Neurologic Wilson Disease: A Challenge for Pediatrician

Dr. Abdullahel Amaan Resident (Phase A), Neonatology. Current Placement: Pediatric Neurology

Wilson Disease

o Wilson disease (WD) is an inherited (autosomal recessive) disorder of

copper metabolism characterized by excessive copper deposition in

the different part of body, primarily in the liver, brain and eyes.

Epidemiology: Occurs worldwide.

Incidence of one in 30,000-50,000 births(‘Nelson’, 20th)

Prevalence of around 30 per 10,00000 population(Ala A, et al.Lancet. 2007)

The age at onset of symptoms ranges from 5 to about 40 years (as early as

2-3Y of age, when mutation causing complete knock out of gene function, to

as late as 80Y with milder mutation) .

Copper Homeostasis

o Copper is the third most abundant trace element in humans (after

iron and zinc).

oThe recommended intake is 0.9 mg/day and 98% of the absorbed

copper is excreted via the liver into the bile and thereon lost in feces.

Why do we need Copper

o Copper serves as a cofactor for many important enzymes like

mitochondrial cytochrome c oxidase, copper–zinc superoxide dismutase

(SOD).(Bull & Cox, 1994).

o Though an essential metal, copper can be toxic, when excess.

Cu Homeostasis

• Copper is absorbed by enterocytes mainly in the duodenum

and proximal small intestine and transported in the portal

circulation,(by Cu-transporting ATPase ATP7A), in association

with albumin and histidine to the liver, where it is avidly

removed from the circulation.

Genetics in WD

• A defect (from mutation) in ATP7B transporter leads to impaired

incorporation of copper into apoceruloplasmin and subsequent low

ceruloplasmin levels and impaired efflux of copper into the bile

canaliculi. Gene for ATP 7B is located at 13q 14.1.

o Over years, Cu gradually accumulates, & ultimately, the liver can no

longer hold more Cu, and the unbound toxic metal spills into the

blood and other tissues.

Cu in Excess

• Unbound or ‘free copper’ can rapidly generate ROS(reactive oxygen

species), producing oxidative stress and destroying the cells.

Pathogenesis, when Cu is in excess ..

• Ultrastructural changes primarily involve the mitochondria, include:

1. increased density of the matrix material,

2. inclusions of lipid and granular material, and

3. increased intracristal space with dilation of the tips of the cristae.

Effect on brain, when Cu is in excess..

• Cavitation and cyst formation, Spongy degeneration,

neuronal loss, pigment and lipid-containing macrophages,

and gliosis- mostly in the corpus striatum, frontal cortex.

Clinical presentations• Subsequently various features of neurological, psychiatric, hepatic

and other organ involvement become evident.

Neuropsychiatric manifestations

Neurological manifestations

o They are the most frequent initial symptoms and seen in 40–60% of the

patients & are associated with midline symptoms of dysarthria, dysphagia,

and poor axial motor control. (Dastur, Manghani, &Wadia, 1968;Taly et al., 2007).

• Dysarthria is the most common neurological feature, resulting from dystonia

in tongue and facial muscles.

Neurological manifestations

• Dystonia also leads to low-volume speech with inadequate

tongue movement and imprecise articulation.

• In patients with severe neurological disability, mutism may

happen.

Neurological manifestations

• Another neurological features are facetious smile/pseudo-laughter,

open mouth with drooling.

• Wilson facies give patients a characteristic facial feature, so much so,

that they start to resemble each other (Aggarwal et al,2009).

Psychiatric manifestations

• Neuropsychiatric manifestations (e.g. Cognitive & behavioral problems,

emotional lability) are described in 20–70% of patients of WD.

Hepatic manifestations

Hepatic manifestations

• 40–50% patients initially present with hepatic manifestations(Scheinberg &

Sternlieb, 1984).

• Patients with initial neurological disability may have either a silent or overt

liver disease.

• The most common mode of hepatic presentation is CLD (Aggarwal et al., 2013).

Hepatic manifestations

• The most fearsome manifestation is fulminant hepatic failure which is

found in 5% of the patients (Catana & Medici, 2012).

In our patient, hepatosplenomegaly & grade II esophageal varice were found.

Ocular manifestation

• KF rings are copper deposits in the corneal Descemet’s membrane,

clinically evident by a greenish discoloration at the limbus.

• They first appear in the upper corneal limbus, followed by the lower

limbus, and then form a complete ring that expands centripetally.

• KF rings can be seen using a torchlight directed tangentially at the

cornea, and however, early rings require slit lamp examination.

Ocular manifestation

• Upto 95% of patients with neurologic symptoms and 44–62% of those

with liver involvement have KF rings. (Scheinberg & Sternlieb, 1984).

• Sunflower cataract are also found

with WD.

Our patient had predominant neurological manifestation & there was KF ring in his eyes.

Hematological manifestations

• Coombs-negative hemolytic anemia from copper toxicosis and unexplained

thrombocytopenia, leucopenia, or pancytopenia from hypersplenism alerts a

physician to the possibility of WD (Scheinberg & Sternlieb, 1984).

Diagnosis:

Diagnosis

• Diagnosis of WD in patients presenting with EPS or behavioral

problems is usually straightforward and aided by the presence of KF

rings, Wilson facies, abnormalities on brain scan, and clinical or

subclinical liver disease.

Investigations

Serum ceruloplasmin,

24-h U Cu excretion,

LFT ,

brain imaging, and

in selected cases, liver biopsy help establish the diagnosis of WD.

Ref:Roberts

and

Schilsk

y.HEPA

TOLO

GY, Vol. 4

7, No. 6

,

2008

Investigations

• Most patients with Wilson disease have decreased ceruloplasmin

levels (<20 mg/dl).

In this patient, S Ceruloplasmin level was low (04 mg/dl).

Investigations• 24H Urinary Cu excretion (usually <40 μg/day) is increased to >100 μg/day and

often up to 1,000 μg or more/day.

• In equivocal cases,(when U Cu excretion 40-100μg/day), Penicillamine challange

test is the diagnostic tool. During the 24 hr urine collection patients are given two

500 mg oral doses of d-penicillamine 12 hr apart; affected patients excrete >1,600

μg/24 hr.

In this patient, 24H U Cu level was 545μg. Thus we didnt go for Penicillamine Challange test.

Investigations

• Liver biopsy is gold standard for measuring the hepatic copper content

(N <10 μg/g dry weight) but is only required if:

1. clinical signs and investigations do not allow a final diagnosis or

2. if another liver disorder is suspected.

• In Wilson disease, hepatic copper content usually exceeds 250 μg/g dry

weight.

Investigations

• Neuroimaging:

MRI and CT scans reveal damage in the basal ganglia (and occasionally

in the pons, medulla, thalamus, cerebellum, and subcortical areas).

• Genetic analysis is the gold standard for diagnosis of WD but has

remained an impractical diagnostic tool as there are over 600 WD

mutations described and many new continue to be reported.

• Again, in 20% cases, no genetic mutation can be detected. While

identification of WD mutations confirms WD, inability to find mutations

does not conclusively exclude the disease. (Coffey et al., 2013).

Treatment

Treatment

• All symptomatic patients & all presymptomatic patients require

lifelong decoppering with careful clinical tracking.

• Decoppring ensures presymptomatic individuals to remain symptom

free and patients with even serious neurological diability improve &

return to nomal life, resuming to school.

Ref:Aggarwal & Bhatt, Int Review of Neurobiology, vol-110, 2012

Decoppering

• The major attempt is life long restriction to dietary copper intake to

<1 mg/day & Cu chelation.

Foods such as:

chocolate, nuts,

brown wheat, brown rice, corn flecks, dried rice,

legumes (e.g. beans and lentils), dark green leafy vegetables,

shell fish, beef, mutton, liver, brain, kidney,

mushroom, potato, beet root, carrot, fruits (coconuts, papaya),

noodles , macaroni, biscuit, fast food, ice cream, coffee,

coca cola, Pepsi, 7Up should be avoided.

Dietary restriction

• Once symptoms regress (indicating adequate decoppering), these

dietary restrictions can be relaxed (Pfeiffer, 2011).

Treatment.. Chelation

• The initial treatment in symptomatic patients is the administration of

copper-chelating agents, which leads to rapid excretion of excess

deposited copper.

Ref:

• So, authors recommends TM + Zinc – as the first choice for neurologic

& psychiatric manifestations in WD.

• If TM is not available, then Zinc alone as the 2nd choice, or Zinc +

Trientine as the next choice of drug.

‘ Some researchers have successfully used zinc in the initial treatment of neurologic Wilson’s Disease’.15,43,44

• The 1st drug of choice in neuropsychiatric WD is Ammonium

tetrathiomolybdate (TM), because of its rapid control of free copper,

and low toxicity, causing < 5% neurological deterioration (G.J. Brewer,

Journal of Hepatology 42 (2005))

• TM forms a tripartite complex with protein & copper. If given with

meals, TM complexes with food and renders that complex

unabsorbable.

MOA of TM

• If given in empty stomach, TM is absorbed into the blood stream and forms

the three way complex with freely available copper & albumin and prevents

its cellular uptake.

• The initial dose is 120 mg/day (20 mg between meals tid and 20 mg with

meals tid).

We could not start Ammonium tetrathiomolybdate as it is not available in

Bangladesh.

Chelation ...

• The second drug of choice here is triethylene tetramine dihydrochloride (TETA,

trientine) at a dose of 0.5-2.0 g/day for adults and 20 mg/kg/day for children. It

mobilizes Cu from hepatic & other stores.

• Here neurological deterioration occurs in 20% cases(G.J. Brewer, J of Hepatol 42 (2005))

We could not start trientine, as it is also not available in Bangladesh.

Ref:

.. Chelator, zinc alone?

• Regarding Zinc alone as a chelator in a patient with Wilson Disease,

some other authors give different opinion.

Zinc, MOA ..

• Zinc inhibits intestinal absorption of Cu, by inducing metallothionein.

• Oral zinc is absorbed by the enterocytes and bound to the induced

metallothionein, trapped within the enterocytes, preventing its

absorption into the portal circulation.

• The bound Zn and Cu are then excreted in feces when the cells are

sloughed.

.. Chelator, zinc alone?

.. Chelator, zinc alone!!

• According to them, “Zinc does not chelate the stored copper in the body.

• The negative cooper balance induced by zinc-mediated impairment of

copper absorption is too small for zinc to be an effective as monotherapy

in symptomatic patients.

• Even neurological and hepatic deterioration, with fatal outcome, had

been reported following use of zinc in some symptomatic individuals”.

Penicillamine as a chelator..

• When TM & Trientine are not available, in that cases, some authors

advise for Penicillamine as an initial chelator chelator.

(Aggarwal & Bhatt. Update on Wilson Disease,Int R of Neurobiol, 2012)

Penicillamine as a chelator..

• As 10-50% of patients initially treated with penicillamine shows

neurologic worsening.

Penicillamine toxicity ..

• Hypersensitivity reactions occur 10–20% patients, within the first few

weeks to months of commencing penicillamine. However, the

incidence is much lower, if penicillamine is initiated gradually.

• The reactions include fever, rash, and lymphadenopathy, and usually

resolve with short-course steroids.

Penicillamine toxicity ..

• Late reactions are observed after years of penicillamine therapy.

These include drug-induced SLE, NS, Goodpasture’s syndrome,

hemolytic anemia, and thrombocytopenia.

• Long-term use of penicillamine may also lead to easy bruising or

recurrent subcutaneous bleeding due to penicillamine-induced

inhibition of collagen and elastin cross-linking.

Chelation we’ve started..

• As we had no other options, thus we had started Penicilamine by

adopting a ‘start low, go slow’ protocol to reduce the potential

toxicities.

• D-penicillamine is given in a dose of 20 mg/kg/day for pediatric

patients, in 2 divided doses,⅟2 H before or 2H after meal, for adults

and

Zinc..

• Zinc is used as monotherapy in presymptomatic individuals, adjuvant

therapy, maintenance therapy, in patients who have been decoppered with penicillamine or trientine (Sinha & Taly, 2008).

• Zinc is administered as acetate, sulfate, or gluconate salts. Zinc acetate is

better tolerated than zinc sulfate, is given 25 mg 3 times/day in children

older than 5years.

• Zinc has not been associated with neurological worsening (Roberts & Schilsky,

2008).

Hepatic transplantation ..

• Liver transplantation should be considered for patients with:

1. fulminant liver disease,

2. decompensated cirrhosis, or

3. progressive neurologic disease (which is controversial).

Liver transplantation is curative, with a survival rate of approximately 85-90%.

Prognosis

• The prognosis for patients receiving prompt and continuous chelation is variable and

depends on: time of initiation of chelation and individual response to them.

Follow up

• After initiating treatment, patients are assessed at weekly intervals for

3-4 weeks to track neurological worsening, drug-related adverse

effects, and compliance.

• Generally, no clinical benefit is seen in the first few months of

initiation of therapy.

GAS for WD

• WD progress and treatment response measured by using a multisystemic, validated

WD-specific scale, the Global Assessment Scale for WD (GAS for WD). GAS for WD is a

two-tier scale that can be administered by the patient’s bedside.

• Tier 1 measures WD-related disability across four domains: liver (L), cognition and

behavior (C), motor (M), and osseomuscular (O). Each domain is scored on an

ascending six-point scale (0–5).

• Tier 2 assesses WD-related neurological dysfunction across 14 items. Each item is

graded on an ascending five-point scale (0–4) and summed to obtain the total tier 2

score (0–56) (Aggarwal, 2009).

Follow up Schedule ..

• When there is no immediate complication & compliance is ensured, then

the patient is followed up at fortnightly for 2months monthly for

3months 3monthly for 2 times 6monthly for 2years subsequently

yearly for life long.

Ref: G.J. Brewer, F.K. Askari / Journal of Hepatology 42 (2005)

• S free Cu = S Cu – 3 x S. Ceruloplasmin.

• Normal free Cu value is 10-15 mg/dl. In untreated WD, it is as high as 50mg/dl.

• Its level < 25 mg/dl indicates a good chelation

Usually:

the Wilsonian characteristic facies disappears within 5-6 months,

KF ring within 8-12 months &

neurological features within 1-3 years of therapy (Aggarwal , 2009)

Natural History

• WD is a progressive disease, and fatal if untreated.

• A dreaded complication of WD is fulminant hepatic failure having

100% mortality rate.

• Untreated patients can die of hepatic, neurologic, renal, or

hematologic complications.

Family screening

• Family members of patients with WD require screening:

1. 24 H U Cu level,

2. Detection of KF ring by slit lamp,

3. determination of the S Ceruloplasmin level.

We had advised for such screening for his other siblings.

THANK YOU

Extra documents

• Other causes of KF rings are cholestasis, primary biliary cirrhosis and "cryptogenic" cirrhosis,

Clinical Features

• Unusual manifestations include:

1. arthritis,

2. pancreatitis,

3. nephrolithiasis,

4. cardiomyopathy, and

5. endocrinopathies (hypoparathyroidism).

In our case, there was no such features.

Diagnosis• In a study cohort, patients with WD consulted on an average of six doctors

including specialists (range 2–11) before WD was diagnosed(Aggarwal et al.,

2009). Thus maintaining a high degree of suspicion is the key to early

diagnosis.

• Unexplained jaundice, neurological symptoms, osseomuscular problems,

alterations in liver function tests, in a child should promptly considered for

WD.