GRAND ROUND

D R. A B D U L L A M A K IS U P E RV I S E D BY D R. FAT I M A N E A M A

CHILD WITH ATAXIA

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

PRESENT HISTORY

• No history of fever

• No history of nystagmus or eye problem• • No history of skin lesion

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

SOCIAL HISTORY

• 1 of family of 11 members• Parents : consanguineous .. cousins• Living in owned house

• He is In 1st intermediate grade at school ‘should be in 2nd but failed due to change in activity & performance’

• No contact with sick persons

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

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

PHYSICAL EXAMINATION

Eye : Pupils: equal, reactive to light

No nystagmus

Fundus : normal

DIFFERENTIAL DIAGNOSIS

?? Ataxia

Any suggestion ??

DIFFERENTIAL DIAGNOSIS

According to Presentation

ACUTE ONSET: - WITH RAPID IMPROVEMENT - WITH PROLONGED OR INTERMITTENT COURSE

INSIDIOUS ONSET - SLOW PROGRESSION OF ATAXIA - INTERMITTENT OR STATIONARY COURSE

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

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

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).

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

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

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

DIFFERENTIAL DIAGNOSIS

?? Ataxia with elevated liver

enzyme

Again Any suggestion??

DIFFERENTIAL DIAGNOSIS

• Autoimmune : ?? SLE

• Metabolic : ?? Mitochondrial disorders - Pyruvate carboxylase deficiency

• Neurodegenrative disease : ?? wilson’s disease

INVESTIGATIONS

• ANA negative

• Serology : normal except for past EBV infection

• Vit b12 : normal

• Iron study : normal

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

FURTHER EVALUATION

Ophthalmology :

?? Kayser–Fleischer ring

INVESTIGATIONS

• Serum copper : low

• Serum Ceruloplasmin : low

• Urine copper : high

• Zinc : high

INVESTIGATIONS

CT brainBilateral basal ganglia hypodensity Suggest of : metabolic disease or hypoxic change

MRI spine

IMPRESSION

13 year old boy with Wilson’s disease

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

MANAGEMENT

Started on :

• D. PINICILLAMINE 500mg BD PO• Vit B6 ( PYRODIXIN) 500 mg OD• PREDNISONE (by hematologist due to thrombocytopenia)• ZANTAC

FURTHER INVESTIGATIONS

Bone marrow aspiration :

• Varriable cellularity BM showing increased erythropoisis , adequate megakaryocyte . Granulopoiesis is reduced • Hemophagocyteosis• No evidence of involvment by lymphoma

• ?? Hemophagocytic lymphohistiocytosis

FURTHER INVESTIGATIONS

• Abdominal US : suggestive of liver cirrhosis No portal HTN

• Abdominal CT : splenomegally

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 involved2. Ataxia worsened3. More depressed4. Increase slurring 5. Refuse to walk

PROGRESS

• Last seen in the clinic , he had : 1. Resting tremor 2. Dystonia in arms3. Dysphasic

so started on L-DOPA , CARBI-DOPA AND ANTI CHOLENERGIC medications

DISCUSSION

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

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

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

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,

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

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

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

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

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

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

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

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

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.

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

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

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

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]

TREATMENT

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

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..

TREATMENT

PHYSICAL THERAPY

• Physiotherapy is beneficial for patients with the neurologic form of the disease.

SURGERY

• 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

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

Thank you!