Neurology Case Conference

Case 2.1 A 10 year-old girl was brought by her mother for a consult because of poor academic performance. School teachers often observed her to be absent minded described as recurrent but brief periods of blank staring and inattention. This was accompanied by eye blinking, reflex scratching of her head, lip smacking and chewing movements which all lasts for a few seconds. These would occur many times a day and after each attack, the patient would resume his usual activity.

Missing Data 1st episode or onset of symptoms Presence or absence of fever, loose bowel movement, vomiting Previous school performance Family History

Steps in the diagnosis of Neurologic Disease Anatomic diagnosis By History Interpretation of symptoms and signs in terms of physiology and anatomy Syndromic formulation and localization of the lesion Mode of onset and course Elicitation of clinical facts Other medical data By neurologic examination 1. The symptoms and signs are secured by history and physical examination. 2. The symptoms and physical signs considered relevant to the problem at hand are interpreted in terms of physiology and anatomy that is, one identifies the disorder(s) of function and the anatomic structure(s) that are implicated. 3. These analyses permit the physician to localize the disease process, i.e., to name the part or parts of the nervous system involved. This step is called anatomic, or topographic, diagnosis. Often one recognizes a characteristic clustering of symptoms and signs, constituting a syndrome of anatomic, physiologic, or temporal type. The formulation of symptoms and signs in syndromic terms is particularly helpful in ascertaining the locus and nature of the disease. This step is called syndromic diagnosis and is often conducted in parallel with anatomic diagnosis. 4. From the anatomic diagnosis and other medical data particularly the mode and speed of onset, evolution, and course of the illness, the involvement of nonneurologic organ systems, the relevant past and family histories, and the laboratory findings one deduces the pathologic diagnosis and, when the mechanism and causation of the disease can be determined, the etiologic diagnosis. This may include the rapidly increasing number of molecular and genetic etiologies if they have been worked out for a particular process. 5. Finally, the physician should assess the degree of disability and determine whether it is temporary or permanent (functional diagnosis); this is important in managing the patient's illness and judging the potential for restoration of function Appropriate lab tests II III Anatomic Diagnosis IV Pathologic Diagnosis I Adam and Victor’s Principles of Neurology”, 8th ed.

CLINICAL TYPE LOCALIZATION Table 16-2 Common seizure patterns CLINICAL TYPE LOCALIZATION Somatic motor      Jacksonian (focal motor) Prerolandic gyrus    Masticatory, salivation, speech arrest Amygdaloid nuclei, opercular    Simple contraversive Frontal    Head and eye turning associated with arm movement or athetoid-dystonic postures Supplementary motor cortex Somatic and special sensory (auras)    Somatosensory Contralateral postrolandic    Unformed images, lights, patterns Occipital    Auditory Heschl's gyri    Vertiginous Superior temporal    Olfactory Mesial temporal    Gustatory Insula    Visceral: autonomic Insular-orbital-frontal cortex Complex partial seizures    Formed hallucinations Temporal neocortex or amygdaloid-hippocampal complex    Illusions    Dyscognitive experiences (deja  vu, dreamy states, depersonalization)    Affective states (fear, depression, or elation) Temporal    Automatism (ictal and postictal) Temporal and frontal Absence Frontal cortex, amygdaloid-hippocampal complex, reticular-cortical system Bilateral epileptic myoclonus Reticulocortical, frontocentral SOURCE: Modified by permission from Penfield and Jasper. “Adam and Victor’s Principles of Neurology”, 8th ed.

Salient Features 10 year old girl Poor academic performance Absent minded Recurrent, brief periods of blank staring and inattention Accompanied by eye blinking, reflex scratching of her head, lip smacking and chewing movements Occurs many times a day

Differential Diagnosis Neonates (<1month) Infants and Children (>1 month-<12yrs.) Adolescents 12-18yrs. Young Adults 18-35yrs.

Table 16-4 Causes of recurrent seizures in different age groups AGE OF ONSET PROBABLE CAUSEa Neonatal Congenital maldevelopment, birth injury, anoxia, metabolic disorders (hypocalcemia, hypoglycemia, vitamin B6 deficiency, biotinidase deficiency, phenylketonuria, and others) Infancy (1-6 months) As above; infantile spasms; West syndrome Early childhood (6 months-3 years) Infantile spasms, febrile convulsions, birth injury and anoxia, infections, trauma, metabolic disorders, cortical dysgenesis, accidental drug poisoning Childhood (3-10 years) Perinatal anoxia, injury at birth or later, infections, thrombosis of cerebral arteries or veins, metabolic disorders, cortical malformations, Lennox-Gastaut syndrome, idiopathic, probably inherited, epilepsy (Rolandic epilepsy) Adolescence (10-18 years) Idiopathic epilepsy, including genetically transmitted types, juvenile myoclonic epilepsy, trauma, drugs Early adulthood (18-25 years) Idiopathic epilepsy, trauma, neoplasm, withdrawal from alcohol or other sedative drugs Middle age (35-60 years) Trauma, neoplasm, vascular disease, alcohol or other drug withdrawal Late life (over 60 years) Vascular disease (usually postinfarction), tumor, abscess, degenerative disease, trauma a Meningitis or encephalitis and their complications may be a cause of seizures at any age. This is true also of severe metabolic disturbances. In tropical and subtropical countries, parasitic infection of the CNS is a common cause. “Adam and Victor’s Principles of Neurology”, 8th ed.

Distribution of the main causes of seizures at different ages Distribution of the main causes of seizures at different ages. Evident is the prevalence of congenital causes in childhood and the emergence of cerebrovascular disease in older patients. Ropper, A. and Brown, R., “Adam and Victor’s Principles of Neurology”, 8th ed.

Differential Diagnosis Probable Cause Type Infants and Children (>1 month-<12yrs.) Febrile seizure Genetic disorders (metanolic, degenerative, primary epilepsy syndromes) CNS infection Developmental disorders Trauma Idiopathic Complex partial Seizures Generalized Seizures: Atonic Seizures Absence (petit mal) Epilepsy Syndromes JME Lennox-Gastaut MTLE

Complex Partial Atonic JME Lennox-Gastaut MTLE Absence (petit-mal) Types Complex Partial Ictal phase: sudden behavioral arrest or motionless stare Automatisms: Chewing, lip smacking, swallowing, “picking” movements of hands Seconds – an hour Impaired recollection or motionless stare Atonic Briefly impaired consciousness Quick head drop or nodding movement 1 to 2 seconds No post ictal confusion JME Bilateral myoclonic seizures;single or repetetive Consciousness is preserved Myoclonic seizures frequent in the morning Provoked by sleep deprivation One-third have absence seizures Lennox-Gastaut Multiple seizure types Impaired cognitive function Associated with CNS disease, devt. Abnormalities, perinatal hypoxia/ischemia, trauma, infection Impaired cognitive syndrome MTLE Aura Behavioral arrest/stare Complex automatisms Unilateral posturing Postictal disorientation, memory loss dysphasia Absence (petit-mal) Sudden, brief lapses of consciousness, “daydreaming” No loss of postural control Rapid blinking, chewing movements. Can occur hundred times a day Lasts for seconds No postictal confusion Decline in school performance

Clinical Impression: Absence seizure

Absence Seizure Children with idiopathic generalized epilepsies may present with a history of staring spells, but infrequent absence seizures may not be diagnosed until a generalized tonic-clonic seizure has occurred. A type of generalized seizure, lasting for several seconds to minutes and may occur several times a day Segan, S. (2009). Absence Seizures. American Academy of Neurology and American Epilepsy Society

Absence Seizure Other symptoms, such as behavioral problems may be the presenting complaint Although the brief attacks are unrecognized, the lapses of awareness interfere with attention Decline in school performance may be an indication of the onset or breakthrough of absence seizures In symptomatic generalized epilepsies, atypical absence seizures often occur in the setting of developmental delay or mental retardation. Segan, S. (2009). Absence Seizures. American Academy of Neurology and American Epilepsy Society

Absence Seizure On clinical examination, typical absence seizures appear as: Brief staring spells Patients have no warning phase, and if engaged in gross motor activity, such as walking, they may stop and stand motionless or they may continue to walk Unresponsive during the seizure Children have no memory of what happened during the attack; they are generally unaware that a seizure has occurred Segan, S. (2009). Absence Seizures. American Academy of Neurology and American Epilepsy Society

Pathophysiology The pathophysiology of absence seizures is not fully understood Abnormal oscillatory rhythms are believed to develop in thalamocortical pathways This involves GABA-B–mediated inhibition alternating with glutamate-mediated excitation GABA-B inhibition appears to be altered in absence seizures Enhanced burst firing in selected corticothalamic networks may increase GABA-B receptor activation in the thalamus, leading to generalized spike-wave activity Segan, S. (2009). Absence Seizures. American Academy of Neurology and American Epilepsy Society

Absence Seizure vs Complex Partial Seizure An absence seizures can sometimes be confused with a complex partial seizure but each type has its own distinctive features: Asence seizures : never preceded by an aura are of briefer duration – seconds rather than minutes begin frequently and end abruptly the absence attack is always associated with the strikingly typical EEG abnormality of spike and slow wave discharges, usually at a frequency of 3Hz which occur can occur interictally and ictally and are often provoked by hyperventilation

Variants of Absence or Petit-Mal Seizure Atypical petit mal long runs of slow spike-and-wave activity, usually with no apparent loss of consciousness External stimuli such as asking the patient to answer a question or to count will interrupt the run of abnormal EEG activity.

Variants of Absence or Petit-Mal Seizure Lennox-Gastaut syndrome Onset between 2-6years old characterized by atonic, or astatic, seizures (i.e., falling attacks), often succeeded by various combinations of minor motor, tonic-clonic, and partial seizures and by progressive intellectual impairment with a distinctive, slow (1- to 2-Hz) spike-and-wave EEG pattern Triad of West Syndrome: infantile spasms, a characteristic EEG picture (3-Hz hypsarrhythmia), and an arrest in mental development

Diagnostic Work-up

Electroencephalography (EEG) The only diagnostic test for absence seizures Ambulatory EEG monitoring over 24 hours may be useful to quantitate the number of seizures per day and their most likely times of occurrence

EEG: Typical Absence Findings in typical absence seizures include the following: Background activity is normal. In syndromes with frequent absence seizures, such as childhood absence epilepsy, a routine awake recording is often pathognomonic. In syndromes with less frequent absence seizures (juvenile absence epilepsy or juvenile myoclonic epilepsy), an awake recording may be normal; a sleep or sleep- deprived recording may be needed. Typical absence seizures have generalized 3-Hz spike- and-wave complexes

EEG: Typical Absence The spike frequency is often faster at the onset, with a slight deceleration at the end. They can range from 2.5-6 Hz, with the faster frequencies seen in syndromes with older age of onset.

EEG: Typical Absence The onset and ending of these seizures are abrupt; no postictal EEG slowing is noted. Hyperventilation often provokes these seizures and should be a routine part of all EEGs in children. EEG video monitoring demonstrates that clinical seizure manifestations may lag behind the start of ictal EEG activity; bursts lasting less than 3 seconds are usually clinically silent. During the absence seizure, rhythmic eye blinks and mild clonic jerks may be present. As a seizure progresses, automatisms may be seen. Clinical and EEG features may vary considerably in different children.

EEG: Atypical Absence Findings in atypical absence seizures include the following: Background activity is often abnormal, reflecting the diffuse or multifocal underlying encephalopathy of symptomatic generalized epilepsy. Seizures are characterized by slow spike-and-wave paroxysms, classically 2.5 Hz.

EEG: Atypical Absence

EEG: Atypical Absence The onset may be difficult to discern, and postictal EEG slowing may be noted. The clinical correlation of generalized spike-and-wave complexes with clinical seizures is not as clear-cut as in typical absence seizures. EEG-video monitoring can show a more varied alteration of consciousness than in typical absence seizures. If the patient has underlying mental retardation, discerning changes in mental status also may be more difficult in atypical absence. Changes in postural tone, most noticeably head nods, are common.

Clinical and EEG Findings in Typical and Atypical Absence Seizures Segan, S. (2009). Absence Seizures. American Academy of Neurology and American Epilepsy Society

Laboratory Studies Laboratory tests for: Metabolic abnormalities Toxic or drug ingestion Blood levels of electrolytes, glucose, calcium, magnesium Hepatic or renal disease If a clear history of the episodic nature of the attacks is obtained, then the EEG can be diagnostic and laboratory tests may not be necessary.

Imaging Studies  Neuroimaging is not indicated if the typical clinical pattern is present. Neuroimaging findings are normal in idiopathic epilepsies by definition Often ordered if a child presents with a generalized tonic-clonic seizure, to rule out significant structural causes of seizures. If imaging is performed, MRI is preferred to CT scanning. MRI is more sensitive for certain anatomic abnormalities.

Treatment

DEPENDS on the underlying cause Metabolic : correction Structural abnormality: seizure control + consider surgery Tumor Vascular Idiopathic : seizure control

Diagnosis and Classification of seizure disorder choose Anti-epileptic drug of choice Main Goal: Adequate seizure control monitoring of response (seizure-free) and side effects therapeutic monitoring drug interactions

Principles of Treatment Individualized treatment Selection of specific drug for initial therapy is based on specific clinical seizure type Monotherapy is preferred Dose is increased gradually Enough time for steady state to be reached must be allowed Prompt substitution when serious adverse reaction develops If poor seizure control-gradually withdraw first drug while replacing with second drug of choice for seizure type (should not be stopped abruptly) Treatment failures may be due to poor compliance or misdiagnosis Continue treatment to achieve minimum seizure-free period of 3-5 years Katzung Basic and Clinical Pharmacology, 9th ed. The Treatment of Epilepsy, 3rd ed.

Absence seizures Ethosuximide is the drug of choice for typical absence seizure Valproic Acid is the drug of choice for atypical absence seizure used only when treatment tolerance or failure appear with Ethosuximide Wide spectrum AED Katzung Basic and Clinical Pharmacology, 9th ed. The Treatment of Epilepsy, 3rd ed.

Anti Epileptic Drug Glutamate Antagonist GABA agonist Na channel blocker Ca channel blocker Phenobarbital * Phenytoin Carbamazepine Valproic Acid Gabapentin Topiramate Oxcarbazepine Ethosuximide Lamotrigine

Ethosuximide Primary indication: First-line or adjunctive therapy of generalized absence seizures Mechanisms of action: Inhibition of neuronal T-type calcium channels in the thalamus (Type III AED) Usual preparations: Capsules: 250 mg; syrup: 250 mg/5 mL Usual dosages: Initial: 250 mg (adults); 10–15 mg/kg/day (children) Maintenance: 750–1500 mg/day (adults); 15–40 mg/kg/day (children) Dosing frequency: 2–3 times/day Significant drug interactions: Ethosuximide levels are reduced by co-medication with carbamazepine, phenytoin, phenobarbital and rifampicin. Valproic acid may exert synergistic effects with ethosuximide in patients refractory to either drug given alone, and may have variable and inconsistent effects on ethosuximide levels. Serum valproic acid levels may be decreased by ethosuximide. Ethosuximide levels are increased by isoniazid 2 ethyl 2 methylsuccinamide Katzung Basic and Clinical Pharmacology, 9th ed. The Treatment of Epilepsy, 3rd ed.

Ethosuximide Serum level monitoring: usually optimized based on clinical and EEG response. Main advantages: Well-established treatment for absence epilepsy without the risk of hepatic toxicity carried by valproic acid Main disadvantages: Adverse effects common. Unlike valproic acid, ethosuximide does not protect against generalized tonic– clonic seizures Common/important adverse effects: Gastrointestinal symptoms, drowsiness, ataxia, diplopia, headache, dizziness, hiccoughs, sedation, behavioural disturbances, acute psychotic reactions, extrapyramidal symptoms, blood dyscrasias, rash, lupus-like syndrome, other severe idiosyncratic reactions Katzung Basic and Clinical Pharmacology, 9th ed. The Treatment of Epilepsy, 3rd ed.

Valproic Acid Primary indications: First line for atypical absence seizures. First-line therapy of idiopathic generalized epilepsies. First-line or adjunctive therapy of cryptogenic or symptomatic generalized epilepsies. Valuable but not generally first-line therapy for partialseizures Mechanisms of action: Increases brain GABA activity by increasing activity of glutamic acid decarboxylase, inhibition of GABA transaminase, inhibition of succinic semialdehyde dehydrogenase Usual dosages: Initial: 400–500 mg/day (adults); 15 mg/kg/day (children) Maintenance: 500–2500 mg/day (adults); 20–40 mg/day (children under 20 kg); 20–30 mg/kg/day (children over 20 kg) Dosing frequency: 2-3 times a day Serum level monitoring: Dosage usually can be adjusted on the basis of clinical response, but monitoring serum valproic acid levels may be useful in selected cases Branched chain fatty acid structure Lacks the nitrogen or aromatic moiety present in other AEDs Antiepileptic activity greatest for carbon chain length of 5-8 atoms Increasing to 9 atoms imparts sedative effects Katzung Basic and Clinical Pharmacology, 9th ed. The Treatment of Epilepsy, 3rd ed.

Valproic Acid Significant drug interactions : Enzyme-inducing drugs and imipenem antibiotics reduce serum valproic acid levels. Felbamate, stiripentol, isoniazid and other drugs may increase valproic acid levels. Valproic acid inhibits the metabolism of a number of drugs, most notably phenobarbital, lamotrigine and rufinamide. Valproic acid displaces phenytoin from plasma protein binding sites and may inhibit phenytoin metabolism at the same time Common/important adverse effects: Tremor, sedation, asthenia, encephalopathy, extrapyramidal symptoms, nausea, vomiting, hyperammonaemia, weight gain, polycystic ovary syndrome, hair loss, platelet and coagulation disorders, liver toxicity, pancreatitis, teratogenic effects (including spina bifi da) Main advantages: Unsurpassed effi cacy in most generalized epilepsy syndromes. Broadspectrum efficacy in different seizure types Main disadvantages: Weight gain, severe liver toxicity (particularly in children), teratogenicity Katzung Basic and Clinical Pharmacology, 9th ed. The Treatment of Epilepsy, 3rd ed.

Other Modalities Surgical Management surgical excision of epileptic foci in simple and complex partial epilepsies that have not responded to intensive and prolonged medical therapy may be beneficial for some Regulation of Physical and Mental Activity precipitating factors needs to be modified and stressed to the patient moderate amount of physical exercise can also be advised psychosocial difficulties needs to be identified and addressed early The Treatment of Epilepsy, 3rd ed.

Other Modalities Ketogenic Diet Vagal Nerve Stimulation biochemical alteration both in the blood and in the brain possible GABA-mimetic effects of ketosis given the structural similarities of GABA, -hydroybutyrate and acetoacetate Vagal Nerve Stimulation vagal stimulation produces its effects are unclear and it is done through attachment of electrodes to the vagus nerve at the left carotid bifurcation The Treatment of Epilepsy, 3rd ed.

Management American Academy of Neurology Guidelines on CESSATION OF TREATMENT Stopping the treatment may be considered when: The patient has been seizure-free for 2 to 5 years The patient has a single type of seizure The patient has no abnormalities on neurologic examination and has a normal IQ The patient’s electroencephalogram (EEG) has become normal