What is periventricular nodular heterotopia (PVNH)? Symptoms, causes and treatments

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Periventricular nodular heterotopia (PVNH) is a developmental brain disorder that develops when neurons, cells in the brain, do not go to the proper places in the brain during fetal development.

Because they do not migrate to where they’re supposed to be, they end up forming clumps around the ventricles in the middle of the brain.

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It is considered so incredibly rare that its prevalence across the globe is unknown. As many as 10 per cent of people who have PVNH may not present with any symptoms, and thus do not seek out medical attention, making it difficult to estimate the occurrence rates of the disorder.

Symptoms of PVNH

While a small number of people with PVNH don’t experience symptoms, 90 per cent will go on to develop seizures. The types of seizures that people typically have when they are diagnosed with PVNH include focal seizures and generalized tonic-clonic seizures.

Focal seizures, also known as partial seizures, can occur while a person is still conscious and aware or cause a loss of consciousness. In some cases, symptoms may include jerking, stiffness, visual and auditory disturbances, and changes in heart rate and blood pressure.

Generalized tonic-clonic seizures, otherwise known as grand mal seizures, present with a loss of consciousness and more violent muscle contractions, with the loss of consciousness sometimes lasting for minutes after the convulsions have stopped. People who have these seizures may also experience:

• Confusion
• Fatigue
• Severe headaches
• Loss of bowel or bladder function

These seizures often begin during a person’s teenage years, and the type that develops will depend on which area of the brain was affected during development.

In some cases, people with PVNH may also have a mild intellectual disability, but that is not always the case, and many with the disorder have a typical intelligence in line with others their age. When an intellectual disability is present, it can develop as difficulties with reading and spelling.

Some people with PVNH may also have movement difficulties, along with other rare symptoms and signs of the disorder, such as:

• Small head size
• Developmental delays
• Recurrent infections
• Blood vessel abnormalities
• Stomach problems
• Lung disease

It’s also possible that PVNH develops alongside other conditions, such as Ehlers-Danlos syndrome, Williams syndrome and De Morsier syndrome.

Causes of PVNH

PVNH, in the majority of cases, is driven by genetic mutations, specifically in the FLNA gene, which plays a role in the production of a protein known as filamin A. This specific protein is tasked with providing protein filaments to give structure to specific cells, but when the cells don’t have the proper instructions, the normal movement of neurons while the brain is developing in the womb is compromised.

Other gene mutations can also drive the development of PVNH, including the ARFGEF2 gene, which is tasked with providing the instructions on how to make a protein that plays a role in the movement of vesicles within cells. In rarer cases, a duplication of chromosome 5 can lead to extra genetic material during development and lead to PVNH.

Because it is driven by gene mutations, PVNH can be inherited. There are two ways in which this can happen. The first is through an X-linked dominant pattern, which means that only one copy of the mutated gene can lead to the development of the disorder when it is located on the X chromosome. This type of recessive pattern accounts for 50 per cent of all PVNH cases that are considered X-linked and are passed down from a mother.

The other is through an autosomal recessive pattern, which occurs when there are cell mutations in both copies of the gene. In this form, both parents carry a copy of the mutated gene, but neither shows symptoms. People with an autosomal recessive pattern of PVNH typically present with more severe symptoms, such as severe developmental delays and seizures that start in infancy.

How is PVNH diagnosed?

To determine if someone has PVNH, doctors will likely gather a health history and conduct a physical exam, as well as take down any symptoms that are occurring. An MRI of the brain is the first-line diagnostic test to determine whether the condition is present by looking for clumps of nerve cells around the ventricles. In some cases, other tests will be recommended when seizures are present, such as an EEG, which looks for abnormal brain waves that could be driving seizures.

How is PVNH treated?

The first-line therapy for PVNH is medication to stop the seizures from occurring. Anti-seizure medications, including Topiramate, Zonisamide, and Oxcarbazepine, are all options, along with others. Since there is no evidence to suggest that one works better than the others, the right medication for each person with PVNH may differ depending on their specific type of seizures, as well as tolerability and efficacy of the medication.

In the event that medications do not work for someone with PVNH, surgery may be recommended. During surgery, the area of the brain that’s causing the seizures to occur is removed. Surgical removal of the part of the brain that drives seizures can only be done after intensive monitoring to confirm where the seizures originate.

An emerging surgical technique, known as laser interstitial thermal therapy, is a less invasive procedure that may be performed on select patients and involves the removal of the area using laser heat to destroy the affected tissue.

Other potential therapy avenues can include:

• Dietary changes, such as the ketogenic diet or low glycemic index diet, have been used as a conjunctive therapy in different forms of epilepsy
• Neurostimulation, such as vagus nerve stimulation or deep brain stimulation, to regulate electrical activity signals in the brain

The type of therapy for each patient will depend on their response to medication, severity of seizures, and other personal factors such as lifestyle habits.

Outlook and prognosis

The outlook and prognosis for people with PVNH vary widely because no two patients are alike. While some may take a medication and experience a seizure-free life, others may not respond to therapies and have to undergo various therapies before something works. Intellectual disability can also develop in some patients with PVNH, which would require more medical approaches to maintain a good quality of life.

Living with PVNH involves a unique and patient-first approach to determine the best course of therapy based on its presentation.

August 7 is World PVNH Disorder Awareness Day. To learn more, visit PVNH Support & Awareness.