PHYSICIANS MEETPHYSICIANS MEET

A CASE OF SEIZURE A CASE OF SEIZURE

Prof Dr A Gowrishankar’s UnitProf Dr A Gowrishankar’s UnitM4 Unit,02-06-10

PATIENT PROFILEPATIENT PROFILE

• Mr Sigamani, 38 yrs of age

• Non smoker, non alcoholic• Diabetic for 3 yrs on OHA• Presented with seizures for last 2 days• First episode lasted about 5 minutes, GTCS with h/o post

ictal confusion and transient LOC, regained consciousnes with no residual neurologic deficits.

• Subsequently he had 4 episodes on the day of admission, GTCS ,each lasting 5-10 minutes, lost consciousness

• H/o severe throbbing head ache +• H/o vomiting +, non projectile, non bilious

• No h/o fever, blurring of vision• No h/o trauma• No h/o hypertension, CAD, PTB• Not a known epileptic• Patient denied high risk behaviours• Normally born of non-consanguinous marriage

On Examination

• Patient was drowsy, confused, disoriented• Afebrile• Moderately built and nourished• Not pale, anicteric, not cyanosed,no clubbing , no

lymphadenopathy, thyroid appered normal,no pedal edema

• Vitals were stable(PR 82/min,BP 120/86 mm Hg)

System examination:• CVS,RS,Abd : normal

• Neurologic Ex: drowsy, confused.Moves all 4 limbsNo cranial nerve deficits.Pupils bilaterally 2mm, reactingNo involuntary movementsNo meningeal signs.DTR normalPlantar b/l ↓

Fundus: papilledema present

• Treated with 25%dextrose( suspected hypoglycemia),

• Nasal oxygen • IVFluids• Inj.Phenytoin 15-20 mg/kg Loading dose• Inj Mannitol 175 ml IV BD• Inj Ranitidine 50mg IV BD• Inj Cefotaxime 1g IV BD• Inj Diazepam slow iv sos

INVESTIGATIONS

• Hb: 13 g%• TC: 6100, DC : P50L48E2• ESR 6/14• PCV 39%

• RBS- 186• BU- 22• S Cr- 0.9• SE Na 133/ K: 3.9• Urine R/E sugar ++,

albumin- nil, 1-2 pc/hpf

• ECG: normal• CXR: normal

• CT Brain: Hypodensity noted in left parietal region

• Urine ketones: negative• FLP: TC226

TG 222HDL 50LDL 132VLDL 44

• Ultrasound Abd: Fatty liver

• T Aspirin 150 mg OD and• T Atorvastatin 20mg HS were added.

• Patient recovered from post ictal state during first 24 hrs• He was persistently complaining of head ache, severe

enough to disturb even during sleep.• On day 4 patient developed focal seizures involving his

left upper limb.• Seizure was not getting controlled with AED( phenytoin,

carbamazepine, and diazepam during ictal periods)• Patient continued to have seizures for the next 2 days.

• On 7th day of admission patient developed multiple cranial nerve palsies, on left side, VI, VII, IX, X and XII CN were involved.

• He also developed “left hemiparesis”

An urgent MRI was taken which showed venous infarct in the left frontal lobe with superior sagittal and superficial sinus thrombosis.

• Patient was started on heparin 5000U IV TDS• Inspite of AEDs pt had focal seizures with secondary

generalistion.• Patient had to be shifted to IMCU and was sedated,

intubated and ventilated in view of protecting airway.

• Patient recovered over the next couple of days• Seizures seized, CN palsies significantly improved, with

mild hemiparesis• Patient was shifted back to ward on day 12

• The seizure episodes continued for another 6 days but episodes were less frequent and less severe, with occassional worsening of cranial nerve symptoms and hemiparesis.

• On 32nd day when patient was discharged he had residual XII CN palsy with mild hemiparesis.

• Patient was on acitrom 3mg OD with target INR between 2-3, to be continued for 6 months, along with physiotherapy and strict glycemic control.

Date 1/4 2/4 4/4 5/4 6/4 14/4 21/4 24/4 27/4 28/4 30/4

FBS 186 232 226 231 200 183 - - 104 82 119

PPBS (RBS) 254 367 265 - 170 380 156 124 138 -

• Insulin regime• HA 6-6-6 raised upto 12-12-12 premeal.• HM 6-0-4 raised upto 20-0-10

FURTHER INVESTIGATIONS…FURTHER INVESTIGATIONS…

• Cardiac status was normal and ECHO showed no RWMA, normal LV function

• Carotid doppler was normal.

• EEG: B/L potential epileptiform pattern• Ophthalmologic evaluation: media clear, fundus-

Papilloedema present• Mantoux done was negative

• HIV: negative • HBsAg: Negative

THROMBOPHILIA PROFILETHROMBOPHILIA PROFILE

• Protein C 184% ( 70-140)• Protein S 158% (60-150)• S Homocysteine: 34.43 ↑ (5.9-16)• Anti Cardiolipin IgG 1.27 (<10)

Anti Cardiolipin IgM 1.6 (<7)Lupus anticoagulant: Negative

• Serum Fibrinogen: 382 mg/dL (180-350)• ANA : negative• RA Factor: negative• CRP : 24 mg/L ↑ (<6mg/L)

FINAL DIAGNOSIS

• Type 2 Diabetes Mellitus• Dyslipidemia• Cortical Venous Thrombosis • Hyperhomocysteinemia

CORTICAL VENOUS THROMBOSIS• Incidence: 5/million in an year• Accounts for 0.5% of all strokes• Advances in neuroimaging has allowed early diagnosis and

treatment and better understanding of the evolution of the disease

• It reduced the mortality rate from 20-30% to well below 10%• However diagnosis is still overlooked or delayed because of

the remarkable diversity of its clinical symptoms, modes of onset, and neuroimaging signs;

• A cause cannot be found in about 15% of cases• The disorder may occasionally worsen despite anticoagulation• CVT thus remains a diagnostic and therapeutic challenge

CAUSES OF VENOUS THROMBOSIS• INHERITED THROMBOPHILIA

1. Factor V Leiden mutation 2. Prothrombin gene mutation 3. Protein S deficiency 4. Protein C deficiency 5. Antithrombin (AT) deficiency 6. Homocysteinemia 7. Rare disorders

Dysfibrinogenemia

• ACQUIRED DISORDERS 1. Malignancy 2. Presence of a central venous catheter 3. Surgery, especially orthopedic 4. Trauma 5. Pregnancy

• Oral contraceptives • Hormone replacement therapy • Tamoxifen, Bevacizumab,

Thalidomide, Lenalidomide• Immobilization • Congestive failure • Antiphospholipid antibody syndrome • Myeloproliferative disorders • Polycythemia vera • Essential thrombocythemia

• Paroxysmal nocturnal hemoglobinuria • Inflammatory bowel disease • Nephrotic syndrome • Hyperviscosity • Waldenstrom's macroglobulinemia • Multiple myeloma • Marked leukocytosis in acute leukemia • Sickle cell anemia • HIV/AIDS

• 44% - had more than one cause or predisposing factor, and • 22% - Congenital/genetic thrombophilia• 15% - No cause could be found• RECENT STUDIES EMPHASISE the role of

hyperhomocystenaemia hyperhomocystenaemia

• Spontaneous intracranial hypotension• Thalidomide used in a patient with multiple myeloma• Cushing’s syndrome• Erythropoietin • High altitude as reported in the Himalayas• Phytoestrogens and • Shiatsu massage (an oriental technique of neck massage)

CVT-CLINICAL ASPECTS• The most common symptoms and signs are

• Headache • Seizures • Focal neurological deficits • Altered consciousness and • Papilloedema

• Four main patterns have been identified

1.Isolated intracranial hypertension 2.Focal syndrome 3.Cavernous sinus syndrome and 4.Subacute encephalopathy

PRESENTING SYMPTOMS OF CVTPRESENTING SYMPTOMS OF CVT

COMMON SYMPTOMSCOMMON SYMPTOMS• Isolated intracranial hypertension• Focal syndrome (deficit and/or

seizure)• Diffuse encephalopathy• Any combination of the above

RARE SYMPTOMSRARE SYMPTOMS• Cavernous sinus syndrome• Subarachnoid haemorrhage• Thunderclap headache• Attacks of migraine with aura• Isolated headache• Transient ischaemic attacks• Tinnitus• Isolated psychiatric symptoms• Isolated or multiple cranial nerve

palsies

Clinical presentation of CVT is affected by

1. Age ofpatient, 2. Time between onset and admission to

hospital,3. Location of CVT, and 4. The presence of parenchymal lesions.

• Patients with chronic course or delayed clinical presentation may show papilloedema on fundoscopy but this finding is less common in acute cases

ISOLATED HEAD ACHEISOLATED HEAD ACHE

• Headache in the absence of intracranial hypertension, subarachnoid haemorrhage, or meningitis.

• Such cases are essentially associated with LATERAL SINUS THROMBOSIS, which should not be mistaken for lateral sinus hypoplasia.

• The exact mechanism of the headache remains unknown

1. Stretching of nerve fibres in the walls of the occluded sinus 2. A local inflammatory reaction

• MRI: contrast enhancement of the sinus wall surrounding the clot- the “empty delta sign”.

DIAGNOSISDIAGNOSIS

Neuroimaging of the thrombosed vessel

The current gold standard is MRI with MRV( MRI to visualise the thrombosed vessel and MRV to detect the

non-visualisation of the same vessel)

• MRI alone is limited by flow artifacts that can lead to false positives and the absence of hyperintense signal on T1 and T2-weighted images at the onset of acute thrombosis.

• During the first 3–5 days the thrombosed sinus is isointense on T1 and hypointense on T2, and thus very difficult to differentiate from normal veins.

• MRV alone- difficult to differentiate between thrombus or sinus hypoplasia

Echoplanar Susceptibility-weighted images (T2*): More sensitive than T2WI especially within 3 days of onset

T2* SWIT2* SWI

DIFFUSION WEIGHTED IMAGESDIFFUSION WEIGHTED IMAGES

• For imaging of parenchymal lesions

It helps to differentiate • Vasogenic edema(↑app. DC)• Cytotoxic edema(↓app. DC)

ROLE OF D-DIMER ASSAY

• If high index of suspicion… a D-dimer assay is more of negative predictive value(<500 ng/mL)

• But in those patients with isolated head ache with MRI evidence of CVT, 26% had normal D-dimer

PROGNOSISPROGNOSIS

• Very good compared to arterial events• 15% overall death/ dependancy• Poor prognosistic factors

1. CNS infection 2. Any type of cancer 3. Deep venous system thrombosis 4. Intracranial haemorrhage5. Mental status disorder6. Age>37 years7. Male gender

Causes of acute death

1. TRANSTENTORIAL HERNIATION, secondary to a large haemorrhagic lesion

2. MULTIPLE LESIONS 3. DIFFUSE BRAIN OEDEMA 4. STATUS EPILEPTICUS 5. PULMONARY EMBOLISM

• Deterioration after admission occurs in about 23% of patients, with worsening of mental status, headache, or focal deficits, or with new symptoms such as seizures.

TREATMENTANTITHROMBOTIC TREATMENT

Acute phase(No contraindication for anticoagulation)• LMWH 1mg/kg BW s/c• Heparin in full therapeutic dosage or APPT (2 times above

normal)

• Local intravenous thrombolysis*• Mechanical thrombectomy*

Prevention of recurrent thrombotic events with oral anticoagulants• CVT related to a transient risk factor, 3–6months• Idiopathic CVT or related to mild hereditary thrombophilia, 6–

12 months• Recurrent CVT or severe hereditary thrombophilia, indefinite

SYMPTOMATIC TREATMENTSYMPTOMATIC TREATMENTAntiepileptics• Acute phase• Prevention of seizures after the acute phase

Patients with focal haemorrhagic lesions*

Treatment of intracranial hypertension• Acetazolamide• Osmotic therapy• Lumbar puncture (if no parenchymal lesions)• Sedation and hyperventilation

• SURGICAL PROCEDURES (lumboperitoneal shunt,ventriculoperitoneal shunt, optic nerve fenestration)or Hemicraniectomy*

• Impairment of consciousness / herniation / threatened vision

HOMOCYSTEINE and its ROLE IN CVTHOMOCYSTEINE and its ROLE IN CVT

• An intermediary amino acid

• Marked elevation may be seen with Homocystinuria, an inborn error of metabolism, with typical phenotype and premature atherosclerosis

• Due to cystathionine-β-synthase deficiency• AR inhertance

• Less marked elevations: proven risk factors for cardiovascular and venous thrombotic events

• Normal levels 5-15 μmol/L

HOMOCYSTEINE METABOLISMHOMOCYSTEINE METABOLISM

ETIOLOGY OF HYPERHOMOCYSTEINEMIAETIOLOGY OF HYPERHOMOCYSTEINEMIA

1. Genetic defects in the enzymes involved in homocysteine metabolism(MTHFR mutation)

2. Nutritional deficiencies in vitamin cofactors3. Other factors including some chronic medical

conditions and drugs (fibrates, nicotinic acid, CKD- ↓removal, impaired metabolism)

4. Smoking

ATHEROTHROMBOTIC PROPERTIES OF ATHEROTHROMBOTIC PROPERTIES OF HOMOCYSTEINEHOMOCYSTEINE

• Homocysteine has primary atherogenic and prothrombotic properties.

• Histopathologic hallmarks of homocysteine-induced vascular injury include

Intimal thickening, Elastic lamina disruption, Smooth muscle hypertrophy, Marked platelet accumulation, and Formation of platelet-enriched occlusive thrombi

• Moderate (15 to 30 µmol/L) • Intermediate (30 to 100 µmol/L) • Severe (>100 µmol/L)

• METHIONINE CHALLENGE TEST

• IMPLICATIONS:1. Myocardial infarction, other acute coronary syndromes,

and recurrent coronary events 2. Premature coronary heart disease 3. Cardiovascular and total mortality 4. Adverse outcomes after angioplasty 5. Carotid artery stenosis, Stroke , recurrent stroke , and

silent brain infarct

• OTHER ASSOCIATIONSOTHER ASSOCIATIONS

1. Venous thromboembolism2. Obstetric complications3. Birth defects4. Osteoporosis5. Dementia

TREATMENTTREATMENT

• Correcting nutritional inadequacy of folic acid, vitamin B12, and choline (betaine) will lower homocysteine levels

• A diet rich in fruits, vegetables, and low-fat dairy products, and low in saturated and total fat also can lower fasting serum homocysteine

• folic acid (1 mg/day)• vitamin B6 (10 mg/day)• vitamin B12 (0.4 mg/day)

• Normalization in two weeks• ↑folic acid 5 mg/day as needed (<15 µmol/L)• a homocysteine level >30 µmol/L or CKD the initial dose of folic

acid is 5 mg/day• Not recommended for secondary prevention• Genetic testing is available

CORTICAL VENOUS THROMBOSISCORTICAL VENOUS THROMBOSIS

• CVT needs high index of suspicion for diagnosis because of wide spectrum of symptoms and varying signs

• Very good prognosis and mortality only <10% with prompt treatment, near complete recovery in majority

• Inherited(22%) and acquired thrombophilia to be screened

• 15% have no etiologic factors• In 44% cases >1 etiologic factors present• MRI with MRV is the gold std for diagnosis• Role of hyperhomocysteinemia on the rise• Anticoagulation is mainstay of treatment(IV foll. by oral)• Worsening if present even with treatment, surgical

intervention may be needed

HYPERHOMOCYSTEINEMIAHYPERHOMOCYSTEINEMIA

• Can be inherited/ acquired• Severest form is homocystinuria (CBS deficiency), AR

inheritance• MC inherited form is MTHFR mutation(thermolabile)• Normal level is 5-15 μmol/L• Folic acid, B6, B12 deficiency causes acquired disease• Screening to be done in case of atherosclerosis and

thrombophilia including CVT• Treatment is replacement of vitamins• Secondary prophylaxis not recommended

DIABETES AND CVTDIABETES AND CVT

• Neurologic symptoms in DKA are quiet common due to cerebral edema, but reports say CVT could be associated, be suspicious if patient is not responding (dehydration and sepsis could be the precipitating factors)

• coagulation abnormalities such as1. decreased protein C concentration, 2. enhanced anticoagulation response to act. Pr. C 3. activated protein C resistance

• Isolated case reports of CVT (Atleast3) as the presenting symptom in type 1 diabetes with DKA are there in literature

REFERENCESREFERENCES• UpToDate 17.3• Cerebral venous thrombosis: an update

Marie-Germaine Bousser, José M FerroLancet Neurol 2007; 6: 162–70

• HYPERHOMOCYSTEINEMIA AND CEREBRALVENOUS SINUS THROMBOSISMughis Sheerani and Bhojo A. KhealaniSection of Neurology, Aga Khan University Hospital, Karachi, PakistanPak J Neurol Sci 2006; 1(3):136-7

• Hyperhomocysteinemia in cerebral vein thrombosisIda Martinelli, Tullia Battaglioli, Paola Pedotti, Marco Cattaneo, and Pier M. Mannucci

• Diabetic ketoacidosis presenting as a cerebral venous sinus thrombosisKristel DE KEYZER1, Koen PAEMELEIRE1, Matti DE CLERCK2, Dirk PEETERS2 and Jacques L. DE REUCK11Department of Neurology, Ghent University Hospital, Ghent and 2Department of Neurology, AZ

Groeninge, Kortrijk, Belgium• Recurrent Cerebral Venous Thrombosis Associated with Elevated Factor VIII

Mi Jung Kim, M.D., A-Hyun Cho, M.D., Young-Joo No, M.D., Hee-Young Kim, M.D.,Jong S. Kim, M.D.Department of Neurology, University of Ulsan College of Medicine, Asan Medical Center

• Cerebral venous thrombosis during diabetic ketoacidosisS Keane, A Gallagher, S Ackroyd, M A McShane, J A EdgeArch Dis Child 2002;86:204–206