CLINICAL MEET ‘ CASE OF ALTERED

SENSORIUM ’ 6/12/2013

Dr.Ram Raut (JR III) Unit- Dr.D.B.Kadam

Case History 16 yr male student… R/O- Beed. Admitted in private Hospital on 11/11/2013.

With H/O…

1) Headache 3 days back more in occipital area , continuous & moderate intensity. associated with neck pain

2) Sudden onset unconsciousness since 1 day.

No H/O… Vomiting, visual complaints Head injury, Convulsions Chest pain, palpitations, breathlessness Fever, Cough with expectoration. Abdominal pain Substance/drug abuse

• Past History -

• H/o Few Seizures in childhood but not on any Rx.• Not a k/c/o- TB/DM/HTN/CVA/BA/CHD.• No H/O- similar episode in past.

• Family History -

• No significant illness in family.• No H/O Consangious marriage.• No H/O sudden deaths in family.

• Personal History -

• No addictions.

General examination -AfebrileP- 100/min regular.BP- 130/80mm Hg Pallor +No icterus /edema /clubbing /cyanosis No Lymphadenopathy.JVP- Not raised.No e/o neuro-cutaneous markers.

CNS Examination• Unconscious, • Not responding to DPS• GCS- 3/10• Pupils- B/L CCERL• Doll’s Eye- present• Spontaneous Respiration

present.• No meningeal signs• No Cranial Nerve deficit.

Motor examination-

• Nutrition- N• Tone - Increased on right side• DTR -

• Plantars -

BJ +++ ++

TJ ++ ++

SJ ++ ++

KJ +++ ++

AJ +++ ++

Other Systems

• CVS - • S1S2 Normal• No murmurs

• RS - • AEBE clear• No rales/ rhonchi

• P/A - • Soft, Non tender• No organomegaly

?

• Provisional Impression-• ? CVA• ? IC Bleed

• Treatment started .. • IV Mannitol • IV antibiotics• And IV fluids.

• MRI Brain (P+C) - 1) Acute infarct in the right lobe of cerebellum; Restricted

diffusion on DWI.2) Small old gliotic areas in both lobes of cerebellum3) Lacunar ischemic areas in midbrain.

• Aspirin, Atocor started & patient was referred to SGH for further management.

In SGH …• Patient got admitted in MICU.• O/E-

• Afebrile• P- 96/min regular, all peripheral pulses well felt• BP -130/80 mm Hg• RR- 16/min• No P/O/L/I/C/C• JVP- NR

CVS- S1S2 Normal RS- AEBE clear P/A- Soft, NT

L0S0K0

CNS Examination• Comatose • Min responding to DPS• GCS- 5/10• Pupils- B/L CCERL• Doll’s Eye- present• Spontaneous Respiration

present.• No meningeal signs• No Cranial Nerve deficit.• Fundus- B/L WNL

Motor examination-

• Nutrition- N• Tone - Increased on right side• DTR -

•

• Plantars -

BJ +++ ++TJ ++ ++SJ ++ ++KJ +++ ++AJ +++ ++

Investigation 12/11 14/11 20/11

Hb 15.6

TLC 11.6

PLC 234

HCT 54

MCV 91

Creat 1 1.2 0.9

Urea 65 56 54

Na 132 134 137

K 4.5 4.3 4.2

BSL 124 ESR 54

Investigation 14/11 20/11

SGOT 16 15

SGPT 41 43

ALP 134 164

Bilirubin 0.6 0.7

Total proteins 7.2 7

Albumin 4.5 4.3

Globulin 2.7 2.7

PT 21 25

LDH 260 …

Malaria Ag Neg.

Uric Acid 8.2

Investigations …

PBS- Normocytic, few microcytes, mild hypochromia, TLC- 10,000. N72, L26 Platelets adequate. Urine analysis - WNL

• CXR & ECG - WNL

D2

• Patient improved to some extent.

• Neurosurgery reference - Continue conservative management.

• 2 D Echo - No RWMA Good LV contractility. Intact IAS & IVS.

• MRI Brain & Angiography done …

• Acute infarct in Right inferomedial cerebellum

T2/FLAIR Hyper intense.

• Acute infarct in pons T2/ FLAIR hyper intense

Left pontine infract Restricted diffusion on DWI.

• Right inferomedial cerebellum Restricted diffusion on DWI.

MR ANGIO

• Acute infarct in right cerebellum, & left pons & midbrain.

• Gliosis in left cerebellar hemisphere.

• Thrombotic occlusion of left vertebral & basilar artery & right posterior cerebral artery.

• Blood samples withdrawn for thrombotic work up including Serum Homocystine, APLA, ANA p-ANCA, c-ANCA. Sample was also preserved for further workup if requires.

• & LMWH started.

• Now Patient improved neurologically.• Regained consciousness.

• On Neurological examination -

• Conscious & obeying. • No neck stiffness• No cranial nerve deficit.• Right hemi-paresis present.• Plantars- right extensor & left flexor

• Patient was shifted for DSA.

D3

DSA 13/11/2013

• Anterior circulation - normal caliber & blood flow.

• Total occlusion of mid basilar artery immediately distal to the AICA origin.

• B/L PCAs & distal basilar artery fill via B/L Posterior communicans.

Further investigations…

• Right lower limb AV Doppler- No thrombosis or stenosis .

• USG Abdomen - WNL.

• Local USG - soft tissue swelling + But no thrombosis/stenosis of femoral/iliac vessels.

LIPID PROFILE RESULT DESIRABLE VALUE

TOTAL CHOLESTEROL 114 <200

HDL 32 >60

TGs 74 <150

VLDL 14 15-40

LDL 68 <100

• Patient now started accepting oral feeding.

• Able to walk with support.

• Physiotherapy was continued.

• Neurologically improved over next 3-4 days.

• But Pallor +

D4

• Urine R/M- WNL• Urine Hb- nil• LDH- 266• Sucrose lysis test - No e/o lysis.• Retic count- 0.5• CD 55 - 8.8 (N)• CD 59 - 70.5 (N)

Tests done to rule out PNH

Thrombotic work-up

• ANA weakly positive(1.17).

• APLA- IgM & IgG negative.

• Anti thrombin III - WNL

• APTT - 64.

• Serum homocystine- WNL

Factor V Leiden - G1691A mutation- positive (heterozygous).

•Protein C activity - WNL

•Protein S activity- WNL

•Anti- DsDNA- negative.

•P-ANCA - negative

•C-ANCA- negative.

• Final Diagnosis -

Altered sensorium in young male with right hemiparesis

due to

1) Acute right cerebellar infarct (Right PICA Territory)

2) Multiple pontine infarcts (paramedian branches of mid basilar

artery due to complete thrombosis of mid basilar artery ) &

3) Right Midbrain infarct (Right PCA Territory)

(Factor V Leiden mutation positive)

• Stroke at a young age is rare (2.5 to 7.8 /1 lakh children). Basilar artery occlusion is even rarer.

• Early diagnosis of basilar artery occlusion difficult as other neurological disorders such as seizure or basilar migraine might mimic stroke.

• Devastating event, with a mortality rate of 83-92%.

Discussion

The factors affecting functional outcome-

1) Age, 2) Initial clinical status, 3) Location and length of occlusion,4) Etiology, 5) Timing of intervention, recanalization and 6) The degree of collateral circulation.

Recanalization is the principle factor related to functional outcome.

Etiologies-1) Prothrombotic diseases, 2) Anabolic steroid, 3) Inflammatory vasculitis, 4) Spontaneous dissection, 5) Neonatal thrombo-embolism, & 6) vertebral artery dissection.

In our case, the etiology was unclear.

STROKE DUE TO BASILAR ARTERY OCCLUSION

• Hemostasis is defective due to inherited as well as acquired defects.

• Inherited defects associated with bleeding disorders have been known

since centuries (hemophilia A&B and Von Willebrand disease).

• But, inherited defects causing thrombosis are studied only recently.

• & These include- 1) Factor V Leiden (R506Q mutation),

2) Prothrombin 20210A mutation,

3) Antithrombin III deficiency, and

4) Deficiencies of protein C and protein S.

NORMAL HEMOSTASIS

Procoagulant system

Anticoagulant system

Heritable causes of Thrombotic disordersA) ARTERIAL THROMBOSIS B) VENOUS THROMBOSIS

A. Platelet receptors…1) β3 & α2 integrins2) P1A2 polymorphism3) Thrombin receptor PAR-1

B. Redox enzymes1) Pl Glutathione peroxidase2) Endothelial NO synthase3) Paroxonase

C. Homocysteine1) Cystathione B synthase2) 5,10- MTHFR (methylene

Tetrahydrofolate reductase)

D. Protein C Anticoagulant Pathway? Factor V Leiden

A. Procoagulant proteins1) Fibrinogen2) Prothrombin 20210

B. Protein C Anticoagulant Pathway1) Factor V Leiden2) Thrombomodulin

C. Fibrinolytic proteins1) Tissue Plasminogen activator

(tPA)2) Plasminogen activator Inhibitor

(PAI-1)

D. Homocysteine1) Cystathione B synthase2) 5,10- MTHFR

Acquired causes of Thrombotic disordersA) ARTERIAL THROMBOSIS B) VENOUS THROMBOSIS

A. MalignancyB. APLA syndromeC. Hormonal therapyD. Polycythemia VeraE. Essential

thrombocythemiaF. PNHG. TTPH. Heparin induced

thrombocytopeniaI. DIC

A. AGEB. SmokingC. ObesityD. Metabolic

SyndromeE. Hyper- lipidemia

A. AgeB. Previous thrombosisC. ImmobilizationD. Major surgeryE. Pregnancy &

puerperiumF. HospitalizationG. ObesityH. InfectionI. Smoking

• Discovered in 1994 • Most common genetic risk factor for venous thrombosis.----------------------------------------------------------------------------------------

• Initial APC cleavage at the R506 position is required for inactivation of factor V.

• Factor V Leiden mutation may account for 85-95% of patients with APC resistance.

A single point mutation at nucleotide 1691 of the factor V gene,

(known as factor V Leiden)

Substitution of a Glutamine for Arginine at residue 506 (R506Q),

(one of three APC cleavage sites)

Activated protein C resistance (APC-R)

Factor V Leiden ……

Activated Protein C (APC) ResistanceDue to Factor V Leiden

• Activated protein C (APC) is the functional form of the naturally occurring, vitamin K dependent anticoagulant, protein C.

• APC is an anticoagulant which inactivates factors Va and VIIIa in the presence of its cofactor, protein S.

• Alterations of the factor V molecule at APC binding sites (such as amino acid 506 in Factor V Leiden) impair, or resist APC’s ability to degrade or inactivate factor Va.

THE FACTOR V LEIDEN MUTATION

DNA TESTING FOR FACTOR V LEIDEN

NORMAL HOMOZYGOUSHETEROZYGOUS

FVL DNA AMPLIFIED BY PCR, DIGESTED WITH RESTRICTION ENZYME

• Age <50, any venous thrombosis.

• Venous thrombosis in unusual sites (i.e. hepatic, mesenteric, and cerebral veins).

• Recurrent venous thrombosis.

• Venous thrombosis and a strong family history of thrombotic disease.

• Venous thrombosis in pregnant women or women taking oral contraceptives.

• Relatives of individuals with venous thrombosis under age 50.

• Myocardial infarction in female smokers under age 50.

• Routine testing is not recommended for patients with a personal or family history of arterial thrombotic disorders (e.g., acute coronary syndromes or stroke) except for the special situation of myocardial infarction in young female smokers.

Consensus Statement on Factor V Leiden Mutation Testing

•Testing is worthwhile for young patients (<50 yrs) with acute arterial thrombosis in the absence of other risk factors for atherosclerotic arterial occlusive disease.

Journal Français d'OphtalmologieVolume 29, Issue 1 January 2006, Pages 43–46

Visual dysfunction and arterial occlusion: Is there an association with factor V Leiden mutation?  Four case reportsA.-C. Bessero, F.-X. Borruat  

Abstract The Leiden mutation of the factor V gene and the subsequent resistance of factor V to inactivation by activated protein C are associated with a procoagulant state, especially in the venous bed. However, its association with arterial thrombotic disease remains unclear. We report four patients with visual field defects secondary to arterial occlusions and in whom we found a factor V Leiden mutation. These patients, three females and one male, aged 32–58 years, presented with various visual field defects: bilateral aciform scotomas due to multiple infarcts of the nerve fiber layer (one case), superior defect due to anterior ischemic optic neuropathy (one case), homonymous hemianopia due to stroke (two cases). An abnormal resistance to activated protein C and a heterozygous state for factor V Leiden mutation were found in all four cases. In two cases, no other risk factor was found. We hypothesize that factor V Leiden mutation, even in a heterozygous state, might predispose to arterial occlusion in some patients.

Thromb J. 2011; 9: 8.doi: 10.1186/1477-9560-9-8PMCID: PMC3112058 Iraklis Tsangaris, Georgios Tsaknis

Abstract

We report a case of near fatal aortic

thrombosis in a trauma patient

homozygous for mutation of Factor

V Leiden. He responded well to

vascular surgery and intensive care unit

management and was discharged

successfully from the hospital one

month later.

Pediatr Neurol. 2001 Jan;24(1):69-71.

Basilar artery thrombosis in a child heterozygous for factor V Leiden mutation.Verdú A, Cazorla MR, Granados MA, Alonso JA, Casado LF.Pediatric Neurology Unit, Hospital Virgen de la Salud, Toledo, Spain.

Abstract Activated protein C resistance, usually because of factor V Leiden mutation, is considered to be the most common hereditary prothrombotic condition. A 9-year-old male with a basilar artery stroke and activated protein C resistance is described. He found heterozygous for factor V Leiden mutation, is one of several recent reports that suggest that activated protein C resistance is an important risk factor for spontaneous arterial thrombosis in infancy and childhood