Case 1: Astrocytoma

Question 1

Treatments following tumor resection

Answer 1

Cognitive rehabilitation (challenges demonstrating ecological validity)
Cogmed program revealed improvement in WM and attention sustained 6-months afterwards
CBT therapy has been shown to be effective
PT, OT, and SLT

Question 2

Describe temporal lobe seizure semiology

Answer 2

Dominant will not be able to speak or respond to commands
Deja vu and epigastic sensations (almost exclusively mesial)
Epigastric sensation is the most common in patients with TLE (found in 52% of patients - high diagnostic feature)
Visual symptoms can be seen with posterio-lateral temporal lobe lesions
Chewing, sucking, swallowing automatisms
Tonic or dystonic postures of the contralateral arm can be observed
Secondarily generalizing is rare
Fear (especially with the mesial structures)

Question 3

Different types of auras

Answer 3

Somatosensory: tingling, numbness, and electrical feeling
Autonomic: respiratory symptoms (limbic), shivering, urinary urgency
Sexual: erotic feeling (temporal lobe)
Visual auras: Spots, blobs, bars, circles of light, color variations, darkness
Cephalic: ill-defined sensations felt within the head, dizziness, pressure
Auditory: deafness or unformed auditory hallucinations (Heschl STL)
Vertiginous: feeling of displacement or movement (uncommon)
Olfactory: horrible smell (uncinate fits) in medial temporal possibly OFC
Gustatory auras: disagreeable taste
Epigastric or abdominal: feeling nausea, may be painful, butterflies
Emotional: fear ranging from mild to intense
Psychic: Faulty interpretation of presentation

Question 4

Factors that determine severity with tumor outcomes

Answer 4

Biology: radiation/chemotherapy and associated disrupted neurodevelopment, tumor location and type, secondary effects such as surgical effect, hydrocephalus, seizures (AED), and tumors recurrence

Development: age at diagnosis and treatment (risks associated with younger age) and age at onset. Most devastating outcomes are observed in the youngest patients

Females have worse outcomes in some studies

Time: time since diagnosis and treatment (longer time associated with increased impairment). Time since diagnosis negatively correlated with outcomes - diminished FSIQ over time at a rate of 2-4 IQ points per year. More rapid decline in the first few years following treatment, followed by leveling off over time; however, trajectory is moderated by age (younger takes more time to reach plateau) - in general, declines continue for more than a decade following treatment (stagnation and rarely loss of previously acquired skills)

Question 5

WHO grades of severity

Answer 5

Grade I: well differentiated, slow growing, responsive to surgery, non-infiltrative, low proliferative propensity (pilocytic astrocytomas and craniopharyngioma)

Grade II: somewhat infiltrative, moderately differentiated, low proliferative activity, can progress to higher grades (fibillary astrocytoma and ependymoma)

Grade III: infiltrative, poorly differentiated, brisk mitotic activity, often requires adjunctive chemotherapy and/or radiation, tends to progress to higher grades (anaplastic astrocytoma or ependymoma)

Grade IV: undifferentiated, widespread infiltration, high mitotic activity, high degree of necrosis, requires multimodal treatment, propensity for craniospinal dissemination, high rate of recurrence (medulloblastoma and glioblastoma)

Question 6

Incidence rates information

Answer 6

1% of US population have epilepsy - 3 million adults and 470,000 children

5000 new cases of children with brain tumors per year

74% of children with CNS malignancies achieve 5-year survival vs. 58% of children during the 70s-80s.

5-40% of children will experience significant neurocognitive impairment

Question 7

Cause of postictal phase and value

Answer 7

Neuronal exhaustion due to increased metabolic activity of the discharging focus or increased inhibition of the area of focus

Todd Paralysis is a transient paralysis that may occur following focal seizures - usually on one side of the body contralateral to the seizures

Question 7

Keppra mechanisms of action and side-effects

Answer 7

Precise mechanism of action is unknown - differs from known mechanisms involved in inhibitor and excitatory neurotransmissions. May be related to modulation of protein function - binds to SV2A protein (but unknown how works) - inhibits burst firing without affecting normal neuronal excitability - selective suppression

Side effects: Fatigue (15%) coordination problems (3%), behavior problems (agitation in 6% of pediatric trials)

Question 8

Late effects in brain tumor

Answer 8

Deficits can emerge years after treatment

Pattern of decline is age-dependent - younger patients show more immediate decline with attenuation over time while older patients demonstrate a more protracted decline with evaluation deficits typically not present until 18-24 months post treatment

Question 9

Phases of epilepsy

Answer 9

Ictal - during the seizure (involves epileptogenic zone)
Interictal - periods in between seizures or convulsions (can include irritative zone)
Postictal - after the seizure

Question 10

Etiology of TLE

Answer 10

Cortical dysplasia is most common finding in pediatric
Cryptogenic: there is no lesion or neuroimaging and histopathology fails to show abnormality
Vascular in 5%

Surgery is more difficult in non-lesional surgery
Higher rate of generalized tonic-clinic seizures and reduced rate of seizure freedom after surgery (50% vs. 76%) because more complex epileptogenic region and network

Question 11

Ketogenic diet

Answer 11

High-fat, low-carbohydrate, moderate protein diet
Ketones are made in the body
Fat becomes the primary fuel
Ketones are one of possible mechanisms of action of the diet
Other theories are glucose stabilization +

Certain types of epilepsy LGS, myoclonic epilepsy, Dravet syndrome, infantile spasms, TSC

Over 50% experience reduction and 10-15% become seizure-free. Some people experience increased alertness, awareness, and responsiveness

Liver and kidney need to be monitored - need to supplement diet

Question 12

Cause of hippocampal sclerosis

Answer 12

Excessive neural activity, such as status epilepticus, is associated with seizure induced neuronal loss, neurogenesis, and abnormal synaptic reorganization, gliosis, and molecular plasticity

Continuous neural reorganization could contribute to progressive brain damage and HS

Sometimes preexisting lesions predisposed. But also, MTLE show progressive hippocampal neocortical atrophy

Question 13

Fibrillary astrocytoma

Answer 13

Low grade infiltrating astrocytoma, slow growing, typically supratentorial (most commonly temporal and frontal), infiltrates into surrounding brain tumor and is more difficult to remove surgically

Question 14

Neurocognitive profile in brain tumor

Answer 14

Deficits in processing speed, executive functions, and memory are the most vulnerable and affected overtime - hinders learning, particularly in those with concurrent seizures requiring AED and children with third ventricle or cerebellar tumors

disruptions in verbal memory, visuospatial skills, and motor functions in a group of children treated with surgery exclusively

Limited studies on premorid deficits to establish a “true” baseline level of functioning - most time the initial assessment occurs during the course of chemotherapy

Question 15

Outcomes for tumor resection in temporal and extratemporal epilepsy surgery

Answer 15

65-87%

Question 16

Mechanisms of epileptogenesis with tumors

Answer 16

Type of tumor, Microenvironment: tumors have increased metabolic requirement and eventually to hypoxia; process causes glial cell swelling and damage increasing neuronal excitability and facilitating epileptogenic activity; risk of epilepsy further increases because of increased inward-sodium currents at the level of the astrocytic cell membrane, and Genetics: some studies have suggested role of certain genes in tumor-related epilepsy

Question 17

facts epilepsy and tumor rates

Answer 17

third of patients with brain tumors and epilepsy
75% being focal and only 20% being generalized
Low-grade astrocytoma is 75% - TLE low-grade astrocytomas is 46%

Most tumor-related seizures first appear early in the value was going on over a course of the disease, usually as a presenting manifestation – in 10-30% of brain tumor patients, epilepsy develops later in the disease course

Question 18

Secondary seizures in tumors and risk factors

Answer 18

In cases with secondary focus becomes completely independent epileptic generator that needs to also be removed to achieve seizure freedom in intractable patients

Young age and long disease duration have been proposed as being the main risk factors for secondary epileptogenesis - earlier resection can prevent - shorter epilepsy duration at the time of tumor resection is an important predictor of postoperative seizure freedom

Question 19

Seizure freedom with tumors without surgery

Answer 19

Many patients have recurrent seizures (60-80%) despite the use of AEDs. First-line AEDs fail in about 60% of patients and of the remainder, a similar proportion of second-line treatments with monotherapy or polytherapy fails

Question 20

Risk of intractable epilepsy with tumor

Answer 20

tumor are at higher risk of later developing epilepsy (recurrent seizures), even with prophylactic trials of AED treatment – 50% of those with tumor-related epilepsies may become medically intractable (a risk that is significantly higher than seen with other epilepsies)

medical intractability occurs in up to 50-60% of patients with seizures and brain tumors

Question 21

Why do patients with low-grade astrocytomas remain medically refractory

Answer 21

Due to an overexpression of proteins belonging to the multidrug resistance pathway – multidrug resistant gene (MDR) found in astrocytoma

Other mechanisms proposed include AED resistance in brain tumors caused by concomitant use of chemotherapy agents

Risk for drug-drug interactions during use of AEDs and chemotherapeutic agents

Question 23

Seizure freedom with surgery

Answer 23

Patients with intractable temporal lobe epilepsy – the number of 3-year postoperative seizure free incidences for the group that underwent lesionectomy plus spike-positive site resection equated to 90.9%. In contrast, group that underwent lesionectomy only was 76.9% after 3 years postoperatively (retrospective)

On 9 year follow up, studies report that 65% of patients remain seizure free with brain tumors in the temporal lobe; separate study was 81% over 10 year follow up

Likelihood of seizure freedom is lower when there is normal MRI scans and cortical dysplasia is lower than patients with HS, tumors, or vascular lesions – for normal MRI, 62% reported seizure freedom at 10 years in one study

In children and adolescents, only 33% were seizure free for 5 years without AEDs – some data suggest risk for seizure recurrence when people stop AEDs

Question 24

Medulloblastoma surgery risk for neurocognition

Answer 24

suffer cerebellar mutism syndrome (CMS; a complication considered to be related to surgical intervention)

Transient features of this syndrome include acute mutism, irritability/agitation, ataxia, and hypotonia that typically emerges 2-3 days after resection and can last from days to months

Length of these symptoms relates to outcome such that longer time to resolution relates to greater long-term impairments

the acute symptoms, various neurocognitive deficits persist including executive dysfunction, particularly related to attention, cognitive and behavioral flexibility, strategic planning, and initiation

Young patients who developed CMS following surgery for medulloblastoma were more likely to exhibit brainstem and cerebellar medullary angle involvement pre-operative

There is also evidence of significantly greater atrophy of the total cerebellum, vermis, and brainstem in children with CMS compared to those without CMS 1 year post-operatively. A difference of 15 IQ points between the groups on average was evidenced and 60% of the CMS group measured in the impaired range, compared with only 14% in the non-CMS group

There is a recent understanding of the relationship of the cerebellum to higher order cognitive functions, including executive functions and emotional regulation

Question 25

Neuropsychological findings with chemotherapy

Answer 25

Head Start II study suggested that within the first 2 years post-treatment, young children with malignant brain tumors treated with chemotherapy and autologous hematopoietic cell transplant (AuHCT) were spared some of the neurocognitive consequences associated with early radiation therapy

Similarly, children with medulloblastoma treated with chemotherapy alone were shown to function significantly better than children who received radiation, although still significantly worse than normal controls

More susceptible to neurocognitive deficits with intrathecal methotrexate compared to those treated with intravenous MTX or controls. Patients performed worse on all neuropsychological measures; however, another small study of children with chiasmatic-hypothalamic tumors reported no significant change in IQ over time related to MTX delivery

Timing of chemotherapy, specifically MTX, has also been shown to relate to outcome. The effect is pronounced in females as well as in the younger cohort. IT MTX is more commonly associated with the development of leukoencephalopathy, which also impacts neurocognitive functioning

Question 26

Treatment for ADHD in cancer survivors

Answer 26

Stimulants: There is good evidence to support methylphenidate to address issues of attention and working memory in childhood cancer survivors

Warning of sudden death reported in children and adolescents with structural cardiac abnormalities or other serious heart problems

Response rates are not as robust as ADHD population (45% vs. 75%) – lower response rates may be related to differences in the etiology of attentional symptoms and increased prevalence of co-morbid learning problems, neurologic impairment, and lower rates of hyperactivity

There is no specific data on the use of stimulant medications other than methylphenidate in survivors although they may also benefit from amphetamine, dextroamphetamine, or atomoxetine