    • Expressive language more impaired than receptive
    • Dysnomia is common – may contribute to verbosity and circumstantial speech
    • Hypergraphia – excessive and compulsive writing
    • Reported memory problems may actually reflect subtle language difficulties
  • Perceptual-motor skills
    • TPT has been sensitive – total time, memory, and localization scores
    • Bender-gestalt – patients perform more poorly than controls
  • Memory
    • May reflect effects of continued abnormal activity or damage to CNS
    • Memory disturbance may be related to nature, extent, and location of pathology in temporal lobes
    • Long-term memory more affected than short-term memory
    • Localization of onset may affect memory impairments (i.e., verbal vs visual)
  • Attention
    • Deficits in attention tend to be present regardless of IQ
      • Generalized seizures – tend to show deficits on measures of sustained attention
      • Focal seizures – greater deficits on measures of selective attention
  • Executive functions
    • Trail making test, WCST, Category test
    • Frontal lobes affected by temporal/hippocampal discharges through temporal-frontal pathways
  • Motor skills
    • Decreased reaction time and psychomotor speed; overall slowing
  • Learning disabilities/Achievement
    • Higher risk for learning disorders
    • Etiology unclear
    • Seizure type, duration of disorder, severity of seizures and AED’s have NOT been found to be related to academic underachievement
    • May be related to impairments in language, memory, and attention

Factors Affecting Cognitive Deficits

  1. AED toxicity
  2. Etiology
    1. People with idiopathic seizures score higher on IQ tests
    2. Symptomatic epilepsy
  3. Seizure type and frequency – greater deficits seen with:
    1. Tonic-clonic, atypical absence, mixed seizures
    2. History of status epilepticus
    3. More frequent seizures
    4. Longer duration of disorder
  4. Early seizure onset
  5. Poor seizure control
  6. TLE surgery: Non-dominant temporal lobectomy – no consistent changes in cognition; Dominant temporal lobectomy – depressed verbal memory fairly common. Risk factors for post-op decline in verbal memory: dominant resection, intact pre-op neuropsych memory testing, intact pre-op Wada memory testing, absence of mesial temporal sclerosis (MTS) on imaging

Psychological findings:

  • Higher prevalence of depression (especially males with complex partial)
    • Higher suicide rates
  • Children with epilepsy have higher rates of psychiatric disturbance than general population
  • Neurological and psychosocial factors contribute to increased risk for psychological maladjustment
  • Neuro variables: underlying brain damage, localized epileptogenic activity in areas regulating emotion, etc
  • Family variables: significant predictors of behavior problems

Epilepsy Syndromes Based on Location

Temporal Lobe Epilepsy (TLE)

  • Group of conditions resulting in paroxysmal discharge within the temporal lobe; multiple etiologies
  • Unifying feature: vulnerability of temporolimbic structures (amygdala, hippocampus) to epileptogenesis – vascular anatomy; convergent inputs from multiple sensory areas; special excitability as reflected in bursting and kindling; NMDA receptors and pathological plasticity
  • Common denominator of TLE: temporal lobe spike focus
  • Common ictal manifestations (in sum: varied, complex, and difficult to differentiate from spontaneously occurring behavior; complex partial seizures):
  • Sensory alterations – subjective, but not necessarily any objective findings
  • Motor symptoms – automatisms, twitching, eye movements, speech problems, transient weakness, etc.
  • Autonomic manifestations – flushing, shortness of breath, apnea, cardiac symptoms, nausea/epigastric rising, etc.
  • Hallucinations/illusions – in any sensory modality; includes metamorphosia, micropsia, and macropsia
  • Experiential manifestations – memory flashbacks, déjà vu, jamais vu, feeling of a presence, depersonalization, derealization, etc.
  • Emotional manifestations – often negative, sudden, unpredictable, inappropriate (fear – most common)
  • “Typical” interictal behaviors** (i.e., “TLE personality”): preoccupation with religion/morality/ philosophical issues, hypergraphia, hyper/hypo sexuality, viscosity, increased irritability/temper outbursts, schizophrenia-like psychosis, fearfulness, humorlessness
    • Left sided focus: intellectualized affect, thought disorder, reflective style
    • Right sided focus: overemotionality, affective disorder, impulsive style; artistic creativity
  • Behaviors are “opposite” that seen in Kluver-Bucy syndrome (damage to temporolimbic structures resulting in placidity, hypersexuality, hyperphagia, hypermetamorphosis, loss of social bonds):
  • CAVEAT: I believe that current thinking and research questions the validity of a so-called “TLE personality”. In general, it is not supported by recent evidence.

Complex Partial Seizures of Extratemporal Origin

  • Relatively few cases documented in the literature

Clinical Characteristics of Complex Partial Seizure (CPS) of Frontal Lobe Origin:

  • Frequent seizures, often in clusters with many per day
  • Brief seizures lasting less than one minute
  • Sudden onset and offset with little or no postictal confusion
  • Prominent motor automatisms, usually complex
  • Aggressive sexual automatisms as part of motor automatisms
  • Vocalizations of variable complexity
  • Frequent warnings, usually nonspecific
  • Complex partial status epilepticus possible
  • Bizarre attacks that appear hysterical
  • Stereotyped pattern

In Sum: similar to Temporal Lobe Epilepsy (TLE); bizarre movements and vocalizations, behavioral automatisms

Clinical Characteristics of CPS of Occipital Lobe Origin:

  • Elemental visual hallucinations
  • Contralateral eye deviation
  • Pulling or movement sensation in eyes in the absence of detectable motion
  • Rapid forced blinking or eyelid flutter
  • Ictal blindness – blackout or whiteout secondary to rapid spread via the splenium (infrequent)
  • Static visual field defects

Recovery, Sparing, and Reorganization of Function

Recovery of Function

  • Theoretical mech of recovery
    • 1st stage recovery: first few weeks/ days after onset of stroke is critical time of regrowth (recovery from acute effects of metabolic & membrane failure, ionic and NT imbalance, hemorrhage, cellular rxn & edema)
    • 2nd stage recovery: mech largely unknown; most likely see compensation with large lesions (see below)
  • Theories of cog recovery (note these aren’t exclusive/ independent of one another)
    • theory of equipotentiality & embryogenetic analogy
      • researchers like Lashley would argue that strict localization of fx not true b/c you see recovery of fx following BD (e.g., speech)
      • Lashley argued for the mass action theory that it was extent of damage (not damage to specific locale) which resulted in more impairment
        • only did work with animals, however would remove more and more layers of c.cortex to show greater impairment (general) with more removal did argue for basic fx location (i.e., cerebellum- coordination; medulla- vitals such as respiration & arousal)
        • compared the plasticity of cerebral cortex to embryogenetic capacity of organism to dev fully from fertilized ovum
    • redundancy via vicarious fx
      • there’s a bio protective mech built in an organism, anticipating injury; thus redundancy in structures that can substitute for damaged areas (notion of areas taking over for other areas)
      • Pavlov argued for this (many potential conditioned reflex paths that are never used by normal organism)
      • Lashley thought that preservation of a part of a system concerned with same fx is necessary for their to be recovery of fx
      • Bucy argued that although certain regions might take over during recovery of fx but normally might not be involved/ necessary for normal fx (e.g., RH take over of lang following aphasia)
    • H substitution
      • notion, particularly with speech/ lang, RH capable of assuming speech fx (comprehension- nouns better than verbs) & automatic nonpropositional speech
      • support from:
        • WADA studies in Ss who recovered from LH aphasia, RH injection produced aphasic speech;
        • rCBF studies showing RH hypometabolism in aphasic stroke pts, PET also shows this along with great deal of hypometabolism ipsilateral intact tissue surrounding the infarct (suggesting some ipsilateral reorganization/ contribution too)
    • Hierarchical representations
      • notion that fx represented at several levels & damage at higher levels releases lower ones from inhibition & leads to compensation
      • see this most frequently with multiplex cortical sensory and cortical/ subcortical visual systems (collicular, thalamic compensation for O damage)
    • Diaschisis
      • Manakow’s principle (est from 2nd stage of recovery)
      • acute damage to NS (stroke deprives surrounding fx connected tissues from innervation, become inactivated)
      • fx regained/ returned once innervation is restored or regained from somewhere else
    • Regeneration
      • both regeneration and collateral sprouting (axonal, dendritic) has been shown in mammalian NS; denervation hypersenstivity may explain why some central structures become more responsive
      • however, a neuron, once it dies, cannot be regenerated nor can you see new neuron growth in the human CNS
      • if neuronal cell body is injured & dies, rest of neuron parts disintegrate & degenerate; rarely see axonal regeneration in CNS, but do in PNS, abortive if seen b/c of env Fs (such as lack of trophic substances in adult CNS, glial scars, etc.) or intrinsic Fs (inappropriate metabolic responses of CNS cells to injury, lack of appropriate protein production to help CNS regrowth, etc.)
    • Fx compensation (see below)
    • Dennervation supersensitivity
      • after denervation in damaged area, remaining fibers/ postsynaptic processes may become overly sensitive to residual NTs
      • idea that small amnts of NTs lead from prelesion neurons in order to activate new postlesion pathway (growth)
      • however, most axonal regeneration has shown to be retractive and limited
  • Recovery from aphasia
    • Fs affecting recovery:
      • Etiology:
        • CHI show most rapid recovery whereas less rapid in stroke pts
      • aphasia type
        • anomic, conduction & transcortical aphasia have best prognosis
      • severity
      • age
      • greater plasticity/ transfer of fx in immature system (critical periods of dev)
      • sex & handedness
        • some claim L handers recover better
        • some say M more prone to posterior vs F anterior damage resulting in aphasia (strokes more likely to be seen with posterior, why more M seen as aphasic, perhaps appear more aphasic b/c greater % of M aphasics due to strokes whereas F might have more CHI)
      • anatomical & fx variations
        • anatomy of speech is variable and individual variations in intral and interhemispheric distribution of various fx components may contribute to extent mature brain is able to compensate after a single nonprogressive lesion
      • time course for recovery
        • see most recovery during 1st 3mos after onset; after 6 mos, rate of recovery significantly drops; for most, spontaneous recovery doesn’t seem to appear after 1 yr
      • linguistic features of recovery (various components show different recovery rates):
        • naming, oral imitation, Y/N responses, comprehension of nouns seem most resistant to BD and might be partially mediated by RH
        • studies have shown that highest recovery rates found in BA group (low-fluency, high-comprehension group); whereas WA pts showed recovery in Y/N comprehension & repetition tasks, BA recovered in all tasks except word fluency
      • lesion site & location in recovery
        • in WA, instrumental that areas that surround the superior T area are spared (for recovery of fx to be seen)
        • lesion size also effects extent of recovery (most important factor)
      • other Fs: premorbid intelligence, health & social milieu, age, ed, occupational status, etc.

Sparing/ Plasticity of Fx (early BD)

Theories

  • critical periods of development: Hubel & Weisel’s work
    • lesions before 1 (greatest impairment & reduced IQ)
  • lesions btwn ages 1-5 (allows relative reorganization and sparing of lang fx)
    • lesions from age 5 up (shows little/no sparing)
    • Kennard’s principle: generalization that sparing of fx follows infant lesions;
    • now know it’s not always true, and sometimes early BD associated with worse fx outcome
    • speech survives early BD, but some elements may not survive (i.e., syntax, nonlang fx) and general IQ declines
  • effects of BD on language
    • lang ds in childhood following BD usually short-lived and recovery is nearly complete
    • transient lang disordered following RBD more common in kids than adults (suggests lateralization not complete)
    • Woods & Teuber looked at lang with prenatal or early postnatal BD
      • lang survived after early LBD
      • much of survival due to occupation of potential lang zones in RH
      • shift of lang not without a price (v-s usually impaired)
      • early lesions to RH produce deficits similar to those in adulthood
      • LHD (depressed V and PIQ) & RHD (depressed PIQ only)
  • reorganization of lang
    • series of studies by Rasmussen & Milner (WADA, dichotic listening task):
    • lesions of both anterior & posterior speech zones for lang (see shift to RH for lang) found also bilateral representation of speech in TLEs
    • also found rare to see recovery of speech after age 5 and if seen, due to interhemispheric organization (ipsi)
    • several TLE studies have also shown that bilateral and RH lang more likely to be seen after an early age of onset

Compensation/ Reorganization of Fx

  • following large lesions, most likely see compensation of focal cog or lang loss most likely involving:
    • ipsi cortical structures physiologically & antomically connected to damaged structures (e.g., LTLE could have some sparing of verbal memory due to good tissue beyond the extent of the sclerotic hippocampus, such as parahippocampus, entorhinal cortex, etc.)
    • contralteral homologous areas (this is the notion of reorganization; e.g., speech which is often bilateral or RH in TLE with early seizure LTLE onset)
  • explains recovery with a behavioral rather than neural mech; notion that BD organism dev new slns to pblms using residual structures
  • Studies
    • Animals
      • early studies by Kennard showed that there is greater plasticity in infants; found that unilateral lesions to precentral motor cortex of newborn monkeys have minimal effects compared to same lesion in adult monkeys
      • Hubel & Weisel showed that there are critical periods of dev (depth perception, complex cells of visual system- respond to bars of light) and that kittens with eyes sewn shut during these critical periods never learn to dev these
      • G-R removed DLPF in monkeys (infant & adult) finding that learning of delayed responses unaffected in prenatal or infants but adult monkeys failed to learn this; argued that DLPF not innate in solving delayed response tasks, but dev this fx later
    • Human
      • despite good recovery in children, unilateral BD still results in overall decrement in IQ, with PIQ more affected
      • Miner found that children, after CHI, did better in comparison to adults on cog measures
      • Fletcher argues that even though you might see recovery of fx in child, still disrupts normal dev of cognitive growth and will see more deviant patterns of dev (i.e., more likely to dev LD later)
      • Kolb pointed out that FBD during 1st year of life inevitably results in lowered IQ & poor performance on tests sensitive to F fx
      • Finger argued that although an injury may trigger neuronal growth, the ensuing changes may not always be beneficial for individual (inappropriate, fast-growing connections, exaggerated growth, misconnections) & that recovery may be an epiphenomenon

Plasticity

Brief Summary

  • when there is significant recovery of function it is associated with a remodeling of the cortical circuitry; when there is no recovery, there is also a lack of cortical change or a dendritic atrophy of the remaining neurons

Definition of Plasticity

  • the brain’s capacity for continuously changing it structure, and ultimately its function throughout a life time; allows the brain to respond to environmental changes or changes within the organism itself. Plasticity can include:
    • maturational/developmental changes
    • change with experience – for learning and remembering information
    • recovery after brain injury – brain must reorganize at least in part to recover fxn
    • maintaining function despite aging (response to natural cell death)

Concepts regarding recovery of function (must be differentiated from compensation)

  • More extensive for language function than most other cognitive functions
    • re: there appears to be limits to recovery
  • Recovery may be reversible
    • as patients age the mechanisms that promoted recovery earlier in life may be called on to compensate for neuronal deterioration (due to aging)
      • may lead to a return of the symptoms of the earlier brain injury
  • Recovery varies with the age at assessment; cortically injured subjects may grow into or out of deficits depending on the area damaged, the behavior measured and the extent of injury
  • Not all plasticity is valuable – it may take away from the development of other skills
  • Enriched environments
    • increase: cortical thickness, dendritic branching and the number of synapses in the cortex; so does training an animal on specific tasks!
  • Three possible outcomes in behavioral functioning following brain injury
    • compensation – change in strategy or a substitution of a new behavior for the lost one
    • diaschesis – restitution of the original behavior; recovery from some sort of nonspecific effect of the injury (e.g., swelling)
    • recovery associated with neurological changes
  • Three neurological implications of brain damage
    • Death
      • many neurons that are not directly injured lose their synaptic inputs which can lead to death
    • Survival w/reduced total input
    • Reinnervation (either in whole or in part)
    • In most cases all three events occur
    • Atrophy is not an inevitable result of cortical injury; synaptic remodeling may be more common than previously thought

Some basic neuroanatomy info

  • all species have the same number of neurons in a “column” of cortex, despite having brains of different thickness. The difference in cortical thickness is due to dendrites, axons, blood vessels, and glial cells – which allow the brain to have more synapses.
  • increasing the processing capacity is associated with an increase in synapses
  • mechanism behind neuronal migration:
    • re: cells develop along the walls of the ventricle, and must traverse the cells and fibers of the inner layers
    • neurons migrate along specialized filaments, known as radial glial fibers
    • after cell migration is complete these glial fibers disappear and may be transformed into another type of glia – astrocytes
      • b/c these glial are not present in the mature, neural repair or regrowth is difficult since a dividing cell will have no way to get to an injured area
  • it may be possible that damage early in life may occur when these glial cells are still there, making recovery more possible
    • Kolb has shown that it is very difficult to make cortical lesions in infant rats b/c the brain seems to regrow the lost region.
  • B/c the developing brain goes through different processes the same lesion at different times may have different effects; there may be more plasticity during the period of overproduction of synapses as the brain could just keep the needed synapses that might normally have died

General Methods of plasticity

  • Sources of plasticity include
    • spontaneous recovery
      • resolution and absorption from hematomas, decrease in swelling and return of electrolyte and neurochemical balance
    • neurostructural changes as discussed below
    • Specific mechanisms likely underlie more than one form of change (b/c the nervous system is likely to be conservative in its construction)
      • so the mechanism for learning may also form the basis of other behavioral changes such as recovery from brain injury
      • cortex is more likely to be plastic than other areas of CNS. Within the cortex, some structures are likely to be more plastic than others. e.g., language fxns are probably more plastic than spinal reflexes (b/c more advantageous)
      • significant recovery in behavior is associated with growth in the dendritic trees – and thus the number of connections
      • Enriched environments have been shown to increase the rats’ synaptic connections and decrease their dendritic spine density – so, the changes were not merely due to a growth in more connections, but also a remodeling of the dendrites, with the synapses farther apart
      • decreasing spine density may allow for more room for future experience-dependent synapses to be formed so, animals with “enriched neurons” would be able to change more quickly as they learn new things; i.e. learning makes the brain more responsive to subsequent experiences; i.e., plasticity has made the brain more plastic.
      • w/o some areas of afferent and efferent connectivity the remaining cortex is unable to compensate for the loss (no matter how many new synapses are formed)
    • neocortical activity influences plasticity so, in experiments studying fxnl recovery the very act of testing the animals may actually alter the recovery process!

More Specific Methods of Plasticity

  • re: the main way the brain modifies itself is through change at the synapse which may occur in
    • changes in axon terminals
    • dendritic arborization
    • spine density or
    • altering existing synapses
  • so, aspects of recovery include:
    • diaschisis
    • axonal growth – from damaged axons and collateral sprouting from intact axons. Some axonal growth merely involves an increase in the amount of transmitter available
    • dendritic growth – refers to the expansion of the dendritic surface, which again implies the formation of new synapses. expansion can occur by the development of more dendritic material or in an increase in the number of spines, or an increase in receptor activity
    • glia changes – glial cells may play a key role in stimulating plasticity in the neuron; there is a correlation b/t the intensity of the astrocyte response to injury and the extent of fxnl recovery (rats with frontal lesions on day 10 have an exaggerated astrocyte response, while those with day 1 lesion have no astrocyte response. It is proposed that astrocytes may produce some type of trophic factor(s) that may contribute to synaptic growth and fxn recovery
    • synapse supersensitivity – compensates for loss of presynaptic elements – remaining dendrites b/c hypersensitive to incoming stimuli
    • substitution – existing intact brain structures assume fxns previously held by lesioned areas
      • substitution of fxn – active reorganization of brain-behavior relationships
      • redundant representation of some structural systems

The Developing Cortex

  • studies have shown that many cortical areas are capable of assuming the structure and fxns of virtually any other area. But, as the cortex develops its plasticity decreases and it b/c constrained by its gross connectivity.
  • the stages of development: cell proliferation, cell differentiation, dendritic and axonal growth, synaptogenesis, cell and synaptic death, and gliagenesis
  • cell proliferation appears to be largely complete by the 5th month of gestation
  • cell migration may continue even postnatally

The Aging Brain

  • As we age there is a continual loss of neurons, but also a continual increase in the number of connections in each of the remaining cortical neurons
    • this allows us to maintain functioning w/o behavioral loss well until old age.
  • in dementing diseases this increase in synapses fails to occur, so there is behavioral loss much sooner
  • this suggests that plasticity following injury may be more successful in younger animals than in older ones b/c there are more remaining neurons to change. Clinically this suggests that those people with brain damage early in life may not be as successful in putting off the effects of age on the brain
    • older rats who are lesioned have difficult recovering and in fact show significant atrophy in dendritic arborization
    • but older rats who have been placed in an enriched environment still show increased dendritic arborization (i.e., plasticity) – no studies to date on enriched and then lesioned rats

The role of the type and extent of injury on plasticity

  • patients with closed head injuries show more complete and rapid recovery from aphasia than do stroke patients
    • perhaps because stroke damages larger regions of both cortical and subcortical tissues within the language areas
  • there is marked variability in the extent to w/c recovery occurs depending upon type of injury
  • we can predict that in the case of small lesions there may be changes in the remaining cortex that can underlie the recovery of fxn, but in larger lesions there may be changes in other cortical regions that allow the compensatory mechanisms to be more efficient with practice (i.e., if behavior after injury is compensatory there must be some underlying changes in the brain to accommodate this)
  • unilateral lesions allow more dendritic growth and behavioral recovery than bilateral lesions (even very small lesions in contralateral hemidecortication interferes with recovery and dendritic growth)
  • factors that affect outcome of lesions:
    • timing of lesion during development; once a brain region has b/c fxnl the same damage may produce very different results
    • gender

The Effect of Brain Damage in Infants

  • cognitive deficits associated with lateralized brain insult are generally less specific in children than in adults; therefor expression of deficit may be different (or transient); e.g., children rarely demonstrate aphasia (and even if they do, it resolves rapidly)
  • some believe that “plasticity” is due to the capacity to form or substitute new strategies to successfully fulfill a lost skill
  • Lennenberg proposed that language develops rapidly during ages 2 -5 and then more slowly during puberty. If damage occurred during the rapid development, it may be possible to shift language fxns to the intact right hemisphere – so no chronic aphasia; damage after this time would not permit reorganization thus poorer prognosis
  • but children with left-hemisphere damage in speech zones often show deficits in right-hemispheric fxns as well as an overall drop in IQ
  • lesions occurring before the age of 1 yr. produce more severe impairments in IQ than those occurring later in life
  • Effects of Lesions in Children
    • damage to children’s frontal lobes could have more severe results than similar damage in adults
    • Kolb has found that mean IQ may be compromised by early frontal injuries – mean IQ about 85; (preliminary data suggests that IQ may be even worse if damage occurs in first year of life)
  • Effects of Lesions in Rats (who do not have epilepsy following brain damage)
    • lesions during the end of the mitotic phase or during cell migration is particularly damaging (in humans this period likely begins during 3rd trimester up to about 6 days of age) but, injury during dendritic growth allows for better recovery (in humans – may include up to the 2nd year of life)
      • may depend on area since for example, the visual cortex develops more quickly than the frontal area
      • this principle was true regardless of the location of damage
      • so, there appears to be a time in early development when injury is devastating and a later time when there is substantial recovery of fxn (has been seen in cats and monkeys too)
      • even restricted frontal lesions on postnatal days 1-5 lead to a wide range of behavioral abnormalities not seen in similar lesions in adulthood
      • unilateral lesions allow substantially more recovery than bilateral lesions (even if the lesions are rather large); it is suggested that as long as one fxnl system is intact, the brain is able to recruit recovery mechanisms, but if both systems are damaged, it is more difficult

Effects of Hemidecortication

  • regardless of age, after the complete removal of the left hemisphere most people are capable of some language and do not experience the dense global aphasia seen in patients with large left hemisphere strokes
  • full scale IQ is usually at least one standard deviation below the mean (but surprisingly normal considering the extent of the removal) – but there is variability (some patients have had above average IQ’s)
  • Left hemisphere “recovery” is more complete than right hemisphere “recovery” – in fact, left decorticates show surprisingly good language, but visuospatial and constructional capacities are compromised with removal of either hemisphere
  • damage to the remaining hemisphere (no matter how small) can significantly impair recovery
  • age effects of hemidecortication
    • the age relationship is reversed (compared to cortical damage); thus, behavioral outcome is better in animals with earlier lesions (rather than 7-10 days); this actually makes sense, b/c it is believed that poor behavior outcome after cortical lesions is due to a compromise in the remaining hemispheric growth; in hemidecorticated brain there is no compromise
    • thus, the absence of the hemisphere early may have some “beneficial” effect on the growth and development of the remaining, normal hemisphere

Other Theories of Temporal Effects of Brain Damage

  • Kennard – earlier rather than later damage is preferable in sparing function
  • Dobbing – later rather than earlier damage is preferable in sparing function
  • In reality, outcome is multifactorial and neither of above holds true in every case
  • Integration of above two says that brain damage during infancy and early childhood may prove less devastating in outcome than damage either during fetal development or in the mature brain

Pituitary & Hypothalamus

ANATOMICAL AND CLINICAL REVIEW

  • The pituitary and hypothalamus constitute a unique region of the nervous system. In addition to conventional synaptic transmission, both structures utilize soluble humoral factors as a major source of afferent and efferent information.
  • The pituitary and hypothalamus form the link between the neural and endocrine systems
  • The hypothalamus is the central regulator of homeostasis
  • The hypothalamus interacts with and helps regulate “H.E.A.L.”:
    • Homeostatic – hunger, thirst, sexual desire, sleep-wake cycles, etc.
    • Endocrine – control of endocrine system via pituitary
    • Autonomic control
    • Limbic mechanisms
  • Overall Anatomy of the Pituitary and Hypothalamus
    • The hypothalamus is part of the diencephalon and it forms the walls and floor of the inferior portion of the third ventricle (recall the third ventricle is like two dinner plates placed together)
  • It is separated from the thalamus by a shallow groove on the wall of the third ventricle called the hypothalamic sulcus
    • On the ventral surface of the brain, portions of the hypothalamus can be visualized just posterior to the optic chiasm (the tuber cinereum, or “gray protuberance”, between the chiasm and mammilary bodies, and the mammilary bodies themselves which form the posterior portion of the hypothalamus)
    • Infundibulum (“funnel”) arises from tuber cinereum and continues inferiorly as the pituitary stalk
    • The anterior portion of the infundibulum is called the median eminence, where hypothalamic neurons release regulating factors that are carried by portal vessels to the anterior pituitary
    • The pituitary gland lies within the pituitary fossa, which is bounded by the anterior clinoid process and posterior clinoid process, which, together with parts of the sphenoid bone, form the sella turcica (“Turkish saddle”)
    • The sella turcica is just above the sphenoid sinus, which allows the pituitary fossa to be accessed by a transphenoidal surgical approach (e.g., to resect pituitary tumors)
    • Within the pituitary fossa the pituitary is surrounded by dura
    • The pituitary stalk communicates with the main cranial cavity through a round hole (in the middle of the diaphragma sella)
    • The lateral walls of the pituitary fossa form the cavernous sinus
    • Given the location of the pituitary and other “sellar” and “suprasellar” structures just behind and inferior to the optic chiasm, tumors in this region can compress the optic chiasm causing visual problems, including bitemporal hemianopia

IMPORTANT HYPOTHALAMIC NUCLEI AND PATHWAYS

  • Major Hypothalamic Nuclei
    • The hypothalamic nuclei can be divided into four major regions, from anterior to posterior and into two different medial and lateral areas
    • Fibers of the fornix pass through the hypothalamus on the way to the mammilary body, dividing the hypothalamus into a medial hypothalamic area and a lateral hypothalamic area
    • Lateral hypothalamic area: lateral hypothalamic nucleus and several smaller nuclei
    • Medial forebrain bundle: carries many connections to and from the hypothalamus, and between other regions
    • Periventricular nucleus: thin layer of cells lying closes to third ventricle
    • Preoptic area: embryologically “separate” from the hypothalamus, but functionally part of the hypothalamus
    • Lateral preoptic nucleus and medial preoptic nucleus: rostral continuations of the lateral and medial hypothalamic areas, respectively
  • Anterior to Posterior
    • Some neurons located in both the supraoptic and the paraventricular nuclei contain oxytocin or vasopressin and project to the posterior pituitary
    • The suprachiasmatic nucleus (SCN) is the “master clock” for circadian rhythms; it receives inputs from retinal ganglion cells conveying information about day-night cycles
    • The arcuate nucleus is one of the hypothalamic nuclei projecting to the median eminence to control the anterior pituitary.
  • Hypothalamic Control of the Autonomic Nervous System
    • descending autonomic fibers originate mainly from the paraventricular nucleus and project to the brain stem and spinal cord.
    • inputs to the hypothalamus that regulate autonomic function come from numerous synaptic and humoral (chemical) sources. One important input source is the amygdala and other regions of the limbic cortex.
  • Hypothalamic-Limbic Pathways
    • the subiculum of the hippocampal formation, a limbic structure, projects to the mammillary bodies of the hypothalamus via the fornix
    • the mammillary bodies project via the mammillothalamic tract to the anterior thalamic nucleus, which in turn projects to limbic cortex in the cingulate gyrus.
    • The amygdala has reciprocal connections with the hypothalamus via the strial terminalis and the ventral amygdalofugal pathway.
    • These connections explain the relationship between emotional factors and autonomic responses. This is why your palms get sweaty and your stomach feels bad when you’re very nervous.
    • The connection with homeostatic pathways include the immune system as well. This explains why depressed individuals may be more susceptible to infection
  • Other Regionalized Functions of the Hypothalamus
    • the lateral hypothalamus is important in increasing appetite; lesions to this area cause a decrease in body weight
    • the medial hypothalamus, especially the ventromedial nucleus, appears to be important in inhibiting appetite, and medial hypothalamic lesions can cause obesity
    • thirst appears to result from the activation of osmoreceptors in the anterior regions of the hypothalamus
    • the anterior hypothalamus appears to detect increased body temperature and activates mechanisms of heat dissipation; anterior hypothalamus lesions can cause hyperthermia.
    • The posterior hypothalamus functions to conserve heat. Sexual development and differentiation involves an interplay of neural and endocrine signals, many of which appear to be regulated by the hypothalamus

ENDOCRINE FUNCTIONS OF THE PITUITARY & HYPOTHALAMUS

  • the pituitary receives arterial blood from the inferior and superior hypophysial arteries, which are both branches of the internal carotid artery
  • The anterior pituitary produces six important hormones:
    • adrenocoticotropic hormone (ACTH)
      • stimulates the adrenal cortex to produce corticosteroid hormones, which are important for maintaining blood pressure, controlling electrolyte balance, and promoting glucose mobilization into the blood stream.
    • growth hormone (GH)
      • causes the liver, kidneys, and other organs to produce insulin-like growth factors which promote increased growth of the long bones and other tissues
    • prolactin
      • causes the mammillary glands to produce milk
    • thyroid-stimulating hormone (TSH)
      • stimulates the thyroid gland to produce hormones (T4 and T3) which promote cellular metabolism
    • luteinizing hormone (LH)
      • regulate ovarian hormones responsible for the menstrual cycle and oogenesis in females
      • regulates testicular hormones and spermatogenesis in males
    • follicle-stimulating hormone (FSH) (same functions as LH)
      • regulate ovarian hormones responsible for the menstrual cycle and oogenesis in females
      • regulates testicular hormones and spermatogenesis in males
  • The Posterior Pituitary produces two hormones
    • oxytocin
      • causes contractions of smooth muscle in the breast for milk letdown and contractions of the uterus during labor
    • vasopressin (antidiuretic hormone)
      • participates in osmotic regulation by promoting water retention by the kidneys, allowing concentration of the urine

Clinical Notes

  • When a deficiency across all pituitary hormones occurs, this is called panhypopituitarism, which can be caused by several lesions or conditions of the pituitary and hypothalamic regions.
  • On rare occasions, pituitary tumors can undergo spontaneous hemorrhage resulting in pituitary apoplexy. Patients with pituitary apoplexy present with sudden headache, meningeal signs, unilateral or bilateral cavernous sinus syndrome, visual loss, hypotension, and depressed level of consciousness.
  • Pituitary adenoma
    • The most common sellar or suprasellar region abnormality that causes endocrine disturbance, but other lesions in this region that can produce similar clinical symptoms include craniopharyngioma, aneurysms, meningioma, and other lesions.
    • a slow-growing histologically benign tumor arising from cells in the anterior pituitary
    • mean age of diagnosis is 40 years; some cases occasionally occur in adolescents or elderly
    • the pituitary will often continue to secrete hormones, but at abnormally high levels, resulting in several endocrinological syndromes – even small pituitary tumors (e.g., <1mm) can cause significant endocrine abnormalities
    • some adenomas do not result in abnormal hormone secretion but rather grow large and thereby leading to hydrocephalus and brainstem compression which leads to headaches and/or visual disturbances (e.g., bitemporal hemianopia – characteristic sign)
    • treatment options include medication, surgery, and radiotherapy
    • if surgery is indicated, a transsphenoidal approach is usually taken (i.e., through the sphenoidal sinus, usually by means of pathway through the mouth and/or nose)
    • prolactin secreting adenomas typically cause amenorrhea in women, hypogonadism in men, and galactorrhea, infertility, hair loss, decreased libido, and weight gain in both sexes.
    • Growth hormone-secreting adenomas cause acromegaly, a slowly progressive overgrowth of bones and soft tissues – can lead to gigantism in adolescence. It can also lead to arthritis, infertility, hypertension and/or diabetes)
    • ACTH-secreting adenomas cause Cushing’s disease which results in “cushingoid” appearance (round moon-shaped facies and truncal obesity) and acne, hirsutism, purplish skin striae, thin-appearing skin, easy bruising, poor wound healing, hypertension, diabetes, edema, immunosuppression, osteoporosis, avascular necrosis of the femoral head, amenorrhea, decreased libido, myopathy, fatigue, and psychiatric disturbances including mania, psychosis, and depression.
    • The dexamethasone suppression test is often used in diagnosis of adenomas.
    • TSH-secreting adenomas are a rare cause of hyper- and hypothyroidism (which are more commonly caused by thyroid d/o’s like Grave’s disease and tumors)
  • Diabetes insipidus (DI)
    • production of large amounts of dilute urine
    • can be caused by deficiency of ADH in neurogenic DI or by insensitivity of the kidneys to ADH in nephrogenic DI
    • symptoms include severe thirst, polyuria, and polydipsia
    • neurogenic DI (also called central DI) usually caused by neurosurgery, head trauma, or neoplastic lesions in the pituitary-hypothalamic region or in the third ventricle
  • Hyperthyroidism
    • symptoms include: nervousness, insomnia, weight loss, tremor, excessive sweating, poor temperature regulation, and frequent bowel movements
    • thyroid opthalmopathy – inflammation of orbital tissues
    • proximal muscle weakness, tremor, dyskinesias and dementia
  • Hypothyroidism
    • lethargy, weight gain, cold intolerance, hair loss, depression, constipation, neuropathy, carpal tunnel, myalgia, ataxia and dementia.
    • when untreated in utero or infancy

Peds Brain Tumors

Epidemiology and Basic Background

  • 1500 children diagnosed yearly in U.S.
  • 80% occur within first 10 years of life
  • 60% occur in the posterior fossa, the “back vault” of the skull below the tentorium (i.e., cerebellum and brainstem). This is very different from adults, who typically get supratentorial tumors.
  • 5-year survival now 50%, though this varies based on age, tumor type, tumor location
  • Low-grade astrocytomas, which can often be treated by surgery alone, have excellent long-term survival if entire visible tumor is removed (i.e., “gross total resection” – 90% survival at as long as 10-20 year follow-ups). Can be deadly if they are intrinsic in the brainstem and thus not amenable to surgical removal.
  • High grade gliomas (e.g., glioblastoma muliforme, are often deadly and require aggressive treatments). Also, even Primitive Neuroectodermal Tumors (PNETs) are often more malignant, and require more aggressive treatments. For example, “standard risk” medulloblastomas have a 5-year survival rate of 50-80% after surgery, chemotherapy and radiotherapy.

Treatment Options and Neuropsych Effects

Neurosurgery

  • Biopsy, shunt/stent placement (in the event of acute obstructive hydrocephalus), or resection (removal of the tumor or part of the tumor)
  • Surgery is fairly ubiquitous in brain tumors
  • Neuropsych effects
    • No consistent relationship between percent of tumor resected and cognitive outcome
    • Surgical approach may affect outcome (techniques getting better and better every year)
    • Surgical complications are associated with poor outcome
    • Surgery may increase risk for cognitive deficits, but only slightly. Many kids with posterior fossa low-grade astrocytomas do great after only surgical removal.

Chemotherapy

  • Antineoplastic, steroid, others (e.g., AEDs). Note that many people think only of the antineoplastic drugs as “chemotherapy”, but in fact these kids are often put on many meds with potential cognitive effects.
  • Most administered into bloodstream, but Methotrexate is intrathecally administered (i.e., directly into CSF).
  • Neuropsych effects
    • Possible short-term effects include drops in fine motor speed/coordination and performance on drawing/copying tasks. This may be due to an at least partially reversible peripheral neuropathy.
    • Long-term cognitive effects are clearly less marked than radiation, although the variety of chemotherapy agents, combinations, and delivery systems makes generalizations difficult. There is some evidence of long-term effects on reaction time for several chemo agents.
  • Intrathecal methotrexate accentuates the long-term effects of radiation on cognition.
    • Though not typically considered “chemotherapy”, steroids are often administered. There is some evidence that long-term steroid use can affect reading & math performance, immediate attention span, and visual-constructional/drawing skills.

Radiotherapy

  • Craniospinal (hitting the whole CNS axis). Helps reduce metastases (including those in high-risk, non-CNS cancers such as leukemia) while also hitting tumor site.
  • Focal (hitting the tumor site from multiple angles to minimize exposure to healthy tissue)
  • Craniospinal with local boost (combine lowered-dose craniospinal with a focal hit to the tumor site). In this case, the craniospinal aspect is meant to head off metastasis.
  • Stereotactic radiosurgery (aka “gamma knife”; very focal with precise boundary measurements). Not as useful if tumor margins are not distinct on imaging or if there is a risk for metastasis.

Neuropsych effects

  • Long-term declines in IQ can result from whole-brain radiation, at a rate of 5-7 FSIQ points/year. This is different from adults.
    • Decline has delayed onset (1-2 years?), and its not clear when decline stops (2 yrs post? 10?)
    • Whole-brain radiation is more deleterious to younger kids’ IQ than to older kids’ IQ (see graph below from Radcliffe et al., 1994). This is a uniquely developmental phenomenon.
  • Relationship between radiation dose and IQ decline is unclear, though there is evidence that reducing the dose to the whole brain and using a focal boost to the tumor has a better outcome
  • No single profile of neuropsychological effects, though the following are often affected:
    • Memory
    • Attention
    • Fine motor speed and coordination
    • Mathematics skills
    • Visual-spatial & Visual construction skills
    • Mechanisms for cognitive morbidity include vasculo-occlusive changes, white matter degeneration/poor myelination, and subsequent skill stagnation that leads to IQ decline.

Other Medical Factors Affecting Neuropsych Outcome

  • Supratentorial tumors in the cerebral hemispheres may be associated with greater long-term impairment than midline and infratentorial tumors
  • Original tumor size and residual tumor volume not consistently associated with neuropsych outcome
  • Recency of symptom onset may be predictive of cognitive outcome, as recent symptom onset and rapid decline may be proxies for more aggressive tumors that will require more aggressive treatments.
  • Cranial nerve and motor impairments can affect functional status.
  • Treated acute obstructive hydrocephalus is not related to eventual cognitive outcome (differs from chronic hydrocephalus)
  • No research yet on the cognitive impact of other sequelae of increased intracranial pressure
  • Though common (esp. in hemispheric tumors), the effect of seizures themselves on inter-ictal functioning is unclear. However, AEDs can carry cognitive side effects
  • Also common, treated endocrine dysfunction seems not to have a measurable cognitive effect.

Parkinson’s Differentials

What Parkinson’s is Not: Parkinsonian Look-Alikes

With so many people who show Parkinsonian symptoms not being correctly diagnosed as having Parkinson’s, it is also worthwhile noting that a number of people initially diagnosed with Parkinson’s have another disease, a “Parkinson’s look-alike,” instead. Most often these people are still considered to have Parkinsonism by the community, but their treatment protocol may be substantially different from that of persons who have idiopathic Parkinson’s.

Here are some of the conditions with which Parkinson’s may be initially confused:

Benign Essential Tremor

  • A common condition that may appear in the elderly and slowly progress over the years. The tremor is usually equal in both hands and increases when the hands are stretched out in front of the patient or when the hands are moving. The tremor may involve the head but spares the legs. Patients with Benign Tremor have no other Parkinson’s features, and there is usually a family history of tremor. Parkinsonian Tremor and Benign Tremor generally respond to different drugs. A small number of patients with Benign Essential Tremor (less than five percent) develop PD.

 

Shy Drager Syndrome

  • A condition in which the earliest and most severe symptoms are those of insufficiency of the Autonomic Nervous System: dizziness on standing, bladder difficulty, and impotence. These autonomic symptoms are followed by PD symptoms such as rigidity, tremor, bradykinesia, postural instability, and gait difficulty. There is some question among neurologists as to whether the Shy Drager Syndrome is a form of PD or a separate disease.

 

Normal Pressure Hydrocephalus

  • An uncommon condition that consists of difficulty walking resembling PD), mental changes (resembling senility), and urinary incontinence. The condition is caused by an enlargement of the fluid cavities (Ventricles) in the brain that compress the parts of the brain that regulate walking and thinking. Normal Pressure Hydrocephalus differs from the more familiar hydrocephalus of childhood, which results from the blockage to the flow of spinal fluid. No such blockage is found in patients with Normal Pressure Hydrocephalus. There is no known cause of Normal Pressure Hydrocephalus. The Condition may respond to a shunt: a tube placed in the ventricle which drains off the excessive fluid and carries it away.

 

Striato-Nigral Degeneration

  • An uncommon disorder in which patients become stiff and slow and develop difficulty with balance and walking. Usually patients do not have tremor and cannot be distinguished from patients with PD on the basis of a neurological exam. Patients with Striato-Nigral Degeneration however do not respond to Levadopa. Only after death can this disorder be distinguished from PD because in Striato-Nigral Degeneration most of the damage is in the Striatum and not the Substantia Nigra. This is the reverse of the situation with PD.

 

Pseudobulbar Palsy

  • A common disorder that occurs in patients with disease of the blood vessels of the brain (Arteriosclerosis). Arteriosclerosis is especially likely to occur in patients with high blood pressure or diabetes. Patients who develop Pseudobulbar Palsy do so because they suffer numerous small strokes (ministrokes), many of which are so mild that patients are unaware of them. The ministrokes usually damage the part of the brain that controls balance and walking, the same area involved in PD. The two disorders may not be distinguished on the basis of a neurological examination alone. Patients with Pseudobulbar Palsy do not respond to antiparkinsonian drugs. In the past, many patients were thought to have PD on the basis of Arteriosclerosis alone (arteriosclerotic PD). Currently, Arteriosclerosis is not believed to be the cause of PD.

 

Progressive Supernuclear Palsy

  • An uncommon disorder in which patients develop Paralysis of their eye movements, difficulty in speaking, rigidity, and senility. This disorder causes changes in the brain that are similar to those of PD, but are even more extensive. Patients with this condition do not respond to antiparkinson drugs.

 

Wilson’s Disease

  • A rare inherited disorder that appears in patients below the age of 40. This disease involves the brain and the liver. This excess results in damage to these two organs. Early diagnosis is important in this disease as treatment prevents further damage to the brain and liver.

 

Hallervorden Spatz Disease

  • Also a rare, inherited progressive disease that begins in late childhood. Hallervorden Spatz Disease is associated with the accumulation of excessive iron in certain parts of the brain. There is no treatment for this disease.

 

Olivopontocerebellar Degeneration

  • An uncommon disorder in which patients have difficulty with balance and walking, often called Ataxia. The patients may have an action or sustention tremor, but do not have rigidity or bradykinesia. The disorder results from a deterioration of the nervous system, including the Cerebellum, the Pons (a part of the brain stem), and the Olives (a part of the Brain Stem and Spinal Cord). Olivopontocerebellar Degeneration does not respond to antiparkinson drugs.

 

Huntington’s Disease

  • An inherited disease which usually begins early in middle life. It is characterized by involuntary movements (dyskinesias, chorea) associated with changes in behavior, personality, and mood. The chorea (which resembles the involuntary movements caused by Levedopa) may precede, occur simultaneously, or follow the mental changes. The disease, when fully developed, is easily distinguished from PD. However, the symptoms of a childhood form of Huntington’s disease may resemble PD. Levadopa usually worsens the symptoms of Huntington’s disease…

 

Dystonia

  • An inherited disease that begins in childhood and is progressive. The patients develop unusual postures of the head and neck, arms and legs. This is called Generalized Dystonia (Dystonia Musculorum Deformans). A variation of the disease, Segmental Dystonia, develops in adulthood and involves only one part of the body, e.g. the head and neck (Torticollis or Wryneck). …

 

Brain Tumors

  • Tumors of the brain that are close to the substantia nigra or the striatum may exert local pressure on these structures. This local pressure may, in turn, result in the appearance of symptoms that resemble PD. A CT or NMR scan of the brain will exclude the possibility of a brain tumor as the cause of the Parkinsonian symptoms

 

Nutritional Deficiencies

Some Common Nutritional Deficiencies

  • Korsakoff’s Disease – related to thiamine deficiency
  • Folic acid/folate deficiency – implicated in a progressive condition of mental deterioration with concomitant cerebral atrophy. It is also implicated in spina bifida/neural tube defects.
  • Vitamin deficiencies – affect anorexic young women (who show subtle neuropsychological deficits), and in the elderly (whose intake of nutrients falls below recommended standards) who show similar deficits. In the elderly undernourishment with regard to vitamins B12, B6, and folate may occur.
  • Malabsorption of vitamins, fats and other critical substances – usually related to starvation, gastrectomy, gastric bypass surgery and inflammatory bowel disease leads to neuropathies.
  • Niacin deficiency – pellagra (dementia, dermatitis, diarrhea – the three D’s)
  • Combined System Disease (pernicious anemia, or B12 deficiency) – causes a neuropathy overshadowed by spinal cord impairment.
  • Fat-soluble vitamin deficiencies and clinical signs
    • Vitamin A – Night blindness, hyperkeratosis, skin changes
    • Vitamin D – Hypocalcemia, osteomalacia, rickets, hypophosphatemia
    • Vitamin E – Neuropathy, hemolytic anemia
    • Vitamin K – Prolongation of prothrombin time, easy bruising
  • Alcohol provides 7 kcal/g, but lacks in vitamins and minerals, can result in Wernicke’s encephalopathy and macrocytic anemia, respectively. Patients who do not respond to oral supplements may require subcutaneous injections of vitamins. If a diuretic is being taken, serum potassium, zinc and magnesium levels should be closely monitored.

Sources of Vitamins and Minerals

  • Thiamine (Vitamin B1)
    • Found abundantly in all varieties of food stuffs and is rapidly destroyed with cooking. Deficiency occurs in alcoholics, patients undergoing peritoneal dialysis, long administration of Glucose. Deficiency symptoms can be “Tingling and numbness” of fingers and toes.
  • Riboflavin (Vitamin B2)
    • Found in milk, meat, fish, leafy vegetables and is also destroyed with cooking. Deficiency causes sore mouth, apthous ulcers, anaemia.
  • Niacin (Vitamin B5)
    • Found in whole grain cereals, nuts, fish, meat. Deficiency can be associated with a high intake of maize. Symptoms are rapid loss of weight, diarrhea, fatigue and sometimes even severe loss of memory (dementia).
  • Pyridoxin (Vitamin B6)
    • Found in meat, vegetables, whole grain cereals. Deficiency can occur in alcoholics, pregnancy, intake of certain drugs like Isoniazid (Anti T.B. drug), oral contraceptives. Symptoms of deficiency are Seborrhoeic dermatitis ( a dandruff-like condition of scalp, eyebrows), cuts on the lips (Chelitis), burning sensation of the tongue, tingling and numbness of hands and legs.
  • Cobalamine (Vitamin B12)
    • Found in kidney, eggs and milk. Cobalamin is an essential intrinsic factor required for the formation of Hemoglobin.
    • Deficiency can be found in patients with impaired gastric absorption, pancreatic diseases. Symptoms are anaemia, low B.P., tingling and numbness of extremities, redness and burning of tongue (glossitis).
  • Vitamin C (Ascorbic Acid)
    • Found in fresh vegetables , citrus fruits. Deficiency can cause bleeding gums, delayed healing of colds, Pupura (bleeding disorder).
  • Folic Acid
    • Found in green, leafy vegetables. Defective absorption in cases with chronic gastric problem can lead to deficiency. Also in patients undergoing Dialysis, Hyperthyroidism, pregnancy. Deficiency symptoms include Megaloblastic Anaemia, Glossitis, Chelitis.
  • Vitamin A
    • Found in animal food, carrot etc. Deficiency causes dryness of eyes and skin, night blindness, corneal ulcers.
  • Vitamin D
    • Found in milk, fish, eggs, butter. Inadequate exposure to sunlight also can cause deficiency.In children it causes rickets and Osteomalacia (softening of bones) in adults, muscle weakness and muscular cramps.

Additional Resources

The following web sites are also useful resources.

http://apps.medsch.ucla.edu/nutrition/nutritdef.htm

http://apps.medsch.ucla.edu/nutrition/nutritpath.htm

Nonverbal Skills

Definitions

Visual-perceptual

Form or pattern discrimination; color, shape, features of object regardless of location

Visual-spatial

Processing of visual orientation or location in space; depth, motion

  • “Types” of visual-spatial processes
    • Object localization- ability of any sensory system to locate object in space
    • Line orientation- human cortex has detectors of line orientation; damage to right posterior disrupts this function, regardless of sensory modality
    • Spatial synthesis- perceived spatial features of an object that make it “that object”
    • Spatial attention- ability to pay attention to either right or left hemispace; contralateral parietal lobe
    • Spatial mental operations- mental rotation (imagining an object if displace along a line); mental reflection (imagining an object reflected in a mirror)

Constructional ability (constructional praxis)

Ability to draw or assemble an object from component parts

  • Integrative aspect- people with deficits may be able to reproduce components of design but not integrated whole
  • on command or copying

Memory

  • Spatial memory- short term; long term; discrete lesion (right hippocampus; thalamic mesiodorsal nucleus) can cause memory deficits with preservation of spatial perception
  • Topographical memory- find way around; relies on landmark recognition, spatial attention, spatial memory

Development of Skills

Visual-spatial skills

Development of locomotion essential to development of visual-spatial skills

  • Once child walks or crawls, changes way view space and increases strategies to solve spatial problems
  • When infant allowed to move independently rather than being carried by others, has better grasp of spatial features
  • Research shows strong correlation between self-produced movement and visual tracking

Verbal Representation of Visual-Spatial Concepts

Consistent developmental picture across languages in comprehension and elicitation

  • In, on , under, next to
  • Between, in back of, in front of (using a featured object¬)
  • In back of, in front of (using a nonfeatured object)

Construction of 3-D Objects

  • “Small scale models”- using everyday objects to represent other things (ex- pretend chair is a stove; long, flat block could be road or house depending on orientation)
  • Uni-dimensional representation- forms are linear; house may be stack of blocks, but each block stands for a feature
  • Two-dimensional representation- starts creating overall shape with blocks; begin to overlook boundaries of blocks and depict surface of object; uneven block on top for chimney
  • Three-dimensional representation- building on all three axes; positions blocks so many facets join other blocks; builds interior vacant space

Drawing

  • Interest in crayons; making marks
  • Point-plot representations- spatial plotting of features of an object; features not contoured or connected
  • Beginning figure-ground relationship- more visual-spatial likeness of object (long strokes for hair)
  • Three dimensional space- scenes with figures side by side

Neuroanatomy

Right Hemisphere

  • More white matter; less gray matter
  • More associative cortex
  • More interconnections
  • Advantage for processing complex information; many modes within an single task
  • Configurational processing; material that cannot be described adequately as a string of symbols (faces, 3D objects)
  • Preference for global aspects
  • Involvement in language- integration of relationships in verbal/written discourse; integrating verbal output; making verbal expression appropriate for context/emotion; humor; alternative meanings; intonation; prosody

Anterior Parietal Lobe

  • somatosensory cortex
  • involved with somatic sensation and perception

Posterior Parietal Lobe

  • inferior posterior lobule- high order somatosensory and visual cortical fields
  • superior posterior lobule- somatosensory association cortex
  • integrating discrete elements into whole
  • spatial, constructional, topographical skills

Where vs. What Streams

  • Dorsal Visual Stream- “where”; info regarding spatial analysis and orientation; runs along top side of cerebrum from occipital to parietal visual areas
  • Ventral Visual Stream- “what”; info regarding shape, pattern; runs along underside of cerebrum from occipital to temporal visual areas

Temporal Lobe

Nonverbal analogues of left hemisphere

  • nonverbal sound discrimination, recognition, comprehension
  • visual, auditory, tactile memory (faces, designs, melodies)
  • anterior- storage; posterior- retrieval

Tests

Visual attention

  • Cancellations tasks
  • Line bisection
  • Picture description- ask describe what in picture or count certain object in picture
  • Reading- omit part of line
  • Written expression- copy sentences

Visual recognition

  • JLO
  • Recognize objects under distorted conditions
  • Facial recognition
  • Discriminate rotations of objects
  • Visual organization; incomplete figures
  • Fragmented visual stimuli (Hooper)
  • Ambiguous stimuli

Constructional skills

  • Drawing tasks (VMI, Rey; copy vs free draw)
  • Building tasks

Memory

  • Visual recognition
  • Visual reproduction
  • Visual learning

Disorders

Visual Agnosia

  • Inability to recognize object
    • Associative- person can still draw or describe major details of stimuli
    • Apperceptive- person cannot draw or match visual stimuli
  • Agnosia vs anomia- if person can still describe what object is and what used for (only a naming deficit) then it is anomia

Prosopagnosia

  • Inability to recognize previously known faces and learn new ones
  • Applied to any visually ambiguous stimuli (ex. farmer not being able to recognize cows)
  • Can perform generic recognition (say that a car is a car) but no specific membership (can’t say which manufacturer of car)
  • Intact emotional recognition

Facial Processing

  • Inability to recognize facial emotion- bilateral amygdala damage
  • Deficit in social judgment of faces (judge as approachable and trustworthy)- amygdala

Simultanagnosia

  • Inability to comprehend overall meaning of stimulus- can identify and describe isolated elements
  • Can see parts, but not the whole
  • Example- person looking at eyeglasses, says there’s a circle, another circle, stick and cross bar, concludes it must be a bicycle
  • Difficulty understanding meaning of complex thematic pictures or seeing card combinations of a “hand” although know relative value of cards

Pure Alexia

  • Word blindness- impaired ability to read single words or sentences
  • Can copy them, normal visual acuity, normal recognition of nonverbal stimuli
  • Lesion that disconnects language-related temporo-parietal cortex from visual association area

Disorders of Location and Orientation

  • Deficits-inability to locate a building, find one’s room, describe either verbally or by map how to get someplace
  • Can be caused by neglect or impairment of visuospatial memory- can no longer conjure up previously stored memories to get bearings and establish route
  • Bilateral posterior lesions

Unilateral Spatial Neglect

  • Tendency to neglect one-half of extrapersonal space- integrated disorder of attention and vision
  • Tests involve having person draw a symmetrical picture (clock, flower).
  • Neglect occurs contralateral to the brain lesion.
  • Most often in acute phase of recovery.
  • Seen with more frequency and severity after right hemisphere than left hemisphere lesions.
  • Also seen following lesions of cortical and subcortical parietal lobe, dorsolateral frontal lobe, cingulated gyrus, thalamus, and reticular formation.

Balint’s Syndrome

  • Disorder of spatial analysis
  • “Acquired disturbance of ability to perceive the visual field as a while, resulting in unpredictable perception and recognition of only parts (simultanagnosia) which is accompanied by impairment of target pointing under visual guidance (optic ataxia) and inability to shift gaze at will toward new visual stimuli (ocular apraxia)”
  • Three major components-
    • Visual disorientation (simultanagnosia)
    • Optic ataxia (deficit of visually guided reaching)
    • Ocular apraxia (deficit of visual scanning)
  • Visual disorientation is core. Person only able to grasp fraction of visual field, and this fragment is not stable and moves erratically. As a result, objects disappear from view, so can’t describe more than one or two parts of an object. Also fail to orient to new stimuli unless happens to be in window of vision
  • Optic ataxia- person can point to parts of body, garments, sound, but not to visual stimuli
  • Ocular apraxia- cannot direct gaze voluntarily toward new stimulus. Normally, person produces a quick saccade toward something new. Can’t do this, even if told something is there.
  • Bilateral damage to occipitotemporal region

Constructional Apraxia

  • “apraxia of the psychologist”- seen more in evals than in real life
  • inability to assemble, join, or articulate parts in a unitary structure.
  • parietal dysfunction, usually right
  • Drawing- left hemisphere damage leads to drawing that is spatially correct, but oversimplified with omission of details
  • Drawing- right hemisphere damage leads to fragmented drawing; may have details but lost whole of picture and spatial relations; may neglect left side
  • Block constructions- left hemisphere damage see maintenance of 2×2 or 2×3 configuration but error with internal details; tend to recognize when incorrect
  • Block construction- right hemisphere damage break configuration, but see internal details; do not appreciate when incorrect; may skew to right space

Disorders Demonstrating Deficits in Nonverbal Abilities

  • Syndromes
    • Velocardiofacial syndrome
    • Williams syndrome
    • deLange syndrome
    • Sotos syndrome
    • Turner syndrome
  • Anomalies of brain or CNS
    • hydrocephalus
    • spina bifida
    • congenital hypothyroidism (insufficient production of thyroid hormones; this hormone facilitates glial cell production)
    • MS
    • Metachromatic leukodystrophy

Hydrocephalus

  • Increase in CSF volume in ventricular system
  • Can result from structural abnormality blocking CSF outflow (Arnold Chiari)
  • Children with IVH can develop as a result of blockage of CSF reabsorption
  • Also associated with TBI, infectious diseases, tumor
  • Classified three ways
    • Complicated (associated with other clinical problems) or noncomplicated
    • Communicating (obstruction occurs in subarachnoid spaces, where CSF is blocked as it leaved fourth vent) or noncommunicating (obstruction within vent system)
    • Congenital or postnatal
  • Consequences on brain development
    • Stretch or destroy CC
    • Affects white matter tracts, especially projection fibers near midline
    • Disrupt myelination, resulting in reduced cortical mantel, reduced brain mass, and thinning of posterior brain regions.
    • Multiple surgeries to correct shunt
  • Neuropsych
    • PIQ < VIQ
    • visual-spatial/ visual-motor < language
    • some studies kids with shunts did worse
    • some language probs: rapid retrieval of info; automaticity; language discourse; cocktail party speech
    • deficits in both verbal and visual memory
    • executive deficits
    • Studies show relationship between size of corpus callosum and nonverbal skills

ALL

  • cancer of blood-forming cells in bone marrow; peak incidence 3-5 yrs of age
  • strikes when CNS highly vulnerable to insult
  • treatment goal is total eradication of disease; 95% chance of remission; > 50% chance of remission for 5 years.
  • treatments are bad for CNS: radiation, intrathecal chemo, steroids
    • cortical atrophy; lead to ventricular or subarachnoid space dilation
    • leukoencephalopathy: myelin degeneration; white matter of both hemispheres; watershed areas
    • mineralizing microangiopathy :degeneration of microvasculature; dystrophic calcifications of adjacent areas; CNS calcifications of gray matter, primarily around BG
  • Neuropsych deficits are late effects
    • 10 pt IQ drop
    • nonverbal < verbal; arithmetic < reading
    • nonverbal memory < verbal memory
    • attention problems; difficulty focusing and planning responses
    • executive deficits
    • diminished response time and motor speed
  • Risk factors associated with treatment effects
    • Age: myelin still developing; < 5 is bad
    • Gender: impairment more prevalent and severe in females; females more vulnerable to radiation/methotrexate combo (males may be more vulnerable to steroids)
    • Treatment: combo of radiation and intrathecal methotrexate worse than just XRT. XRT dose > 2000 cGy and higher MTX associated with leukoencephalopathy
    • Sequence of treatment: lower CNS pathology when IT MTX given before XRT rather than after. Hypothesized that radiation affects integrity of BBB, allowing increased penetration of MTX and reduced clearance of MTX from brain.

TBI

  • Primary injury: coup/contrecoup; contusions and hemorrhages
  • Secondary injury: edema, hematoma, seizure; major causes of tissue loss
  • Late effects: white matter degeneration; cerebral atrophy; ventricular enlargement
  • White matter degeneration primary pathological change in brain. As edema resolves, reduction in myelin, resulting in reduced bulk of cerebral white matter. Damage greatest in CC, parasaggital areas, internal capsules, and pons.
  • Neurospych
    • Decline in IQ
    • PIQ more affected because of task demands, which require fluid problem solving and rapid motor output vs previously acquired info, which remains relatively intact
    • after acute stage, language skills relatively intact; can see subtle problem with naming and fluency and discourse
    • deficits in both verbal and visual memory
    • deficits in attention and executive skills

Nonverbal LD

  • Rourke- Final Common Pathway of White Matter
  • Syndrome or cluster of features related to dysfunction of white matter; processing multi-modal novel info and spatial info
  • Three areas of deficits
    • neuropsychological
    • academic
    • social-emotional
  • Where does it fit in as a syndrome?
  • What criteria are used to diagnose?
  • Overlap with NLD and Asperger’s- differential diagnosis
    • NLD- neuropsych exam important
    • AD- more of a behavioral diagnosis; looking for more social-emotional problems, behavioral rigidity, restricted interests
  • Overlap with ADHD- social problems related to impulsivity

Neurotransmitters and Drugs of Abuse

Dopamine

Synthesis and Metabolism

Phenylalanine —> Tyrosine —> DOPA —> Dopamine (DA)

Anatomy

  • Synthesized mainly in neurons located in the ventral midbrain (substantia nigra pars compacta & ventral tegmental area)
  • Three projection systems:
    • Nigrostriatal Pathway: Substantia nigra to caudate and putamen (implicated in Parkinson’s)
    • Mesolimbic Pathway: Midbrain to limbic structures (implicated in positive symptoms of psychosis)
    • Mesocortical Pathway: Midbrain to prefrontal cortex (implicated in working memory and other executive skills and cognitive deficits and negative symptoms of Schizophrenia)

Conditions Due to Deficits in Dopamine Synthesis

Phenylketonuria (PKU)

  • Inherited disorder of enzyme that breaks down phenylalanine into tryrosine
  • Results in excessive phenylalanine (excreted in urine) and dopamine depletion
  • If not put on very low phenylalanine diet, the individual will develop mental retardation. Even on diet, executive functioning deficits occur.

Parkinson’s Disease

  • Deficit in conversion of precursors into DOPA, which results in diminished DA
  • Involuntary movement disorder with both “positive symptoms” (e.g., tremor, especially when on L-Dopa), and “negative symptoms” (e.g., bradyphrenia, bradykinesia)
  • Treated with L-Dopa (which boosts DOPA levels), drugs that reduce L-Dopa metabolism outside of the CNS (which allows for lower L-Dopa doses and fewer systemic side effects), or DA agonists

Conditions Due to Excessive Dopamine Activity

Synthetic Causes

  • Excessive L-dopa
  • Cocaine
  • Amphetamines

Endogenous Causes

  • Tardive Dyskinesia Probable increased DA sensitivity due to antipsychotics. Results in visual hallucinations, psychosis, hyperkinetic movement disorders (e.g., dystonia, chorea)

Norepinephrine (NA) and Epinephrine

(norepinephrine is also known as noradrenaline)

Synthesis and Metabolism

Dopamine —> Norepinephrine —> Epinephrine

Anatomy

  • NA synthesized primarily in locus ceruleus (located near fourth ventricle in the rostral/dorsal pons)
  • Projects to the entire forebrain through the thalamus
  • Ascending norepinephrine projection system implicated in modulation of attention, sleep-wake states, mood
  • Epinephrine synthesized in adrenal gland
  • Outside CNS, major neurotransmitters in the sympathetic nervous system

Related Disorders

  • ADHD: Psychostimulant or SNRI (Strattera) treatment enhances noradrenergic transmission and/or reduces reuptake
  • Neuronal depletion of locus ceruleus in Parkinson’s can lead to depression and sleep disorders
  • Noradrenergic transmission also seems to be important in mood disorders including depression and bipolar and anxiety disorders
  • NA depletion can result in orthostatic hypotension and other symptoms of reduced sympathetic n. system activity
  • Excessive NA causes tremor, sympathetic nervous system overactivity (e.g., bronchodilation, arterial dilation)

Serotonin

Synthesis and Metabolism

Tryptophan —> 5-Hydrotryptophan —> Serotonin (5-Hydrotryptamine or 5-HT)

Anatomy

  • Synthesized in dorsal raphe nuclei of the midbrain and pons
  • Projects to entire forebrain including cortex, thalamus, and basal ganglia
  • Many different receptor types result in a variety of symptoms/behaviors associated with 5-HT disorders

Related Disorders

  • Low 5-HT> depression, anxiety, OCD. Also found in Parkinson’s (esp. if depressed) and Alzheimer’s
  • Excessive 5-HT> LSD and Ecstasy are serotonin agonists that cause psychosis and hallucinations

Acetylcholine

Synthesis and Metabolism

Acetyl CoA + Choline —> Acetylcholine (ACh)

Anatomy

  • Synthesized mainly in nucleus basalis of Meynert and adjacent nuclei in the basal forebrain
  • Two kinds of receptors:
    • Nicotinic: Involved almost exclusively at neuromuscular junction
    • Muscarinic: Involved in cerebral cortex (especially in arousal and memory functioning)

Related Disorders

  • Alzheimer’s Disease: Deterioration of nucleus basalis of Meynert implicated in memory dysfunction. Anticholinesterases (e.g., Cognex, Aricept) show some effectiveness in slowing progression a bit.
  • Botox inhibits Ach release from presynaptic neuron, resulting in localized loss of muscle tone
  • Neuroleptics can cause anticholinergic side effects (e.g., confusion, drowsiness, dry mouth); those that tend to produce the least extrapyramidal symptoms (see DA, above) tend to have more anticholinergic side effects.

Glutamate

Synthesis and Metabolism

Glutamine —> Glutamate

Anatomy

  • Major excitatory amino acid; NMDA receptor modulates Calcium channel flow
  • Projects throughout central nervous system

Related Disorders

  • Excessive Glutamate: Causes excitotoxicity, a probable cause of cell death in TBI, stroke, other disorders.

Gamma-Aminobutyric Acid (GABA)

Synthesis and Metabolism

Glutamine —> GABA

Anatomy

  • Major inhibitory transmitter; opens Chloride (Cl-) channels and closes Calcium channels, hyperpolarizing cells
  • Widespread in entire central nervous system, but highest in striatum, hypothalamus, spinal cord, and temporal lobes.

Related Disorders

  • GABA Deficiency: Implicated in epilepsy and, sometimes, chorea
  • Many antiepileptic medications increase GABA activity

Several Drugs of Abuse

(not including alcohol)

Cocaine

Pharmacology

  • CNS Stimulant
  • Blocks re-uptake of DA, NA, and serotonin, while also causing release of DA into synaptic cleft

Desired Effects

  • Euphoria
  • Increased vigilance

Overdose

  • Agitation, paranoia, delusions, hallucinations
  • Strokes (or heart attacks) and seizures
  • Long-term use: involuntary movement disorders (e.g., “crack dancing”: inability to stand still)

Withdrawal

  • Emotional “crash”: dysphoria, anhedonia, strong craving for drug
  • Rebound of REM sleep (which was suppressed while on drug), resulting in vivid, disturbing dreams

Amphetamine

Pharmacology

  • CNS Stimulant, lasting much longer than cocaine
  • Blocks re-uptake of DA while also causing release of DA into synaptic cleft

Desired Effects

  • Euphoria
  • Increased vigilance (many ADHD drugs are amphetamines or amphetamine-like)

Overdose

  • Paranoia, delusions, hallucinations
  • Strokes (or heart attacks) and seizures
  • Long-term use: involuntary movement disorders

Withdrawal

  • Emotional “crash”: dysphoria, anhedonia, strong craving for drug
  • Rebound of REM sleep (which was suppressed while on drug), resulting in vivid, disturbing dreams

Opioids

Pharmacology

  • Can affect DA and other neurotransmitters, but primary effect at opiate receptors

Desired Effects

  • Pain reduction
  • Anxiety reduction
  • Sleepiness

Overdose

  • Coma, “pin-point pupils” (miosis), and respiratory depression
  • Cerebral hypoxia
  • Rarely associated with seizures or cerebral hemorrhages

Withdrawal

  • Strong craving for drug
  • Dysphoria, autonomic hyperactivity

PCP (Phencyclidine)

Pharmacology

  • Central analgesic, depressant, and hallucinogen
  • Blocks re-uptake of DA, NA, and serotonin, prevents glutamate from activating NMDA receptor

Desired Effects

  • Low doses like alcohol use
  • Higher doses cause both positive and negative symptoms of schizophrenia

Overdose

  • Muscle rigidity, vertical nystagmus, stereotypies, blank stare, unresponsiveness
  • Seizures that can lead to status epilepticus
  • Violent, psychotic behavior

Marijuana

(especially the THC in it)

Pharmacology

  • Affects THC receptors in cortex, basal ganglia, hippocampus, and cerebellum

Desired Effects

  • Calming
  • Reduced nausea or vomiting
  • Mood elevation

Negative Effects

  • Slowed mentation
  • Sedation
  • Sometimes hallucinations at high doses
  • Sometimes lasting inattention
  • Fluency problems
  • Impaired executive functioning

Neurologic Exam

Mental Status

  • Level of Alertness, Attention, and Cooperation:
    • Can use test of working memory and attention (e.g., digit span; w-o-r-l-d/d-l-r-o-w)
    • What is being tested? Altered consciousness can stem from:
      • Damage to brainstem reticular formation
      • Bilateral lesions of the thalami or cerebral hemispheres
      • Can be mildly impaired in unilateral cortical or thalamic lesions
      • Toxic or metabolic factors may lead to impaired consciousness b/c of their effects on these structures
  • Orientation
  • Memory
    • Tests e.g.’s include asking patient to recall 3 items or a brief story for a delay of 3-5 minutes and can evaluate patient’s memory about own history
    • What is being tested?
      • Problems with immediate memory more likely related to attention
      • Difficulties recalling info after 1-5 minutes may implicate the limbic memory structures in the medial temporal lobes and the medial diencephalon
  • Language
  • Spontaneous speech – observe fluency, phrase length, and abundance of spontaneous speech; observe for paraphasic errors, neologisms, or grammatical errors
  • Comprehension
  • Naming
  • Repetition
  • Reading
  • Writing
  • Gerstmann’s Syndrome
    • Deficits in calculations, right-left confusion, finger agnosia and agraphia
    • Deficits in all 4 areas implicate the dominant parietal lobe
  • Apraxia:Inability to follow a motor command that is not due to a primary motor deficit or language impairment
  • Implicates language areas and adjacent structures of the dominant hemisphere
  • Neglect and Constructions
    • Extinction on double simultaneous stimulation – patients can detect stimulus affected side when presented alone, but when stimuli are presented simultaneously on both sides, only the stimulus on the unaffected side may be detected
    • Anosognosia – unawareness of deficits on the affected side of their body
    • What is being tested?
      • Hemineglect is most common in lesions of the nondominant parietal lobes
      • Can occasionally be seen in right frontal lesions, right thalamic or basal ganglia lesions and rarely in lesions of the right midbrain.
      • In left parietal lesions, a much milder neglect can be seen affecting the patient’s right side
  • Sequencing Tasks and Frontal Release Signs Evaluating for signs of frontal lobe damage such as:
  • Perseveration
  • Motor impersistence – a form of distractibility in which patients only briefly sustain a motor action in response to a command such as “raise your arms”
  • Auditory go-no-go test
  • Frontal release signs – e.g., grasp reflexes
  • Changes in personality and judgment
  • Logic and Abstraction
  • Delusions and Hallucinations
    • Can be seen in toxic or metabolic abnormalities and other causes of diffuse brain dysfunction as well as in primary psychiatric disorders
    • Abnormal sensory phenomena can also be caused by focal lesions or seizures
  • Mood

Cranial Nerves

  • Olfaction (CN I)
    • Not often tested unless specific pathology such as subfrontal tumor is suspected
    • Do not use noxious orders as they may stimulate pain fibers from CN V.
  • Opthalmoscopic Exam (CN II)
    • Allows direct visualization of damage to retina, optic nerve atrophic changes, papilledema and other important abnormalities
  • Vision (CN II) check for:
    • Visual acuity
    • Color vision (red desaturation is a sign of subtle asymmetry in optic nerve function)
    • Visual fields
    • Visual extinction
    • What is being tested?
      • Lesions in front of the optic chiasm (eye, optic nerve_ cause visual deficits in one eye while lesions behind the optic chiasm (optic tract, thalamus, white matter, visual cortex_ cause visual field deficits similar for both eyes
  • Pupillary Responses (CN II, III)

see p. 59 for full details

  • Extraocular Movements (CN III. IV, VI)
    • checked by having patient moving eyes without moving their head
    • Test for smooth pursuit by having a patient follow a moving object
    • Test convergent movements – does patient demonstrate a dysconjugate gaze (eyes not fixated on same point) – results in diplopia(double vision)
    • Saccades – eye movements used to rapidly fixate from one object to another (look at my thumb, look at my finger)
    • Optokinetic nystagmus – abnormalities in smooth pursuit eye movements

Motor Exam

Only relevant info is detailed here – for full review see pages 63-70

  • Observation
    • Observe for sings of involuntary movements and tremors – associated with lesions in ganglia or cerebellum (tremors can also occasionally be seen in peripheral nerve lesions)
  • Muscle Tone Testing

Evaluates for resistance or rigidity by asking patient to relax and then passively move each limb- helps to distinguish between upper motor neuron and lower motor neuron lesions

  • Signs of lower motor neuron lesions – weakness, atrophy, hyporeflexia (reduced reflexes)
  • Signs of upper motor neuron lesions – weakness, hyperreflexia, and increased tone.
    • In acute upper motor neuron lesions, there is often flaccid paralysis with decreased tone and reflexes; over time (hours to weeks) increased tone and hyperreflexia usually develop
  • Increased tone can also occur in basal ganglia dysfunction
  • Slow or awkward finger movements or toe tapping in the absence of weakness can signify an abnormality in the corticospinal pathways, but can also occur in lesions of the basal ganglia or cerebellum
  • Reflexes
  • Plantar Response – tested by scraping an object across the sole of the foot…
    • Normal response is downward contraction of the toes
    • Abnormal response – Babinski sign – is characterized by an upgoing big toe and fanning outward of the other toes. Toes that do not move up or down (called “silent”) are also considered abnormal.
  1. 1Abnormal in all adults, although present in infants up to the age of about 1 year
  2. 2Where localized? Upper motor neuron lesions anywhere along the corticospinal tract
  • Frontal release signs – reflexes normally present in infants but that are pathological in adults (from frontal lobe lesions)
    • These include the grasp, snout, root and suck reflexes

Coordination and Gait

Re: disturbances of coordination and gait can be caused by lesions in many other systems other than the cerebellum

  • Ataxia – abnormal movements seen in coordination disorders;
    • Overshoot is commonly seen and is sometimes referred to as past pointing
  • Dysdiadochokinesia – abnormal alternating movements
  • Appendicular ataxia – affects movements of extremities and is usually caused by lesions of the cerebellar hemispheres and associated pathways
    • Can be tested by having patient complete rapid alternating movements, finger-nose-finger test, or heel-shin test
  • Truncal Ataxia affects proximal musculature, especially that are involved in gait stability, and is caused by midline damage to the cerebellar vermis and associated pathways
    • Romberg test – ask patient to stand with their feet together with eyes open and then to close their eyes – if they then sway or lose balance suggests impairment in the proprioceptive or vestibular systems
    • Can be used to implicate the midline cerebellar region (however, similar deficits can be seen with lesions in other parts of the nervous system such as upper or lower motor neurons or basal ganglia)
  • Gait
    • Evaluate patient’s tandem gait (walking in a straight line heel to toe); patients with truncal ataxia caused by damage tot he cerebellar vermis or associated pathways will have particular difficulty with this task, since they tend to have a wide-based, unsteady gait and become more unsteady when attempting to keep their feet close together.
    • Gait apraxia – rare disorder where person can carry out all movements required for gait normally when lying down – but is unable to walk in standing position; believed to be associated with frontal disorders or normal pressure hydrocephalus

Sensory System

  • Primary Sensation, Asymmetry, Sensory Level
    • Evaluates pain sensation, temperature sensation, vibration sense, joint position sense and 2-oint discrimination (see p. 71 for full details)
  • Cortical Sensation, Including Extinction

Test for:

  • Graphesthesia – can patient identify letters and numbers that are written onto their palm or fingertips
  • Stereognosis – can patient identify objects by touch
  • Tactile extinction on double simultaneous stimulation
  • Deficits in these domains can be due to lesions in peripheral nerves, nerve roots, posterior columns or anterolateral sensory systems in spinal cord or brainstem, thalamus, or sensory cortex

Coma Exam

Please refer to pages 73 – 78 for full review

  • Conditions that can be mistaken for coma:
    • Large lesions involving frontal lobes or their connections can cause a condition resembling coma called akinesia or abulia – in this state patient has profoundly decreased initiative and minimal responsiveness, but the eyes are usually open and there may be occasional normal-appearing movements
    • Catatonia
    • Locked-in syndrome – consciousness and sensation may be normal, but the patient is unable to move because of a lesion in the brainstem motor pathways or because of peripheral neuromuscular blockade