About DIPG

Most people have never heard of this disease, because it is so rare. The name Diffuse Intrinsic Pontine Glioma basically tells you most of what it is. A glioma is a tumour of the brain originating from the cells that support the neurons, or thinking cells. The pons is an area of the brainstem which controls many vital functions of the human body as will be described.  A diffuse intrinsic tumour is one which grows inside the matter itself and not well localised to that area. So to sum it up, DIPG is a brain tumour found in one of the trickiest places of the brain, growing in a manner inconducive to surgery and affects to the child's breathing, heart function, sleep, swallowing, bladder control, hearing, equilibrium, taste, eye movement, facial expression and sensation and posture.In the US, brainstem gliomas have been reported to make up 2.4% of all intracranial tumors in adults and 9.4% of intracranial tumors in children. Brainstem gliomas account for approximately 10-20% of all childhood brain tumors. The incidence in adults is lower than that in children younger than 16 years. A tendency for brainstem gliomas to follow a more indolent course in adults than in children has been noted; in adults, these tumors are more likely to be low grade and remain localized.  

About the Pons

The central nervous system is composed of the brain lodged in the skull and the spinal cord in the spine. The brainstem is found at the back and below the brain, connecting the brain to the spinal cord. It is divided into 3 parts: the medulla, which is closest to the spinal cord, the midbrain adjacent to the brain and in between them, is the pons. The reason its called this is because it actually looks like a bridge!

Inside the pons so much stuff goes on. Simply stated, it acts as a relay station between the cortex where all the instructions are generated for the body to work, and the cerebellum where these instructions are modulated into smooth, sequential actions before it reaches the concerned part of the body. It also plays a role in dreaming. Being the site of origin of certain cranial nerves, called cranial nerve nuclei, any lesion of the pons can manifest in many forms:

CN V--The  Trigeminal nerve carries sensation from the face to the brain. Changes in sensation from the                    face may occur. As the mandibular nerve is a branch of the trigeminal, chewing is also affected.

CNVI-- The abducens nerve innervates the lateral rectus muscle, the muscle causing the eye to look                           outwards.  Hence converging squint on the side of the lesion is a common presentation

CNVII- Facial nerve-- changes in facial expression,  taste, tears and salivation.

CNVIII- Vestibulocochlear nerve--- hearing and equilibrium is affected, leading to instability on standing or walking and complaints of dizziness

The pons also deals with sleep, swallowing and bladder control, but more importantly, it has the pneumotaxic centre which controls changing from inspiration to expiration. Hence, lesions of the pons can present with breathless and difficulty breathing.

BRAINSTEM GLIOMAS

Brain tumors are not a single kind of tumor, but include several different tumor types.

As a group, these are the most common solid tumors in children less than 15 years of age, and account for approximately 20% of all cancers diagnosed in this population. Other important facts about tumors that occur in the brain and spinal cord include the following:

Tumors can arise at any age in any area of the brain and spinal cord, although some specific types of pediatric tumors tend to occur more often in certain parts of the brain.

Brain tumors are categorized by the type of malignant cell and by the area of the brain in which they develop.

The terms "benign" and "malignant" as usually applied to tumors are not as useful when describing CNS tumors. Because the brain and skull are located inside a fixed amount of space, even "benign" or slow-growing tumors can cause serious problems.

Most brain tumors tend NOT to “metastasize” or spread to distant areas to other parts of the body outside the brain and/or spinal cord (CNS). They do, however, tend to recur locally, or spread to other areas of the CNS.

These tumors have a predilection to originate from the left side. Most are located in the pons; however, medulla and midbrain may be involved as well. Brainstem gliomas are highly aggressive brain tumors. Anatomic location determines the presentation. With pontine lesions, cranial nerve or long tract signs are observed commonly.

Based on the histology (observation of the cells under the microscope following biopsy), the WHO has divided the brainstem gliomas  into 4 Grades based on nuclear atypia, vascular proliferation, mitoses and necrosis (grade 4). In simpler terms, the cells look abnormal, more blood vessels are proliferating, multiply too fast, die quickly

1- Benign: Juvenile pilocytic astrocytoma

2- Fibrillary: Diffuse astrocytoma

3- Anaplastic astrocytoma- has lack of structure in the cell

4- Glioblastoma multiforme- most serious kind

This classification is rarely used because brainstem gliomas are rarely biopsied.

Although biopsy or resection is not typically performed on brainstem gliomas, vascular endothelial growth factor (VEGF) receptors are an important pathway in the invasion and growth of supratentorial glioblastomas by promoting the growth of new blood vessels. Epidermal growth factor receptors (EGFR) are present in 25% of glioblastomas and are important in the growth of these tumours as well. The presence of these receptors may aid in the response to various targeted therapies.

Symptoms and signs

• Double vision, abnormal eye movements or squinting
• Weakness in arms or legs
• Unsteady gait; problems with walking and coordination
• Difficulty in swallowing
• Dysarthria- slurred speech
• Headache
• Drowsiness
• Nausea, and vomiting.
•  Rarely, behavioral changes or seizures may be seen in children. 
• Older children may have deterioration of handwriting and speech.
• Pontine lesions usually present with any or all of the above signs and symptoms, depending on location and extension. 
• Midbrain and lower brainstem/upper spinal cord signs and symptoms may be seen with extension of the neoplasm to involve these structures.
• Tectal lesions typically present with headache, nausea, and vomiting.
• Hydrocephalus is a common presentation, especially for tumors in periaqueductal or fourth ventricle outflow locations, because these regions have less tolerance of growth and higher risk of obstructive hydrocephalus.
• Cervicomedullary lesions usually present with dysphagia, unsteadiness, nasal speech, vomiting, and weakness.

Morbidity and mortality

Morbidity is due to the location of the space-occupying lesion and compression of surrounding structures; because these structures regulate basic body functions of blood pressure, respiration, and swallowing as well as motor and sensory functions, compression can produce substantial neurological disability.

Sudden death can result from increased intracranial pressure and subsequent cerebral herniation. This may be a consequence either of edema induced by the tumor or of hemorrhage into the neopla

Cause for DIPG

So far,  nobody knows. As usual, there are many theories out there being tested, but the fact remains that we are still in the dark on this disease. No familial tendency is predominant overall, no genetic or molecular marker hace beein recognised. There is some increased (14%) in patients with pre-existing Neurofibromatosis and also in those who recieved irradiation for tinea capitis, but the evidence is not concrete.

What Investigations are generally done?

• Lab studies of blood chemistry and related body fluids are not helpful as a rule, 
• A lumbar pucture is needed to obtain a sample of cerebrospinal fluid (the clear fluid which bathes the brain and spinal cord) CSF examination is often important for differential diagnosis. The protein content of CSF may be elevated. Because of the risk of increased intracranial pressure due to obstructive hydrocephalus, caution in clinical and imaging assessment prior to lumbar puncture is stressed.
• Tissue confirmation is frequently not feasible with infiltrating, expansile tumors, i.e tumours growing into the matter of the brainstem and which are not well localised. Unless an exophytic component exists, and even then, biopsy cannot always be obtained.

Imaging

MRI is the diagnostic test of choice, but CT scan can also be done

Sample MRI. Source: google images

Procedures

Patients with hydrocephalus, a condition where CSF has built up in the ventricles of the brain because of block in its drainage or increased CSF production, may require ventriculostomy or ventriculoperitoneal shunting for symptomatic relief.

Patients with difficulties in swallowing and diminished gag reflex may need feeding by gastrostomy such as the percutaneous esophagogastrostomy (PEG).

Those patients who have had multiple upper respiratory infections, pneumonia, or altered voice may need postoperative ventilatory assistance

Management

Treatment of brainstem gliomas has been frustrating; at this point, new therapies have yielded little benefit over conventional treatment with radiotherapy alone.

Adjuvant chemotherapy is not used in children because efficacy has not been proven. Data have suggested that preradiation chemotherapy may improve survival in pediatric diffuse intrinsic brainstem gliomas. Its efficacy in adults is similarly unproven, and at present, postradiotherapy adjuvant chemotherapy cannot be recommended. The effectiveness of combined radiotherapy and chemotherapy (typically temozolomide) has not been thoroughly evaluated. The effectiveness of chemotherapy at relapse is uncertain, but it may benefit some patients.

Chemotherapy options, when considered for use in brainstem gliomas, may include conventional agents such as temozolomide and carboplatin/vincristine. Antiangiogenesis agents have been used with success in supratentorial glioblastomas. These include thalidomide and bevacizumab. Bevacizumab is a VEGF receptor inhibitor, approved as monotherapy for recurrent glioblastoma multiforme in May 2009. Drugs (such as erlotinib) targeted against EGFR, when present, have been modestly effective in supratentorial glioblastoma. If chemotherapy is desired adjuvantly or concurrently with radiotherapy, particularly in the pediatric population, the physician should consider entrance into a clinical trial.

Focal radiotherapy is the cornerstone of treatment of brainstem gliomas and can improve or stabilize the patient's condition. The conventional dose of radiotherapy ranges from 54-60 Gy, with doses up to 72 Gy given with hyperfractionation. At present, no benefit has been demonstrated with doses greater than 72 Gy; however, this therapy has not demonstrated efficacy in children.

Response to radiotherapy, in addition to the dose of radiation, depends on several variables such as tumor location, histologic type, and response to early treatment. Patients who underwent radiation therapy for exophytic tumors have been reported to have better survival rates than those treated for tumors without an exophytic component.

Radiotherapy should be administered to any patient with significant and progressive neurologic symptoms. Some adult patients with a tectal or cervicomedullary lesion, or with mild symptoms of long duration, may be candidates for observation alone; radiotherapy can be reserved for patients with clear evidence of tumor progression.

Surgery

Typically, biopsy and/or surgery are not required for diagnosis or treatment of diffuse intrinsic pontine or tectal gliomas and cannot be recommended routinely; diagnosis can be made by MRI alone.

Who to see?

Neuro-oncologist: The neuro-oncologist should be the primary physician supervising the care of these patients. If a neuro-oncologist is not available, a medical oncologist with expertise in treating brain tumors may be consulted for guidance. Otherwise, the patient should be referred to a reputable institution that specializes in the care of patients with CNS neoplasms.

Neurosurgeon: The treating neurosurgeon should have significant experience in resection of CNS neoplasms.

Radiation oncologist

Neuropathologist

Neuroradiologist

Neuropsychologist for pretreatment and posttreatment evaluations, when clinically indicated

Rehabilitation medicine specialist

Source of information:

 Medscape

http://emedicine.medscape.com/article/263311-overview#aw2aab6b6