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2 PRESENT HISTORY 13 year old BAH male presented on 28/10/13 with history of: Unsteady gait 6-8/12 (progressive) Slurred speech 3/12 Loss in weight and appetite Decrease activity And Urinary incontinence Abnormal hand writing

3 PRESENT HISTORY No history of fever No history of nystagmus or eye problem No history of skin lesion

4 PAST HISTORY Full term, product of NVD of birth weight 3.3 kg No history of previous admission or operation No allergy Vaccination : up to date

5 SOCIAL HISTORY 1 of family of 11 members Parents : consanguineous.. cousins Living in owned house He is In 1 st intermediate grade at school ‘should be in 2 nd but failed due to change in activity & performance’ No contact with sick persons

6 PHYSICAL EXAMINATION Child was oriented, cooperative but hypoactive, mask face and looking depressed Vitals: Temp 37, RR 30/min, HR 82/min, BP 112/65 Slurred speech No cyanosis or clubbing No skin rash Ent : normal Chest : gynecomastia CVS : normal Abdominal : liver 2-3cm below CM

7 PHYSICAL EXAMINATION CNS examination:  No facial asymmetry  Tongue or uvula : in midline  Power: weak grip (right more than left)  Tone: hypotonic (right more than left)  Reflexes : normal  sensation : decrease / loss in feet (bilateral) with normal vibration sense  Sever ataxia, wide based gait with positive rhomberg’s test (sway when he standing with closed feet & closed eye)  Meningeal signs: negative

8 PHYSICAL EXAMINATION Eye :  Pupils: equal, reactive to light  No nystagmus  Fundus : normal

9 DIFFERENTIAL DIAGNOSIS ?? Ataxia Any suggestion ??


11 DIFFERENTIAL DIAGNOSIS Acute ataxia with rapid improvement The two commonest causes are: Drug Ingestion: usually Accidental. Overdose of hypnotics, tranquilizers, anticonvulsants especially phenytoin and carbamazepine Acute cerebellar ataxia (Post infectious acute cerebellitis): like varicella, infectious mononucleosis or other viral infections (polio, mumps, coxsackie, herpes, simplex or ECHO viruses phenytoincarbamazepine

12 DIFFERENTIAL DIAGNOSIS Acute ataxia with prolonged or intermittent course The commonest conditions to keep in mind are: - Myoclonic Encephalopathy (Dancing eye syndrome) - Neuroblastoma syndrome - Brain Tumors - Multiple sclerosis - Metabolic disorders

13 DIFFERENTIAL DIAGNOSIS ATAXIA WITH INSIDIOUS ONSET (CHRONIC ATAXIA) Chronic ataxia with slow progression: The commonest causes of chronic slowly progressive ataxia are : brain tumors hereditary ataxias (Friedreich's Ataxia and Ataxia Telangiectasia are the commonest).

14 DIFFERENTIAL DIAGNOSIS ATAXIA WITH INSIDIOUS ONSET (CHRONIC ATAXIAS) Differential diagnosis of a child with chronic or progressive ataxia: BRAIN TUMORS Cerebellar astrocytoma Medulloblastoma Supratentorial tumors CONGENITAL MALFORMATIONS Basilar impression Cerebellar aplasia Dandy walker malformation Chiari malformation Vermal aplasia

15 DIFFERENTIAL DIAGNOSIS HEREDITARY ATAXIAS Autosomal recessive inheritance - Ataxia telangiectasia Friedreich's ataxia - Hartnup's disease Hypobetalipoproteinemia - Refsum's disease Wilson's disease - MSUD Mitochondrial disorders - Marinesco - Sjogren syndrome - Pyruvate dehydrogenase deficiency Ramsay Hunt syndrome - Juvenile GM2 gangliosidosis Juvenile sulfatide lipidosis - Mitochondrial disorders - Ataxia - oculomotor apraxia Ataxia with episodic dystonia Autosomal dominant inheritance - Olivo-ponto-cerebellar degeneration - Machado - Joseph disease X linked inheritance - Adrenoleukodystrophy Leber's optic neuropathy

16 INVESTIGATIONS LABS CBC: WBC=3.3 PMN= 49% L=37% Hb 11.2 Hct 0.34 platlets 110 Coagulation: prologed PT LFT: Alkaline phosphatase & GGT raised

17 DIFFERENTIAL DIAGNOSIS ?? Ataxia with elevated liver enzyme Again Any suggestion??

18 DIFFERENTIAL DIAGNOSIS Autoimmune : ?? SLE Metabolic : ?? Mitochondrial disorders - Pyruvate carboxylase deficiency Neurodegenrative disease : ?? wilson’s disease

19 INVESTIGATIONS ANA negative Serology : normal except for past EBV infection Vit b12 : normal Iron study : normal

20 FURTHER EVALUATION Multiple teams involved ( GIT – METABOLIC – ENDOCRAINE – HEMATOLOGY – OPHTHALMOLOGY) All basic lab repeated CBC – LFT – COAGULATION with (serum & urine) copper, serum ceruloplasmin and zink Metabolic & endocrine work up

21 FURTHER EVALUATION Ophthalmology : ?? Kayser–Fleischer ring

22 INVESTIGATIONS Serum copper : low Serum Ceruloplasmin : low Urine copper : high Zinc : high

23 INVESTIGATIONS CT brain Bilateral basal ganglia hypodensity Suggest of : metabolic disease or hypoxic change MRI spine

24 IMPRESSION 13 year old boy with Wilson’s disease

25 SCREENING After diagnosis, screening done for all members with LFT, CERULOPLASMIN AND COPPER RESULT :?? 2 of his sisters have lab result suggest wilson’s disease

26 MANAGEMENT Started on : D. PINICILLAMINE 500mg BD PO Vit B6 ( PYRODIXIN) 500 mg OD PREDNISONE ( by hematologist due to thrombocytopenia ) ZANTAC

27 FURTHER INVESTIGATIONS Bone marrow aspiration : Varriable cellularity BM showing increased erythropoisis, adequate megakaryocyte. Granulopoiesis is reduced Hemophagocyteosis No evidence of involvment by lymphoma ?? Hemophagocytic lymphohistiocytosisHemophagocytic lymphohistiocytosis

28 FURTHER INVESTIGATIONS Abdominal US : suggestive of liver cirrhosis No portal HTN Abdominal CT : splenomegally

29 PROGRESS Followed by multiple teams including Psychiatry team After starting treatment, Liver enzyme start to coming down but : 1.c/o knee pain … orthopedic team involved 2.Ataxia worsened 3.More depressed 4.Increase slurring 5.Refuse to walk

30 PROGRESS Last seen in the clinic, he had : 1.Resting tremor 2.Dystonia in arms 3.Dysphasic so started on L-DOPA, CARBI-DOPA AND ANTI CHOLENERGIC medications


32 WILSON’S DISEASE Due to a genetic abnormality inherited in an autosomal recessive manner. The abnormal gen for wilson’s disease is on ch 13 (q14-q21) Leads to impairment of cellular copper transport. Prevalence of approximately 1 case in 30,000 live births in most populations

33 PATHOGENESIS Defective mobilization of copper from lysosomes in liver cells, leading to accumulation of copper in the liver. When copper accumulation exceed the point of retention capacity, copper escape to other organ particularly brain, kidney and cornea Over time, the liver is progressively damaged and becomes cirrhotic. A small percent of patients develop acute liver failure

34 CLINICAL MANIFESTATIONS Patients may present with a wide variety of symptoms (especially those with neurologic symptoms) ●Liver disease: 18 to 84 percent of patients ●Neurologic symptoms: 18 to 73 percent of patients ●Psychiatric symptoms: 10 to 100 percent of patients

35 NEUROLOGIC MANIFESTATIONS Dysarthria – 85 to 97 percent of patients with neurologic Wilson disease ●Gait abnormalities/ataxia – 30 to 75 percent ●Dystonia – 11 to 69 percent ●Tremor – 22 to 55 percent ●Parkinsonism – 19 to 62 percent ●Drooling – 48 to 86 percent ●Chorea ●Athetosis ●Cognitive impairment/dementia ●Seizures ●Hyperreflexia ●Myoclonia ●Urinary incontinence ●Autonomic dysfunction ● Focal manifestations of dystonia include cervical dystonia (torticollis), writer's cramp, dysphonia, dysarthria, or dysphagia,

36 HEPATIC MANIFESTATIONS ●Asymptomatic (steatosis, chronic hepatitis, compensated cirrhosis) ●Abdominal pain (acute hepatitis, acute liver failure) ●Jaundice (acute hepatitis, acute liver failure, cirrhosis) ●Hepatomegaly (acute and chronic hepatitis, acute liver failure) ●Splenomegaly (cirrhosis) ●Ascites (cirrhosis) ●Upper gastrointestinal bleeding (cirrhosis with varices or portal hypertensive gastropathy) ●Peripheral stigmata of chronic liver disease (cirrhosis) ●Mental status changes due to hepatic encephalopathy (acute liver failure, cirrhosis

37 BEHAVIORAL AND PSYCHIATRIC SYMPTOMS ● Depression ●Declining school performance ●Personality changes (which may be subtle) ●Irritability ●Labile mood ●Inappropriate behavior ●Bipolar affective disorder ●Psychosis ● Cognitive impairment — Two main categories of cognitive impairment in Wilson disease have been described, a frontal syndrome and subcortical dementia

38 OCULAR MANIFESTATIONS Kayser-Fleischer rings : are brownish or gray-green rings that are due to fine pigmented granular deposits of copper in the cornea. Seen in about 98 percent of patients with neurologic manifestations and about 50 percent of patients with hepatic manifestations. often only detected by slit-lamp examination Sunflower cataracts

39 OTHER MANIFESTATIONS ● Fanconi syndrome ●Nephrolithiasis ●Arthropathy, most commonly in the knee. ●Gigantism. ●Cardiomyopathy. ●Myopathy. ●Hypoparathyroidism. ●Pancreatitis. ●Impotence. ●Infertility or repeated spontaneous abortions. ●Dermatologic disorders. These include blue lunulae, acanthosis nigricans, and pretibial hyperpigmentation. Dermatologic manifestations may also occur from treatment with penicillamine

40 INITIAL EVALUATION We start the evaluation with: Determination of liver biochemical tests to look for evidence of active inflammation and to assess the AST to ALT ratio (often >2 in patients with Wilson disease) A complete blood count to look for anemia (followed by testing for Coombs-negative hemolytic anemia if indicated) Measurement of the serum ceruloplasmin concentration Measurement of the serum copper concentration An ocular slit-lamp examination Determination of 24-hour urinary copper excretion Molecular testing for ATP7B mutations in siblings of affected patients

41 INTERPRETATION OF TEST RESULTS Low ceruloplasmin (<20 mg/dL or 200 mg/L), low serum copper concentration Kayser-Fleischer rings present: A diagnosis if 24-hour urinary copper excretion is >40 mcg If urinary copper excretion is ≤40 mcg, a liver biopsy should be done or molecular genetic testing Kayser-Fleischer rings absent: if the 24-hour urinary copper excretion is >100 mcg If the urinary copper excretion is ≤100 mcg a liver biopsy should be done or molecular genetic testing

42 INTERPRETATION OF TEST RESULTS Normal or elevated ceruloplasmin (≥20 mg/dL or 200 mg/L), normal serum copper concentration Kayser-Fleischer rings present: A liver biopsy should be obtained regardless of urinary copper excretion, or molecular genetic testing Kayser-Fleischer rings absent: A diagnosis of Wilson disease is excluded if the urinary copper excretion is ≤40 mcg If the urinary copper excretion is >40 mcg, a liver biopsy should be obtained or molecular genetic testing may be done

43 INTERPRETATION OF TEST RESULTS A diagnosis of Wilson disease is established if the hepatic copper concentration is ≥250 mcg/g dry weight A diagnosis of Wilson disease is excluded if the hepatic copper concentration is <50 mcg/g dry weight Screening family members — First-degree relatives of patients diagnosed with Wilson disease should be screened for the disease This approach is similar to that outlined in a 2008 consensus guideline from the American Association for the Study of Liver Diseases and from the European Association for the Study of the Liver American Association for the Study of Liver DiseasesEuropean Association for the Study of the Liver

44 OTHERS A Coombs-negative hemolytic anemia. Serum aminotransferases that are typically less than 2000 int. unit/L. The ratio of the AST to ALT is often >2. The alkaline phosphatase may be normal or markedly subnormal Low uric acid levels. A coagulopathy that is unresponsive to vitamin K. Rapidly progressive renal failure.

45 OTHER MODALITIES Magnetic resonance imaging (MRI) or computed tomographic (CT) scanning of the brain may reveal structural abnormalities in the basal ganglia Cerebrospinal fluid (CSF) copper concentrations in patients with neurologic Wilson disease are elevated three to four times relative to those in patients without Wilson

46 CANCER RISK Whether patients with Wilson disease are at increased risk for hepatocellular carcinoma or other malignancies is unclear. Occasional reports have described hepatocellular carcinoma and cholangiocarcinoma

47 TREATMENT Medication Summary Zinc and penicillamine are lifelong medications Other medications used to treat Wilson disease include anticholinergics, baclofen, gamma-amino-butyric acid (GABA) antagonists, and levodopa, to treat parkinsonism and dystonia symptoms; antiepileptics to treat seizures; and neuroleptics to treat psychiatric symptoms

48 TREATMENT Dietary In general, a diet low in copper-containing foods is recommended with the avoidance of mushrooms, nuts, chocolate, dried fruit, liver, and shellfish. [1]mushrooms nutschocolatefruitshellfish [1]

49 TREATMENT Chelators Chelating agents bind excess copper. Penicillamine (Cuprimine, Depen) Trientine (Syprine) Dimercaprol (BAL in Oil)

50 TREATMENT Nutrients Essential to normal growth and development, and play a role in many metabolic processes Zinc (Galzin) It is approved for patients initially treated with a chelating agent. Pyridoxine (Aminoxin, Pyri-500) Pyridoxine is involved in synthesis of GABA within the CNS..


52 PHYSICAL THERAPY Physiotherapy is beneficial for patients with the neurologic form of the disease. Physiotherapy

53 SURGERY Transplantation Liver transplantation Liver transplantation is an effective cure for Wilson's disease but is used only in particular scenarios because of the risks and complications associated with the procedure

54 PROGNOSIS Untreated, Wilson disease is universally fatal. Copper accumulation in the liver leads to the development of cirrhosis. Among patients with neurologic Wilson disease, the neurologic disease may progress until the patient becomes severely dystonic, akinetic, and mute. The prognosis for patients who receive treatment is excellent, even in some who already have advanced liver disease. survival following transplantation is excellent

55 Thank you!


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