Amyloid and the Nervous System

The nervous system may be effected in the following types of amyloidosis:
  • Hereditary ATTR (ATTRv) (FAP)
  • Other types of hereditary amyloidosis.
  • AL amyloidosis.

The normal nervous system?

  • The brain and the spinal cord make up the central nervous system (CNS)
  • The CNS interlinks with the peripheral nervous system, which through a network of nerve fibers sends messages around the body (hands and Feet etc.)

The peripheral nervous system has three main divisions: Autonomic, Sensory and Motor.

1) Autonomic Nerves:

  • Essential for body’s involuntary movements.
  • Connect to the internal organs
  • Control blood pressure and heart rate, movements in the gut. digestion and bladder function.
  • Carry information from the CNS to organs, glands and blood.

There are two types of autonomic nerves, the sympathetic and the parasympathetic.

  • The sympathetic nervous system prepares the body for intense physical activity and is often referred to as the fight-or-flight response.
  • The parasympathetic nervous system has almost the exact opposite effect and relaxes the body and inhibits or slows many high energy functions.

2) Sensory Nerves:

  • Connect to the skin. Pass information from the sense receptors in the body, back to the CNS.

3) Motor Nerves

  • Control the bodies voluntary movements.
  • Send signals from the CNS to the skeletal muscles telling them when to relax or contract.
The Nervous System

What happens when the amyloid protein deposits in the nervous system?

The amyloid proteins can deposit in the nerve fibers and around the nerves, gradually causing damage and interfering with the information sent between the brain and the organs through the autonomic nervous system.

This can result in what is known as peripheral and Autonomic Neuropathy.

N.B. Peripheral Neuropathy can also be caused by certain chemotherapy drugs but this usually resolves once the treatment has stopped.

Peripheral Neuropathy

There are three kinds of peripheral nerves.

  • sensory nerves, which connect to the skin.
  • motor nerves, which connect to the muscles.
  • autonomic nerves, which connect to the internal organs.

All three kinds of peripheral nerves may be involved or just one.

Symptoms

Symptoms will vary depending on where the nerve involvement is and to what degree, but may include:

  • Unpleasant sensations in the feet. Tingling, burning and numbness which can often be worse at night.
  • These feelings slowly extend up the legs and later into the hands and arms.
  • Sharp and stabbing pains
  • Cramps
  • Pain sometimes caused by the contact between the legs and the bed which ordinarily would not happen. Known as allodynia (a painful sensation following a normally non painful stimulation).
  • Numbness in fingers and lack of fine motor movement resulting in dropping thins are being unable to do up buttons.
  • Muscle weakness in the hands and legs
  • Difficulty with fine movements such as doing up buttons
  • Difficulty with balance.
  • Pain in the hands and fingers due to nerve compression known as Carpel tunnel syndrome.

Autonomic nerves control many body functions:

  • Body temperature
  • blood pressure
  • heart rate
  • digestion
  • urination
  • bowel movements
  • sexual function

If these nerves are damaged by the deposition of the amyloid protein the signal between the brain and the organs will be affected.

Symptoms – painful paresthesia (unusual sensations)

  • Bloating feeling full after a few mouthfuls of food
  • Difficulty in absorbing nutrients
  • Nausea
  • Vomiting, sometimes throwing up undigested food
  • Severe constipation/ Hard bowel movements alternating with diarrhoea/ loose bowel movements
  • Heartburn
  • Difficulty swallowing

  • Dizziness, blurred vision, light headedness especially on standing up (due to blood pressure drop. Known as orthostatic hypertension)
  • Fast heart rate
  • Disturbance of heart rhythm
  • Exercise intolerance because the heart cannot adjust to change in activity.

  • Difficulty urinating.
  • Pain when passing urine
  • Incontinence
  • Urinary tract infections due to difficulties in emptying the bladder.

  • Erectile dysfunction
  • Difficulty achieving and maintaining an erection
  • Ejaculation problems.

Heat intolerance and altered sweating.

Diagnosis

Peripheral neuropathy is a common condition experienced in a number of other diseases such as diabetes.

Peripheral neuropathy due to amyloidosis can only be definitively diagnosed through a tissue or organ biopsy.

  • A tissue biopsy involves taking a small piece of tissue from the body, often the fat pad on the tummy or the lip or a biopsy of the symptomatic organ
  • Staining this biopsy with Congo red, in the laboratory
  • If amyloid is present, the biopsy will appear red under normal light and green (apple-green birefringence) under special polarized light.

  • Further testing on the biopsy will then take place to identify the type of amyloidosis by identifying the protein composition of the amyloid fibrils.
  • It is imperative to identify the “type” as treatment is different for each type of amyloid because there is great variability in presentation this disease has in the past often not been diagnosed or misdiagnosed.

Many tests may be performed to identify organs and tissues affected by the amyloid protein and the degree of organ damage.

  • If there is neuropathy present a nerve biopsy may be done. A nerve biopsy involves taking a small piece of tissues from a nerve usually in the ankle or forearm after a general anesthetic.
  • Nerve conduction studies.

Neuropathy due to amyloidosis may be suspected if amyloidosis has already been diagnosed. A nerve biopsy may then not be needed.

Treatment

The goals of treatment for all types of amyloidosis are:

  • To stop or slow the production of the amyloid protein
  • To support and preserve the affected organs while treatment is being given
  • To maintain and improve quality of life.

Medical care for those with amyloid affecting their nervous system will be given by a multidisciplinary team (not necessarily under one roof and not always seen at the same time) A neurologist will be part of this team. Other Team members will vary according to the type of amyloidosis but there may be a haematologist, cardiologist and renal physician on the team.

Treatments to stop or slow the precursor protein forming the amyloid which subsequently may deposit in the nerves will vary depending on the type of amyloidosis.

In AL amyloidosis chemotherapy or a combination of chemotherapy, novel drugs and steroids and in some circumstances a stem cell transplant, are usually used to control or stop the precursor protein producing the amyloid depositing in the nerves. If the production of the amyloid is stopped there is a chance that the neuropathy may improve but this is often a slow process.

NB. Neuropathy can also be caused by some of the chemotherapy drugs used to treat AL amyloidosis. Patients receiving chemotherapy are constantly monitored. if the neuropathy is progressing, treatment doses may be lowered or changed. Neuropathy due to treatment toxicity usually subsides when that treatment is stopped.

Liver transplantation may be recommended in highly selected ATTRv patients to stop the production of the amyloid and deposition into the nerves.

In hereditary ATTRv Amyloidosis a number of treatments are being trialed and introduced to therapy overseas:

  1. To reduce the production of the TTR protein
  2. To target and silence specific messenger RNA blocking the production of the TTR.
  3. To stabilise the TTR

Go to sections on the different types of amyloid for more in depth information.

Supportive treatments are very important for symptoms caused by neuropathic involvement and pain.

They may include:

  • Anticonvulsants, (gabapentin and Pregablin)
  • Antidepressants
  • Analgesics
  • Treatments for symptoms caused by the nerve damage affecting the urinary system, the intestinal system, the heart and vascular system are extremely important for quality of life and must be addressed by the treating doctors in conversation with the patient
  • Physiotherapy, occupational therapy and palliative care may be very helpful in offering advice on symptom control, balance and many aspects of daily living as patients and families deal with the devastating consequences of advanced neuropathy
  • Advice on appropriate footwear to prevent painless ulcers at pressure points and to protect areas of the foot that lack sensation.
  • In orthostatic hypertension elastic stockings may be helpful
  • Drug treatment may be helpful, midodrine
  • Treatment for dehydration from diarrhea and vomiting
  • Drugs to combat erectile dysfunction
  • Drug therapy or a pacemaker to manage a disturbance of heart rhythm.

Things patients and families can do themselves.

It is important that all patients feel able to talk about their physical and emotional problems living with neuropathy caused by amyloidosis so that these issues can be addressed and they can be given help.

  • Learn as much as possible about your disease and symptoms.
  • Avoid tight clothing
  • Watch your balance, reposition furniture, rugs in the home that may cause a fall
  • Use walking aids if recommended
  • Use gloves when washing up
  • Wear shoes that fit well and do not cause ulcers
  • Always wear shoes outside
  • Take gentle exercise if possible. This helps to keep muscles toned and is good for well being
  • Eat a well-balanced diet
  • Avoid extreme temperatures and always keep hands warm
  • Check temperature of shower water
  • Flight socks can be helpful to some people
  • Having a fizzy drink helps some people with pain and cramping
  • Join a support group
  • Seek individual support and counseling.

Neuropathy often interferes with the patient’s mobility and balance and may leave them wheel chair bound.
Numbness in the hands stops all fine movements which can impair self-care such as dressing and toileting.
Many patients and their families living with advanced neuropathy will experience anxiety, depression and loneliness.

See section on Support

Neuropathy in Amyloidosis – Symptoms & Management

A booklet from the Amyloidosis Research Consortium (ARC) – 2022

Carmel Woodrow: Peripheral Neuropathy

Professor Mary M. Reilly on Neuropathy in ATTR