Lennox-Gastaut Syndrome- A Case Study: By RxVichuZ!! :)

This is my 53rd powerpoint....this is also my first CASE PRESENTATION ....deals with a rare disease....LENNOX-GASTAUT SYNDROME!!!

One of the most disastrous pediatric epilepsies of all time.....!!!
Do go through this....

Vishnu.R.Nair :) :)

1. LENNOX GASTAUT SYNDROME: A CASE STUDY PRESENTED BY: VISHNU.R.NAIR, 5 TH YEAR PHARM.D, NATIONAL COLLEGE OF PHARMACY(NCP).

2. PATIENT DETAILS: NAME: Mr.X AGE : 16 years SEX: Male WEIGHT: 45 kg HEIGHT: 150 cm BMI: 20 IP NO: 202084/17 DEPARTMENT: Neurology DOA: 2/08/2017 DOD: 4/08/2017 DURATION OF HOSPITAL STAY: 3 days.

3. REASON FOR ADMISSION: C/O recurrent seizures PATIENT MEDICAL HISTORY : K/C/O LGS (Lennox- Gastaut Syndrome) Above condition  diagnosed at NIMHANS SOCIAL HABITS : Non-smoker Non-alcoholic

4. KNOWN ALLERGIES : Nil FOOD HABITS : Non-vegetarian PATIENT MEDICAL HISTORY : Inj. Methylpred pulse (every month)

5. LABORATORY INVESTIGATION: DATE 2/8/17 3/8/17 4/8/17 TEMPERATURE(in degree Fahrenheit) N N N B.P(in mm/Hg) 110/80 100/70 130/90 PULSE(in beats/min) 88 80 98 RR(in breaths/min) 20 20 20

6. HEMATOLOGICAL TESTS: HEMATOLOGICAL PARAMETER VALUE OBSERVED HEMOGLOBIN(in g/dl) 16.7 TLC (in cells/ cumm ) 9,500 PLATELET COUNT(in cells/ cumm ) 3,10,000 RBC COUNT(in cells/ cumm ) 5.18 million

7. URINALYSIS: COLOUR Clear PUS CELLS 1-2/ hpf CRYSTALS Nil BACTERIA Present(few) SUGAR Nil WBC Nil RBC Nil CASTS Nil EPITHELIAL CELLS 1-2/ hpf

8. OTHER OBSERVATIONS: SKIN Normal BUILT & NOURISHMENT Normal CVS S 1 S 2 (+) RS NVBS GIT Soft, non-tender CNS WNL

9. DIAGNOSIS : “ LENNOX-GASTAUT SYNDROME”

10. LENNOX-GASTAUT SYNDROME: A PRECISE INSIGHT

11. INDEX/ CONTENTS OF THIS PPT: Definition Epidemiological statistics Etiology Pathophysiology Clinical manifestations Diagnosis Management strategies for LENNOX-GASTAUT SYNDROME. Bibliography/ Reference.

12. DEFINITION: “Pediatric encephalopathy syndrome, characterized by multiple seizure types, mental retardation & abnormal findings on ECG”.

13. LENNOX-GASTAUT SYNDROME AWARENESS DAY: JANUARY 11, EVERY YEAR!

14. EPIDEMIOLOGICAL STATISTICS: Occurs in 1-4% of patients, with childhood epilepsy More common in boys than in girls Prevalence in boys: 0.1 per 1,000 population Prevalence in girls: 0.02 per 1,000 population Age onset: 26-28 months.

15. ETIOLOGY: Mainly occurs due to the following causes: IDIOPATHIC CAUSES CRYPTOGENIC CAUSES SYMPTOMATIC CAUSES: Encephalitis Meningitis Tuberous sclerosis Cortical dysplasia Hypoxia-ischemia injury

16. Traumatic brain injury Infantile spasms.

17. PATHOPHYSIOLOGY: The exact mechanism behind this disease occurrence is not clearly defined, though some theories exist According to one hypothesis  maturation of anterior parts of brain  increases permeability of excitatory inter-hemisphere pathways in frontal areas Involvement of immunogenetic mechanisms in triggering LGS is also reported(via an association between LGS & HLA-Class I Ag B7).

18. CLINICAL MANIFESTATIONS: TONIC SEIZURES: Frequency: 17-95% More common during NON-REM SLEEP B. ATYPICAL ABSENCE SEIZURES: Frequency: 17-100% Associated with incomplete loss of consciousness Eye myoclonias may occur

19. C. ATONIC/ MASSIVE MYOCLONIC/ MYOCLONIC+ ATONIC SEIZURES: Frequency: 10-50% May lead to a sudden fall, causing injuries D. OTHER TYPES : Include: GTCS(15%) Complex partial seizures(5%) Absence Status Epilepticus(SE) Tonic SE Non-convulsive SE

20. E . GENERAL SYMPTOMS: Include: Abnormalities in mental status functions Abnormalities in levels of consciousness Mood instability Personality disturbances Acute psychotic episodes(in older children) Social isolation(in older children) Memory impairment.

21. DIAGNOSIS: ELECTROENCEPHALOGRAPHY: Here  both waking & sleeping EEG is recorded Helps to capture & classify different seizure types in the patient Video/EEG Telemetry is also helpful B. INTERICTAL EEG: Helps to detect prognosis of the disease Used to check spikes pattern observed in an EEG

22. C. NEUROIMAGING STUDIES: MRI is preferred over CT-Scan Used to detect: Brain malformations Tuberous sclerosis Hypoxia-ischemia injury - PET/SPECT scan is not commonly used.

23. MANAGEMENT STRATEGIES FOR LGS: Includes: Goals of therapy Treatment guidelines Pharmacotherapy Non-pharmacotherapy.

24. A. GOALS OF THERAPY: To avoid complications To focus on reducing/eliminating seizure frequency To focus on minimum ADRs, with maximal drug effectiveness To focus on using minimum number of drugs To focus on ameliorating symptoms To improve HRQoL.

25. B. TREATMENT GUIDELINES: Usually, 3 categories of drugs can be used: FIRST-LINE AGENTS SECOND-LINE AGENTS THIRD-LINE AGENTS.

26. FIRST-LINE AGENTS: Based on clinical experience Drugs include: Valproic acid Benzodiazepines(Clonazepam, clobazam, nitrazepam) NOTE: NITRAZEPAM is not FDA-APPROVED for treatment of LGS, yet, it is used in some Western Countries 2. SECOND-LINE AGENTS: These are treatments, that are believed to be effective, based on OPEN-LABEL CONTROLLED STUDIES Drugs include: Vigabatrin Lacosamide .

27. 3. THIRD-LINE AGENTS: They are treatments, that are believed to be effective, based on DOUBLE-BLIND PLACEBO-CONTROLLED STUDIES Include: Lamotrigine Topiramate Felbamate Rufinamide.

28. C. PHARMACOTHERAPY: Drugs include: Valproic acid 10. Clobazam Lamotrigine Topiramate Felbamate Zonisamide Vigabatrin Levetiracetam Rufinamide Clonazepam

29. VALPROIC ACID : Considered as 1 st line choice for treating LGS(for the past 2 decades) More effective in CRYPTOGENIC LGS Used mainly as DIVALPROEX Use in children, greater than 10 years of age ADRs: Hepatotoxicity(if used in children < 3 years of age) Weight gain Alopecia Tremors. - DOSE: 60 mg/kg/day(Max. dose).

30. 2. LAMOTRIGINE : Useful for LGS patients, in spite of high risk of IDIOSYNCRATIC DERMATOLOGICAL REACTIONS Use other anticonvulsant medications along with it, cautiously Start with a low dose, and then titre slowly ADRs: life-threatening hypersensitivity(skin rashes) SJS TEN.

31. DOSAGE REGIMEN: With Valproate: 0.5-5 mg/kg/day; PO Without Valproate: 5-10 mg/kg/day; PO With enzyme-inducing AEDs: 5-15 mg/kg/day; PO Maximum dose: 400 mg/day; PO.

32. 3. TOPIRAMATE: Safe & effective as adjunctive therapy for LGS ADRs: Nephrolithiasis Weight loss DOSE : 6 mg/kg/day; PO.

33. 4. FELBAMATE: Effective in LGS patients High risk of APLASTIC ANEMIA  Mandates this drug to be used as 3 rd /4 th line choice for LGS ADRs: URTI Aplastic anemia Purpura DOSE: Use in patients> 2 years of age Max. dose: 45 mg/kg/day Reduce concomitant dose of CBZ, phenytoin, valproate by 20%.

34. 5. ZONISAMIDE: Effective as long-term adjuvant therapy in LGS patients ADRs: Somnolence Dizziness Nephrolithiasis Avoid usage in children < 16 years DOSE: 600 mg PO daily(Max. dose).

35. 6. VIGABATRIN: Approved by US-FDA in 2009, as: Monotherapy for WEST SYNDROME(in patients, aged 1 month-2 years) Adjuvant treatment for adults with refractory complex partial seizures. ADRs: Somnolence Weight gain Irreversible visual field defects, due to retinal atrophy. Avoid usage in patients, below 1 month of age - DOSE : For patients, aged 1 month-2 years: 150 mg/kg/day(Max. dose).

36. 7. LEVETIRACETAM: Mainly FDA-approved for partial seizures May be used for a number of seizure types in LGS ADRs: Sedation Increased B.P(in children <4 years) Dizziness. DOSE: For patients, aged 4-12 years: 30 mg/kg/day( Max.dose ) For patients, aged >12 years: 1.5 g, BD( Max.dose ).

37. 8. RUFINAMIDE : Drug  modulates sodium channel activity  prolongs its inactivated state Used as adjunct therapy in adults & children aged 1 year or older with LGS ADRs: Dizziness SJS - DOSE : 3,200 mg/day( Max.dose ).

38. 9. CLONAZEPAM: Effective 1 st line AED for LGS DEMERITS : ADRs, with long-term usage Development of tolerance Since there is risk of development of tolerance  it is advised to: Use on alternative days, OR Use alternate 2 BZDs daily.

39. 10. CLOBAZAM: Drug  binds to GABA-A receptor  potentiates GABA-ergic neurotransmission Drug  has an active metabolite(N-DESMETHYL CLOBAZAM)  shows long duration of action Used for LGS in patients, older than 2 years ADRs: Sedation Weight gain URTI - DOSE: 40 mg/day( Max.dose ).

40. D. NON-PHARMACOTHERAPY: Includes: Corpus callostomy Vagus nerve stimulation Focal cortical resection Ketogenic diet Patient counselling tips.

41. CORPUS CALLOSTOMY : Only effective to reduce DROP ATTACKS Considered PALLIATIVE than CURATIVE B. VAGAL NERVE STIMULATION: Done by means of a surgically-implanted programmable device Approved by FDA, as adjunct treatment for reducing seizure frequency in LGS Requires follow-up period within 5 years C. FOCAL CORTICAL RESECTION: Used in rare cases Resection of localized lesion(vascular lesion, tumor)  improves seizure control in LGS

42. D. KETOGENIC DIET: Consists of high ratio of FATS to PROTEINS and CARBOHYDRATES Ratio is usually in between 2:1 to 4:1 Benefits include: Fewer seizures Reduced drowsiness Better behavior Requires fewer number of concomitant AEDs.

43. Diet includes: HIGH FAT(Nuts, cream, butter) LOW CARBOHYDRATES (Starchy fruits, bread, pasta, grains, sugar) ADEQUATE PROTEINS(Pulses, soyabeans ) E. PATIENT COUNSELLING TIPS: Avoid consuming artificial sweeteners/additives Avoid skipping meals, especially breakfast Avoid all “white products”, like: White flour White sugar Table salt White rice.

44. 4. Do not skip taking medicines, without doctor’s approval 5. Get enough sleep(since sleep deprivation can trigger seizures) 6. Manage stress, and avoid stressful situations.

45. TREATMENT GIVEN: T. NAME G. NAME DOSE ROUTE DURATION 2/3 3/3 4/3 Inj. Methylprednisolone Methylprednisolone 1 g i.v OD Y Y Y T. Dianox Acetazolamide 250 mg P/O 1-0-1 Y Y Y T. Benadone Pyridoxine 40 mg P/O 1-0-1 Y Y Y T. Shelcal Ca + Vit.D 3 500 mg P/O 0-1-0 Y Y Y T. Frisium Clobazam 7 mg P/0 ½-0-½ Y Y Y T. Lamotrigine Lamotrigine 100 mg P/O 1-0-2 Y Y Y T. Eptoin Phenytoin 100 mg P/O 1-0-2 Y Y Y T. Levipil Levetiracetam 1 g P/O 1-0-1 Y Y Y T. Topaz Topiramate 10o mg P/O 0-0-1 Y Y Y

46. PROGRESS CHART + ASSESSMENT OF CURRENT THERAPY: DAY 1(2/3/2017): Patient was admitted with c/o recurrent seizures k/c/o LGS(diagnosed at NIMHANS) The following treatment strategy was initiated : INJ.METHYLPREDNISOLONE: Due to various etiologies  a SIGNIFICANT STRESS RESPONSE is experienced by the developing brain  results in LGS Methylprednisolone (steroid) has potential to reset the deranged homeostatic mechanisms of the brain  results in: Reduced convulsive tendency Improved developmental trajectory(www.annalsofian.org)

47. B. T. DIANOX(ACETAZOLAMIDE): Acetazolamide has been shown to be effective in the treatment of some types of epileptic seizures Drug  shows the following actions: Increases seizure threshold Minimizes seizure frequency via its effects on the amount of CO 2 in brain fluids Inhibits chemical pathways that play significant role in seizures. C. T. BENADONE(PYRIDOXINE): Usually indicated for PYRIDOXINE-RESPONSIVE SEIZURES Here, it is indicated to reduce seizure frequency & also helps to prevent exacerbation of clinical seizures &/ encephalopathy during an acute illness.

48. D. T. SHELCAL(VITAMIN D 3 + CALCIUM CARBONATE): Long-term use of AEDs  can result in loss of bone mass & increased risk of OSTEOPOROSIS Calcium & Vitamin D 3 supplementation  improves BMD in patient taking AED!( https://www.wiley.com ) E. T. FRISIUM(CLOBAZAM): Novel 1,5-benzodiazepine, approved by the US-FDA for the treatment of LGS in 2011 Confers less sedative properties compared to other benzodiazepines( Marius Pernea , Alastair G.Sutcliffe . “Clobazam and its use in Epilepsy”).

49. F. T. LAMOTRIGINE: Addition of lamotrigine to other anti-seizure drugs resulted in improved seizure control (Motte et al.,1997)  this shows that lamotrigine is an effective & well-tolerated drug for this treatment-resistant form of epilepsy. G. T. EPTOIN(PHENYTOIN): Drug  shows the following actions, that results in anti-epileptic effects: Drug  promotes Na + efflux / reduces its influx from membranes in motor cortex neurons Drug  slows conduction velocity.

50. H. T.LEVIPIL(LEVETIRACETAM): Mainly FDA-approved for partial seizures May be used for a number of seizure types in LGS T.TOPAZ(TOPIRAMATE): - Safe & effective as adjunctive therapy for LGS - Demonstrated to be effective for LGS( Sachdeo et al., 1999)

51. 2. DAY 2(03/08/2017): Patient is conscious & oriented No fresh complaints noted 3. DAY 3(04/08/2017): No fresh complaints Patient was found to be symptomatically better, & was discharged appropriately. . .

52. DISCHARGE SUMMARY: A 16-year old male patient was admitted, with H/O multiple episodes of atonic, absent & myoclonic seizures He was evaluated in detail in NIMHANS, & was diagnosed to have LGS Patient was advised to have Inj. Methylpred pulse every month He was treated with Inj. Methylprednisolone(1 g) for 5 days, along with other antiepileptics He was advised to review after 1 month, for the next dose of METHYLPRED PULSE.

53. DISCHARGE ADVICE: Patient was prescribed the following medications upon discharge : T. TOPAZ 50 mg(1-0-0) T. LEVIPIL 1 g (1-0-1) T. EPTOIN 100 mg (1-0-2) T. LAMOTRIGINE 100 mg (1-0-1) T. FRISIUM 10 mg (1-0-1) T. DULCOLAX (2 * HS) T. WYSOLONE 40 mg (1-0-0) [For 2 weeks] FOR 1 MONTH

54. POINTS TO PHYSICIAN: Concomitant administration of TOPIRAMATE & CLOBAZAM  increased risk of CNS effects  monitor for increased sedation, respiratory depression! Concomitant administration of TOPIRAMATE & ACETAZOLAMIDE  high risk of NEPHROLITHIASIS!

55. DRUG-BASED COUNSELLING TIPS: T.TOPAZ(TOPIRAMATE): Report to physician if there is change in visual field(visual field defects)! 2. T.LEVIPIL(LEVETIRACETAM): Can be taken with/without food Increase intake of Vitamin B6 rich foods 3. T. EPTOIN(PHENYTOIN): Patient should be advised to maintain good dental hygiene

56. 4. T.LAMOTRIGINE: Although drug can be taken with/without food  taking drug with food/plenty of water is advised(to prevent gastric distress) 6. T.DULCOLAX(BISACODYL): Oral tablet should not be taken WITHIN 1 HOUR OF CONSUMING MILK/ANY DAIRY PRODUCTS For rapid effect  drug should be taken with a glass of water on an empty stomach 7. T.WYSOLONE(PREDNISOLONE): Should be taken after meals/with food/milk to reduce GI effects An increase in the dietary intake of Pyridoxine, Vitamin C, Vitamin D, Folate, Calcium & Phosphorus is recommended

57. DISEASE-RELATED COUNSELLING TIPS: 1. EPSOM SALT: EPSOM SALT  Contains magnesium sulphate  changes psychochemical cell relationships in the brain  reduces frequency of seizures and convulsions Use in the form of: Epsom salt bath (2-3 times/ week) Add half tsp of salt to orange juice / water  drink every morning 2. LIME: Popular Ayurvedic remedy Lime  helps improve blood circulation to brain Also normalizes excess calcium that may hamper brain functionality Use in the form of: (2 tsp. lime juice + half tsp. baking soda + water)  drink daily before going to bed Apply lime juice on head  massage thoroughly for a few mins.  do daily before taking a shower

58. 3. GET ENOUGH SLEEP, AS SLEEP DEPRIVATION TRIGGERS SEIZURES 4. MANAGE STRESS AND AVOID STRESSFUL SITUATIONS 5. FOLLOW A KETOGENIC DIET, COMPRISING: High fat(nuts, cream, butter) Low carbohydrate (starchy fruits, bread, pasta, grains, sugar) Adequate protein (pulses, soybean etc.) Helps treat DIFFICULT TO CONTROL (REFRACTORY) EPILEPSY in children……………..

59. THANK YOU!!!!!!