Neurological Manifestations of Hematological Disorders

DR Bipin Bhimani DM ( Neurology)(NIMHANS)

Well Care Hospital Rajkot

4 Situations

• Scenario 1:

• Known case of hematological disorder leading to neurological problem

• Eg :k/c/o sickle Cell Anemia gets ischemic stroke

Scenario 2

• Neurological problem as a first presenting symptom of a hidden hematological disorder

Eg:Young patient with Cerebra Venous Thrombosis gets diagnosed to have Protein C deficiency.

Scenario 3

• A multisystem disorder affecting both hemato and neuro system

• Eg:A lady with psychosis and thrombocytopenia , turn outs to have SLE

Scenario 4

• Neurological side effect of a drug used for hematological disorder

• Eg: Vincristine induced polyneuropathy

• Eg: 5 F-U causing Toxic leukoencephalopathy

Case 1

• Boy with limping gait

• Orthopedic opinion: Normal xrays, CRP, ASO, RA

• Neuro opinion: Hemogram

• Leukemia with blast crisis ( leading to joint pain )

Case 2:

• Man with headache , early papilloedema • Normal CT and limited MR brain

• High MCV

• Cerebral Venous sinus thrombosis on MR venogram ( due to high Homocysteine /Low B12 )

Case 3:

• Patient with fluctuating symptoms ? Seizures, TIAs, and behavioral changes

• Near normal MR brain

• Blood Ix: Thrombocytopenia

• TTP ( Thrombotic thrombocytopenic Purpura)

Case 4:

• Girl with bilateral watershed infarcts

• ( No hypotension, normal carotid doppler, MRAngio brain, 2 D Echo )

• Idiopathic hypereosinophilia syndrome with neurotoxicity

Case 5:

• Thallasemic girl with paraplegia

• Extramedullary hematopoesis in spinal canal, compressing spinal cord

Hypercoaguble disorders and ischemic stroke

• Pump ( heart)• Pipe ( artery) • Passage ( blood)

Hypercoagubility and ischemic stroke

• Cerebral Venous sinus thrombosis• About 8% of all ischemic strokes • Recurrent strokes • Stroke in young ( < 40), unidentified etiology • Strong family history of non – atheromatous

stroke• “cryptogenic “ ischemic strokes • paradoxical embolus through PFO

Primary/inherited Hypercoaguble states

• Factor V leiden mutation/Activated protein C resistance

• Prothombin gene 20210A mutation• Protein S deficiency• Protein C deficiency• Antithrombin III deficiency • MTHFR gene mutation • Others

Secondary/aquired hypercoaguable states

• APLA syndrome • Polycythemia rubra vera• Essential thrombocythemia • Myeloproliferative disorders• Sickle cell disease, hemoglobinopathies• Paraproteinemia • Iron deficiency Anemia • TTP • Hyperhomocystinemia • Pregnancy,OC Pills, DM,cancer,DIC,Ovarian Hyperstimulation

Syndrome

Thrombophilia work up ( Basic)

• Hemogram• PT, aPTT• Homocystiene• ANA, VDRL• LA, ACLA • APLA • Anti-Thrombin III level• Pro Ce globe

Further workup

• Factor V leiden mutation • Prothombin gene mutation• MTHFR gene mutation

• Protein S functional assay ( Total, free ) • Protein C functional assay

Practical points

• In acute phase levels of protein C ,S etc may not be accurate , so should be repeated again

• Patient should be off anti-coagulants for at least 2-3 weeks (Protein C and S are reduced due to heparin, oral anti coagulants )

Iron deficiency Anemia

• Headache• fatigue• Restless leg syndrome• Ischemic Stroke ( due to Thrombocytosis)

Polycythemia

• Arterial ischemic stroke• Hyper viscosity

syndrome:headache,dizziness,tinnitus,visual blurring,cognitive changes, paresthesias

• Pseudotumur cerebri

• Chorea• Erythromelalgia : painful, hot, red extremities ( small

fiber autonomic dysfunction)

Sickle cell anaemia

• Ischemic stroke• Hemorrhagic stroke• Seizure • Sensrineural Deafness• Retinopathy, blindness • Moya moya syndrome• Pneumococcal meningitis

Thalassemia

• Transient dizziness• Visual blurring• Headache • seizure• Occasional ischemic/hemorrahgic stroke • Motor neuropathy• Spinal cord compression ( Extramedullary

hematopoiesis)

Hemophillia

• ICH often without trauma • Subdural,epidural,intrcerebal,intra spinal • Hematomas can compress peripheral nerves • 3% risk, but mortality is 35% ( over 10 yrs) • Treatment with factor concentrate

Leukemia

• ALL : 5-10% has CNS involvement at diagnosis( leptomeningeal involvement)

Headache, cranial neuropathy, meningismus, cognitive changes, gait, Sphincter disturbances

• AML : less CNS involvement ; chloroma ( granulocytic sarcoma)

Leptomeningeal metastasis

• Common: Leukemia,lymphoma,breast,lung,melanoma

• Symptoms: Headache, N/V,meningismus,cognitive changes, incontinence , cranial neuropathy, radiculopathy

• Diagnosis:MR brain and spine with contrastCSF : 10 ml ( large volume) ,repeated tests , prompt

examination,cytology, flow cytometry

lymphoma

• Hodgkins lymphoma : rare , epidural spinal compression

• NHL : CNS involvement common ( meningeal lymphamatosis)

• Primary CNS Lymphoma ( HIV, transplant patients) : Corpus Callosum , deep Periventricular white matter , frontal lobe

Plasmacell dyscrasias• MGUS : peripheral neuropathy • Multiple myeloma: spinal cord compression, radiculopathy • POEMS syndrome: CIDP like neuropathy• Waldenstrom macroglobulinemia : sensory-motor peripheral

neuropathy , Hyperviscocity syndrome

• Amylodosis: small fiber autonomic neuropathy, Carpal tunnel syndrome

• Hyper viscosity syndrome, hypercalcemia,renal failure ,infection

Practical point

• Any patient with undiagnosed ployneuropathy should be investigated with

• ESR• Sr Proteins• Sr Protein Electrophoresis (SPEP) , IEP ( Immuno-ElectroPhoresis) • Urine for BJP

Hyperviscocity Syndromes

• Blood is much thicker • Normal viscocity : 1.4 to 1.8 cp (centi-poise) units • HVS occurs at > 4-5 units • Increses cells , immunoglobulins ( Polycythemia, leukemia,MM,WM)• S&S: Visual , Neurological , mucosal bleeding• It is an emergency • Rx: Hydration, removal by phlebotomy or apheresis ,

treatment of underlying disorder

Thrombotic Thrombocytopenic Purpura

Pentads of TTP 1. Fever2. Hemolytic anemia (microangiopathic)3. Thrombocytopenia ( purpura)4. Renal dysfunction5. Neurological (CNS) symptoms -fluctuating( TIA, seizure,altered behavior, coma)

• Treatment: Plex, IVIg, splenectomy, corticosteroids

APLA syndrome :

• Migraine• Amaurosis Fugax ,Ischemic Optic Neuropathy (ION)• Arterial or venous ischemic stroke• MS like lesions

• Thrombocytopenia, false positive VDRL, prolonged aPTT, Bad obstetric history

Thrombocytopenia & Neurological disorders ( stroke,seizure,TIAs,encephalopathy)

Mental check list:1) TTP2) LUPUS (SLE)3) APLA Syndrome/ Sneddon syndrome4) AIDS / HIV5) Heparin induced thrombocytopenia(HIT) 6) Valproate induced thrombocytopenia 7) Wilson disease ( Hemato/neuro)

Idiopathic hypereosinophillia Syndrome (IHES)

• > 1500 AEC ( absolute eosinophil count)• Parasitic infection, drugs, allergies, Collagen vascular

disease ( esp Chrug Strauss disease), few leukemias• >1500, > 6 M , No other cause, organ damage

Idiopathic HES • Organs : heart, skin, lung, GI, nervous system • Neurological manifestations: encephalopathy,infarcts,

neuropathies ( MMN,sensory), • Treatment: Aspirin, Steroids, Hydroxyurea

Arterial ischemic stroke and homocysteine

• Hyperhomocysteinemia Recommendations:

• 1 )Routine screening for hyperhomocysteinemia among patients with a recent ischemic stroke or TIA is not indicated

• 2)In adults with a recent ischemic stroke or TIA who are known to have mild to moderate hyperhomocysteinemia, supplementation with folate, vitamin B6and vitamin B12safely reduces levels of homocysteine ,but has not been

shown to prevent stroke .

Nutritional deficiencies

• Vitamin B12 deficiency : SACD ( Subacute Combined degeneration)

Rare disorders

• Histiocytosis X• PNH ( Paroxysmal Nocturnal Hemoglobinuria) • Porphyrias• DIC• GVHD• Transplant complications

Drugs used in Hematological disorders with neurological side effects

• 5 FU : Toxic leukoencephalopathy• Cisplatinum: Sensory

neuronopathy/Ganglionopathy• Cytosine arabinoside : Cerebellar syndrome • L Asparginase: venous sinus thrombosis• Intrathecal Methotraxate neurotoxicity

HEMOGRAM REPORTTEST RESULT UNIT NORMAL RANGE

HEMOGLOBIN : 11.0 gms/100ml [13.0-17; F: 12.0-15.0]

TOTAL W.B.C. : 7,900 per cu.mm [4,000-11000]

PLATELET COUNT : 2,53,000 per c.mm [1,50,000-4,00,000]

DIFFERENTIAL COUNT Neutrophils : 73 % [40-70 %]

Lymphocytes : 25 % [20-40 %]

Eosinophils : 01 % [00-04 %]

Monocytes : 01 % [01-06 %]

Basophils : 00 % [00-0.5 %]

BLOOD INDICESRBC : 4.03 Million/cmm [M 4.5-5: F 3.8-4.8]

PCV : 34.0 % [M 41-51; F 36-45%]

MCV : 84.3 % [ 80-95 %]

MCH : 27.2 cu.micron [27-32 cu.micron]

MCHC : 32.3 % [32-36%]

ERYTHROCYTE SEDIMENTATION RATE1ST Hour E.S.R. : 06 mmHg Men Women

17-50 yr <10 <12

51-60 yr <12 <19

61-70 yr <14 <20

>70 yr <30 <35

ALWAYS EXAMINE HEMOGRAM METICUOUSLY

Take home message • Head is attached to the body !!

• V : vascular• I : Infective• T : Traumatic , Toxic• A : Allergic , anaphylactic • I : Inflammatory ( Demyelinating)• N: Nutritional , neoplastic• S : Systemic

• Basic investigation:

Good hemogram (and a communicative pathologist)

Thank You