Neurofibromatosis (Type 1 and Type 2)
Neurofibromatosis has two different forms, type 1 (NF-1) and type 2 (NF-2). One abnormal gene causes each form.
Neurofibromatosis type- 1 is a condition characterized by changes in skin coloring (pigmentation) and the growth of tumors along nerves in the skin, brain, and other parts of the body. The signs and symptoms of this condition vary widely among affected people.
Beginning in early childhood, almost all people with neurofibromatosis type-1 have multiple “café-au-lait” spots, which are flat patches on the skin that are darker than the surrounding area. These spots increase in size and number as the individual grows older. Freckles in the underarms and groin typically develop later in childhood.
Most adults with neurofibromatosis type-1 develop neurofibromas, which are noncancerous (benign) tumors that are usually located on or just under the skin. These tumors may also occur in nerves near the spinal cord or along nerves elsewhere in the body. Some people with neurofibromatosis type 1 develop cancerous tumors that grow along nerves. These tumors, which usually develop in adolescence or adulthood, are called malignant peripheral nerve sheath tumors. People with neurofibromatosis type-1 also have an increased risk of developing other cancers, including brain tumors and cancer of blood-forming tissue (leukemia).
During childhood, benign growths called Lisch nodules often appear in the colored part of the eye (the iris). Lisch nodules do not interfere with vision. Some affected individuals also develop tumors that grow along the nerve leading from the eye to the brain (the optic nerve). These tumors, which are called optic gliomas, may lead to reduced vision or total vision loss. In some cases, optic gliomas have no effect on vision.
Additional signs and symptoms of neurofibromatosis type-1 include high blood pressure (hypertension), short stature, an unusually large head (macrocephaly), and skeletal abnormalities such as an abnormal curvature of the spine (scoliosis). Although most people with neurofibromatosis type 1 have normal intelligence, learning disabilities and attention deficit hyperactivity disorder (ADHD) occur frequently in affected individuals.
How common is neurofibromatosis type 1?
Neurofibromatosis type 1 occurs in 1 in 3,000 to 4,000 people worldwide.
What genes are related to neurofibromatosis type 1?
Mutations in the NF-1 gene cause neurofibromatosis type 1.
The NF-1 gene provides instructions for making a protein called neurofibromin. This protein is produced in many cells, including nerve cells and specialized cells surrounding nerves (oligodendrocytes and Schwann cells). Neurofibromin acts as a tumor suppressor, which means that it keeps cells from growing and dividing too rapidly or in an uncontrolled way. Mutations in the NF-1 gene lead to the production of a nonfunctional version of neurofibromin that cannot regulate cell growth and division. As a result, tumors such as neurofibromas can form along nerves throughout the body. It is unclear how mutations in the NF-1gene lead to the other features of neurofibromatosis type 1, such as “café-au-lait” spots and learning disabilities.
Symptoms of NF-1
NF-1 is more common and is characterized by multiple (more than 5) tan patches on the skin (caf-au-lait spots), freckles in the groin or armpit, nodules within the iris of the eyes, skin neurofibromas (small, rubbery skin lesions), bone defects, and visual disorders.
Children with NF-1 are susceptible to neurologic complications including masses in the brain and spinal cord.
How do people inherit neurofibromatosis type 1?
Neurofibromatosis type 1 is considered to have an autosomal dominant pattern of inheritance. People with this condition are born with one mutated copy of the NF-1 gene in each cell. In about half of cases, the altered gene is inherited from an affected parent. The remaining cases result from new mutations in the NF-1 gene and occur in people with no history of the disorder in their family.
Unlike most other autosomal dominant conditions, in which one altered copy of a gene in each cell is sufficient to cause the disorder, two copies of the NF-1 gene must be altered to trigger tumor formation in neurofibromatosis type 1. A mutation in the second copy of the NF1 gene occurs during a person’s lifetime in specialized cells surrounding nerves. Almost everyone who is born with one NF-1 mutation acquires a second mutation in many cells and develops the tumors characteristic of neurofibromatosis type 1.
Neurofibromatosis type 1 (NF-1)-formerly known as von Recklinghausen disease after the researcher (Friedrich Daniel von Recklinghausen) who first documented the disorder, is a human genetic disorder. It is possibly the most common inherited disorder caused by a single gene. NF-1 is not to be confused with Proteus Syndrome (the syndrome which may have affected The Elephant Man), but rather is a separate disorder. In diagnosis it may also be confused with Legius syndrome.
There is no cure for the disorder itself. Instead, people with neurofibromatosis are followed by a team of specialists to manage symptoms or complications.
For many NF-1 patients, a primary concern is the disfigurement caused by cutaneous/dermal neurofibromas, pigmented lesions, and the occasional limb abnormalities.
However, there are many more severe complications caused by NF-1, but some of them are quite rare.
The treatment of neurofibromatosis is associated with treating of the signs and symptoms. There is no specific treatment for NF-1, and management includes genetic counseling and early detection of treatable conditions or complications. The asymptomatic patient should be re-examined yearly. Symptomatic patients may benefit from surgery treatment of tumors.
A list of conditions and complications associated with NF-1, and, where available, age range of onset and progressive development, occurrence percentage of NF-1 population, method of earliest diagnosis, and treatments and related medical specialties. The progression of the condition is roughly as follows:
1. Congenital musculoskeletal disorders may or may not be present
2. Cutaneous conditions may be observed in early infancy
3. Small tumors may arise in the retina which can eventually lead to blindness
4. Learning disabilities may arise in preschool children
5. Neurofibromas may occur and cause many dependent neurological conditions and cutaneous and skeletal disfigurement
6. Depression and social anxiety may occur as a result of disabilities caused by the condition
7. Neurofibromas may transition into cancer which can be fatal
A neurofibroma is a lesion of the peripheral nervous system. Its cellular lineage is uncertain, and may derive from Schwann cells, other perineural cell lines, or fibroblasts. Neurofibromas may arise sporadically, or in association with NF-1. A neurofibroma may arise at any point along a peripheral nerve. A number of drugs have been studied to treat this condition.
Neurofibroma conditions are progressive and include:
Plexiform neurofibroma: Often congenital. Lesions are composed of sheets of neurofibromatous tissue that may infiltrate and encase major nerves, blood vessels, and other vital structures. These lesions are difficult and sometimes impossible to routinely resect without causing any significant damage to surrounding nerves and tissue.
Solitary neurofibroma, affecting 8–12% of patients with NF-1. This occur in a deep nerve trunk. Diagnosis by cross-sectional imaging (e.g., computed tomography or magnetic resonance) as a fusiform enlargement of a nerve.
Schwannomas, peripheral nerve-sheath tumors which are seen with increased frequency in NF-1. The major distinction between a schwannoma and a solitary neurofibroma is that a schwannoma can be resected while sparing the underlying nerve, whereas resection of a neurofibroma requires the sacrifice of the underlying nerve.
Nerve root neurofibroma.
Bones, especially the ribs, can develop chronic erosions (pits) from the constant pressure of adjacent neurofibroma or Schwannoma. Similarly, the neural foramen of the spine can be widened due to the presence of a nerve root neurofibroma or schwannoma. Surgery may be needed when NF-1 related tumors compress organs or other structures.
Nerve sheath tumor
Peripheral nerve sheath tumor.
Chronic pain, numbness, and/or paralysis due to peripheral nerve sheath tumor.
Renal artery anomalies or pheochromocytoma and associated chronic hypertension
Central nervous system disease
Occurrence: Epileptic seizures haven been reported in up to 7% of NF-1 patients.
Diagnosis: Electroencephalograph, magnetic resonance imaging, computed tomographic scan, single-photon emission CT and positron emission tomographic scan.
Etiology: Due to cerebral tumors, cortical malformation, mesial temporal sclerosis.
Therapy: Drug therapy (57% amenable) where not resistant (29%).
Intracranially, NF-1 patients have a predisposition to develop glial tumors of the central nervous system, primarily:
Optic nerve gliomas and associated blindness.
Focally degenerative myelin
Another CNS manifestation of NF-1 is the so-called “unidentified bright object” or UBO, which is a lesion which has increased signal on a T2 weighted sequence of a magnetic resonance imaging examination of the brain. These UBOs are typically found in the Cerebral peduncle, pons, midbrain, globus pallidus, thalamus, and optic radiations. Their exact identity remains a bit of a mystery since they disappear over time (usually by age 16), and they are not typically biopsied or resected. They may represent a focally degenerative bit of myelin.
Within the CNS, NF-1 manifests as a weakness of the dura, which is the tough covering of the brain and spine. Weakness of the dura leads to focal enlargement terms dural ectasia due to chronic exposure to the pressures of CSF pulsation.
Acetazolamide has shown promise as a treatment for this condition.
Children with NF-1 can experience social problems, attention problems, social anxiety, depression, withdrawal, thought problems, somatic complaints, and aggressive behavior. Treatments include psychotherapy, antidepressants and cognitive behavioral therapy.
Cancer – MRI image showing malignant peripheral nerve sheath tumor in the left tibia in neurofibromatosis type-1.
Cancer can arise in the form of malignant peripheral nerve sheath tumor resulting from malignant degeneration of a plexiform neurofibroma.
Frequency.: A plexiform neurofibroma has a lifetime risk of 8–12% of transformation into a malignant tumor.
Mortality.: Malignant nerve sheath tumor was the main cause of death (60%) in a study of 1895 patients with NF-1 from France in the time period 1980-2006 indicated excess mortality in NF-1 patients compared to the general populaion. The cause of death was available for 58 (86.6 %) patients. The study found excess mortality occurred among patients aged 10 to 40 years. Significant excess mortality was found in both males and females.
Neurofibromatosis type 2 (NF-2)
What is NF-2?
This rare disorder affects about 1 in 25,000 people. Approximately fifty percent of affected people inherit the disorder; in others the disorder is caused by a spontaneous genetic mutation of unknown cause. The hallmark finding in NF-2 is the presence of slow-growing tumors on the eighth cranial nerves. These nerves have two branches: the acoustic branch helps people hear by transmitting sound sensations to the brain; and the vestibular branch helps people maintain their balance. The characteristic tumors of NF-2 are vestibular schwannomas because of their location and the types of cells involved. As these tumors grow, they may press against and damage nearby structures such as other cranial nerves and the brain stem, the latter which can cause serious disability. Schwannomas in NF-2 may occur along any nerve in the body, including the spinal nerves, other cranial nerves, and peripheral nerves in the body. These tumors may be seen as bumps under the skin (when the nerves involved are just under the skin surface) or can also be seen on the skin surface as small (less than 1 inch), dark, rough areas of hairy skin. In children, tumors may be smoother, less pigmented, and less hairy.
Although individuals with NF-2 may have schwannomas that resemble small, flesh-colored skin flaps, they rarely have the “café-au-lait” spots that are seen in NF-1.
Individuals with NF-2 are at risk for developing other types of nervous system tumors, such as ependymomas and gliomas (two tumor types that grow in the spinal cord) and meningiomas (tumors that grow along the protective layers surrounding the brain and spinal cord). Affected individuals may develop cataracts at an earlier age or changes in the retina that may affect vision. Individuals with NF-2 may also develop problems with nerve function independent of tumors, usually symmetric numbness and weakness in the extremities, due to the development of a peripheral neuropathy.
Neurofibromatosis type -2 is a disorder characterized by the growth of noncancerous tumors in the nervous system. The most common tumors associated with neurofibromatosis type 2 are vestibular schwannomas or acoustic neuromas. These growths develop along the nerve that carries information from the inner ear to the brain (the auditory nerve). Tumors that occur on nerves in other areas of the brain or spinal cord are commonly seen with this condition.
Symptoms and Signs
To diagnose NF-2, a doctor looks for the following:
- bilateral vestibular schwannomas; or
- a family history of NF-2 (parent, sibling, or child) plus a unilateral vestibular schwannoma before age 30; or
- any two of the following:
- juvenile posterior subcapsular opacity (cataract) or juvenile cortical cataract
When do symptoms appear?
Signs of NF-2 may be present in childhood but are so subtle that they can be overlooked, especially in children who do not have a family history of the disorder. Typically, symptoms of NF-2 are noticed between (18 and 22) years of age. The most frequent first symptom is hearing loss or ringing in the ears (tinnitus). Less often, the first visit to a doctor will be because of disturbances in balance, visual impairment (such as vision loss from cataracts), weakness in an arm or leg, seizures, or skin tumors.
What is the prognosis for someone with NF-2?
Because NF-2 is so rare, few studies have been done to look at the natural progression of the disorder. The course of NF-2 varies greatly among individuals, although inherited NF-2 appears to run a similar course among affected family members. Generally, vestibular schwannomas grow slowly, and balance and hearing deteriorate over a period of years. A recent study suggests that an earlier age of onset and the presence of meningiomas are associated with greater mortality risk.
How is NF-2 treated?
NF-2 is best managed at a specialty clinic with an initial screening and annual follow-up evaluations (more frequent if the disease is severe). Improved diagnostic technologies, such as magnetic resonance imaging (MRI), can reveal tumors of the vestibular nerve as small as a few millimeters in diameter. Vestibular schwannomas grow slowly, but they can grow large enough to engulf one of the eighth cranial nerves and cause brain stem compression and damage to surrounding cranial nerves. Surgical options depend on tumor size and the extent of hearing loss. There is no general agreement among doctors about when surgery should be performed or which surgical option is best. Individuals considering surgery should carefully weigh the risks and benefits of all options to determine which treatment is right for them. Surgery to remove the entire tumor while it’s still small might help preserve hearing. If hearing is lost during this surgery, but the auditory nerve is maintained, the surgical placement of a cochlear implant (a device placed in the inner ear, or cochlea, that processes electronic signals from sound waves to the auditory nerve) may be an option to improve hearing. As tumors grow larger, it becomes harder to surgically preserve hearing and the auditory nerve. The development of the penetrating auditory brain stem implant (a device that stimulates the hearing portions of the brain) can restore some hearing in individuals who have completely lost hearing and do not have an auditory nerve present. Surgery for other tumors associated with NF-2 is aimed at controlling or relieving symptoms. Surgery also can correct cataracts and retinal abnormalities.
What is schwannomatosis?
Schwannomatosis is a rare form of neurofibromatosis that is genetically and clinically distinct from NF1 and NF2. Inherited forms of the disorder account for only fifteen percent of all cases. Researchers have identified a mutation of the SMARCB1/INI1 gene that is associated with the familial form of the disease but do not fully understand what causes the intense pain that characterizes this disorder.
What are the signs and symptoms of schwannomatosis?
The distinguishing feature of schwannomatosis is the development of multiple schwannomas everywhere in the body except on the vestibular nerve. The dominant symptom is pain, which develops as a schwannoma enlarges, compresses nerves, or presses on adjacent tissue. Some people experience additional neurological symptoms, such as numbness, tingling, or weakness in the fingers and toes. Individuals with schwannomatosis do not have neurofibromas.
About one-third of individuals with schwannomatosis have tumors limited to a single part of the body, such as an arm, leg, or a segment of the spine. Some people develop many schwannomas, while others develop only a few.
What is the prognosis for someone with schwannomatosis?
Anyone with schwannomatosis experiences some degree of pain, but the intensity varies. A small number of people have such mild pain that they are never diagnosed with the disorder. Most people have significant pain, which can be managed with medications or surgery. In some extreme cases, pain will be so severe and disabling it will keep people from working or leaving the house.
How is schwannomatosis treated?
There is no currently accepted medical treatment or drug for schwannomatosis, but surgical management is often effective. Pain usually subsides when tumors are removed completely, although it may recur should new tumors form. When surgery is not possible, ongoing monitoring and management of pain in a multidisciplinary pain clinic is advisable.
The clinical spectrum of the disease is broad. In other words, people with NF- 2 may develop a wide range of distinct problems:
1. Acoustic nerve: 90% of the patients show bilateral acoustic neuromas on magnetic resonance imaging (MRI).
2. Other cranial nerves and meninges: About 50% of patients develop tumours in other cranial nerves or Meningiomas.
3. Spinal cord: About 50% of the patients develop spinal lesions. Only 40% of the spinal lesions are symptomatic. The spinal tumours in NF-2are separated in two groups. Intramedullary lesions are located within the spinal tissue and usually belong to the so-called spinal astrocytomas orependymomas. The extramedullary lesions are located within the small space between the surface of the spinal cord and the bony wall of the spinal canal. These tumours belong to the Schwannomas and Meningiomas.
4. Skin: If children show neurofibromas, a diagnostic procedure should be performed to decide which form of neurofibromatosis causes the alterations.
5. Eyes: Studies on patients with NF II show that more than 90% of the affected persons suffer eye lesions. The most common alteration in NF-2is the juvenile subcapsular cataract (opacity of the lens) in young people.
“Presenting symptoms” (initial concern that brings a patient to a doctor) of a lesion of the nervus vestibulocochlearis due to a tumor in the region of the cerebello-pontine angle are the following: hearing loss (98%), tinnitus (70%), dysequilibrium (67%), headache (32%), facial numbness and weakness (29% and 10% respectively).
“Clinical signs” (alterations that are not regarded by the patient and that can be detected by the doctor in a clinical examination) of the lesion in discussion are: abnormal corneal reflex (33%), nystagmus (26%), facial hypesthesia (26%).
“Evaluation” (study of the patient with technical methods) shows the enlargement of the porus acousticus internus in the CT scan, enhancing tumors in the region of the cerebello-pontine angle in gadolinium-enhanced MRI scans, hearing loss in audiometric studies and perhaps pathological findings in Electronystagmography.
The signs and symptoms of this condition usually appear during adolescence or in a person’s early twenties, although onset can occur at any age. The most frequent early symptoms of vestibular schwannomas are hearing loss, ringing in the ears (tinnitus), and problems with balance. In most cases, these tumors occur in both ears by age thirty. If tumors develop in other parts of the brain or spinal cord, signs and symptoms vary according to their location. Complications of tumor growth can include changes in vision or sensation, numbness or weakness in the arms or legs, and fluid buildup in the brain. Some people with neurofibromatosis type- 2 develop clouding of the lens (cataracts) in one or both eyes, often beginning in childhood.
NF-2 is inherited as an autosomal dominant condition, although half of affected individuals have NF-2 as a result of a new (de novo) gene mutation. The manifestations of NF-2 result from mutations in (or, rarely, deletion of) theNF-2 gene, located on the long arm of chromosome twenty two (22). Affected individuals need only one mutated or deleted NF-2 gene to exhibit signs of the condition.
The NF-2 gene product known as merlin serves as a tumor suppressor; decreased function or production of this protein results in a predisposition to develop a variety of tumors of the central and peripheral nervous systems.
Increasing evidence indicates that merlin is involved in a number of cellular pathways and works in concert with other proteins to promote cellular adhesion and responses via the growth factor receptor. Understanding these interactions may eventually lead to more effective targeted treatment strategies, since the benign nature of NF-2 lesions makes tumors frequently less responsive to chemotherapy or radiation therapy.
Numerous mutations in the NF-2 gene have been identified, most of which are predicted to result in production of a truncated protein with loss of its usual function.
The estimated incidence of neurofibromatosis type 2 (NF-2) is 1 in 37,000 per year, with about half of affected individuals representing first cases in the family as a result of new, dominant mutations.
Although the genetic change causing NF2 is present at conception, the clinical manifestations occur over many years. The typical age of onset of symptoms is in the late teens to early twenties, but the age range covers the entire life span. Some evidence indicates that age of onset of clinical symptoms is lower in maternally transmitted NF-2. While NF-2 is quite variable in severity from person to person, family studies have shown some intrafamilial consistency in age of onset. Somatic mosaicism for the NF-2 mutation in sporadic cases may also complicate the clinical picture, resulting in underdiagnosis or late diagnosis.
Progression of the disease
In NF-2 Acoustic neuromas usually affect young people, whereas, in sporadic forms of Acoustic neuromas, the appearance of the tumor is limited to the elderly.
There are two forms of the NF-2 : The Wishart-Phenotype is characterized by multiple cerebral and spinal lesions in patients younger than twenty years and with rapid progression of the tumors.
Patients that develop single central tumors with slow progression after age of twenty are thought to have the Feiling-Gardner-Phenotype.
Early diagnosis allows better planning of therapy in young patients with NF II. In many cases, the hearing loss is present for 10 years before the correct diagnosis is established. Early in the disease, surgery for an acoustic neurinoma can protect facial nerve function in many patients. In selected cases of patients with very small tumors and good bilateral hearing, surgery may offer the possibility of long-term hearing preservation.
Patients with the Wishard phenotype suffer multiple recurrences of the tumor after surgical treatment. In the case of facial nerve palsy, the muscles of the eyelids can lose their mobility, leading to conjunctivitis and corneal injury. “Lidloading” (implantation of small magnets, gold weights, or springs in the lid) can help prevent these complications. Other means of preserving corneal health include tarsorrhaphy, where the eyelids are partially sewn together to narrow the opening of the eye, or the use of punctal plugs, which block the duct that drains tears from the conjunctival sac. All these techniques conserve moisture from the lacrymal glands, which lubricates the cornea and prevents injury. Most patients with NF- 2 develop cataracts, which often require replacement of the lens. Children of affected parents should have a specialist examination every year to detect developing tumors. Learning of sign-language is one means of preparation for those that will most probably suffer complete hearing loss.
Operative therapy of acoustic neuroma
There are several different surgical techniques for the removal of acoustic neuroma. The choice of approach is determined by size of the tumor, hearing capability, and general clinical condition of the patient.
The retrosigmoid approach offers some opportunity for the retention of hearing.
The translabyrinthine approach will sacrifice hearing on that side, but will usually spare the facial nerve. Post-Operative cerebrospinal fluid leaks are more common.
The middle fossa approach is preferred for small tumors, and offers the highest probability of retention of hearing and vestibular function.
Less invasive endoscopic techniques have been done outside of the United States for some time. Recovery times are reported to be faster. However, this technique is not yet mainstream among surgeons in the US.
Larger tumors can be treated by either the translabyrinthine approach or the retrosigmoid approach, depending upon the experience of the surgical team. With large tumors, the chance of hearing preservation is small with any approach. When hearing is already poor, the translabyrinthine approach may be used for even small tumors. Small, lateralized tumours in patients with good hearing should have the middle fossa approach. When the location of the tumour is more medial a retrosigmoid approach may be better.
Auditory canal decompression is another surgical technique that can prolong usable hearing when a vestibular schwannoma has grown too large to remove without damage to the cochlear nerve. In the IAC (internal auditory canal) decompression, a middle fossa approach is employed to expose the bony roof of the IAC without any attempt to remove the tumor. The bone overlying the acoustic nerve is removed, allowing the tumor to expand upward into the middle cranial fossa. In this way, pressure on the cochlear nerve is relieved, reducing the risk of further hearing loss from direct compression or obstruction of vascular supply to the nerve.
Radiosurgery is a conservative alternative to cranial base or other intracranial surgery. With conformal radiosurgical techniques, therapeutic radiation focused on the tumor, sparing exposure to surrounding normal tissues. Although radiosurgery can seldom completely destroy a tumor, it can often arrest its growth or reduce its size. While radiation is less immediately damaging than conventional surgery, it incurs a higher risk of subsequent malignant change in the irradiated tissues, and this risk in higher in NF-2 than in sporadic (non-NF-2) lesions.
Chemotherapy–A 2009 clinical trial at Massachusetts General Hospital used the cancer drug Bevacizumab (commercial name: Avastin) to treat ten patients with neurofibromatosis type 2. The result was published in The New England Journal of Medicine. Of the ten patients treated with bevacizumab, tumors shrank in nine of them, with the median best response rate of twenty six percent. Hearing improved in some of the patients, but improvements were not strongly correlated with tumor shrinkage. Bevacizumab works by cutting the blood supply to the tumors and thus depriving them of their growth vector. Side effects during the study included alanine aminotransferase, proteinuria, and hypertension (elevated blood pressure) among others. A separate trial, published in The Neuro-oncology Journal, show forty percent tumor reduction in the two patients with NF-2, along with significant hearing improvement.
Overall the researchers believed that bevacizumab showed clinically significant effects on NF-2 patients. However, more research is needed before the full effects of bevacizumab can be established in NF-2 patients.
Management of Hearing Loss in NF-2
Because hearing loss in those with NF-2 almost always occurs after acquisition of verbal language skills, patients do not always integrate well into the Deaf culture and are more likely to resort to auditory assistive technology. The most sophisticated of these devices is the cochlear implant, which can sometimes restore a high level of auditory function even when natural hearing is totally lost. However, the amount of destruction to the cochlear nerve caused by the typical NF-2 schwannoma often precludes the use of such an implant. In these cases, an auditory brainstem implant (ABI) can restore a primitive level of hearing, which, when supplemented by lip reading, can restore a functional understanding of spoken language.
Drug therapy for NF-2-related meningioma
Sunitinib is being studied for treatment of meningioma which is associated with Neurofibromatosis.
Drug therapy for vestibular schwannoma
Lapatinib is being studied by Jeffrey Allen at NYU Langone Medical Center for treatment of vestibular schwannoma in Neurofibromatsis type 2.
The prognosis of neurofibromatosis type 2 (NF-2) depends on a number of factors, including age of symptom onset, degree of hearing deficit, and number and location of various tumors. Although age of onset is relatively similar within families, the age range can vary from (2-70) years. While the tumors themselves are relatively indolent and do not undergo malignant transformation, studies performed in the late 1980s and early 1990s showed clearly that significant rates of mortality and morbidity are associated with the diagnosis of NF-2.
One such study suggested that the survival from the time of actual diagnosis averages fifteen years; however, this may be changing for the better with improved diagnosis, surgical techniques, surveillance, screening, and recognition of mild disease (due in part to increased physician awareness and availability of molecular diagnostic options).
Morbidity and mortality
Vestibular schwannomas are the most common and well-recognized feature of NF-2 leading to significant morbidity. Symptoms of tinnitus, gradual hearing loss, and even vestibular dysfunction are frequently the initial signs of NF-2. Although unilateral hearing loss is the number one presenting symptom, bilateral deafness would be expected to eventually occur in most affected individuals. Untreated vestibular schwannomas can extend locally and may result in brainstem compression, hydrocephalus, and facial nerve palsy.
Dumbbell-shaped spinal cord schwannomas are quite common in NF-2 and result in significant morbidity; they present a great therapeutic challenge. Spinal cord ependymomas, astrocytomas, and meningiomas also occur, but less frequently. Intracranial meningiomas, on the other hand, are a frequent finding; they may be asymptomatic, or they may cause a variety of symptoms and CNS deficits.
Nonvestibular schwannomas occur in more than half of patients and are often diagnosed in patients with an earlier age at diagnosis of NF-2. Cranial nerves III and V are most commonly involved, but the rare occurrence of jugular foramen schwannomas potentially impacting the glossopharyngeal, vagus, and/or spinal accessory nerves may lead to dysphagia, esophageal dysmotility, hoarseness, or aspiration.
On the other hand, nonvestibular schwannomas in patients with NF-2 tend to be more indolent and to grow slowly over time. This can complicate treatment decision making, since options include surgery, radiation therapy, and watchful waiting.
Posterior subcapsular, or juvenile, cataracts can predate CNS symptomatology. These cataracts may progress over time, leading to decreased visual acuity. A fair percentage of affected individuals are found to have retinal hamartomas or epiretinal membranes that may or may not be visually significant.
Sensory motor polyneuropathy is seen in some individuals with NF-2 who may or may not have identifiable tumors along the length of the peripheral nerve(s) of interest.
The neurofibromatoses are a group of three genetically distinct disorders that cause tumors to grow in the nervous system. Tumors begin in the supporting cells that make up the nerve and the myelin sheath (the thin membrane that envelops and protects the nerves), rather than the cells that actually transmit information. The type of tumor that develops depends on the type of supporting cells involved.
Scientists have classified the disorders as neurofibromatosis type 1 (NF-1, also called von Recklinghaus disease),neurofibromatosis type 2 (NF-2), and a type that was once considered to be a variation of NF-2 but is now called schwannomatosis. An estimated 100,000 Americans have a neurofibromatosis disorder, which occurs in both sexes and in all races and ethnic groups.
Symptoms of neurofibromatosis vary greatly, but generally they get worse over time. Some people have symptoms that are mild or not noticeable at all. In other people, neurofibromatosis causes significant disability.
Other early symptoms of neurofibromatosis include: tinnitus, poor balance, headache, facial pain, or facial numbness, caused by pressure from the tumors, may also occur.
Neurofibromatosis can cause skin changes, bone deformities, and other problems. The disease can cause developmental abnormalities. Patients with neurofibromatosis have a higher incidence of learning disabilities.
The most common nerve-associated tumors in NF-1 are neurofibromas (tumors of the peripheral nerves), whereas schwannomas (tumors that begin in Schwann cells that help form the myelin sheath) are most common in NF-2 and schwannomatosis. Most tumors are benign, although occasionally they may become cancerous.
Why these tumors occur still is not completely known, but it appears to be related mainly to mutations in genes that play key roles in suppressing cell growth in the nervous system. These mutations keep the genes—identified as NF-1, NF-2 and SMARCB1/INI1—from making normal proteins that control cell production. Without the normal function of these proteins, cells multiply out of control and form tumors.
Neurofibromatosis causes unchecked growth of tissue along the nerves. This can put pressure on affected nerves and cause pain, severe nerve damage, and loss of function in the area served by the nerve. Problems with sensation or movement can occur, depending on the nerves affected. The condition can be very different from person to person, even among people in the same family.
Guidelines for Treatment
Treatments for both NF-1 and NF-2 are presently aimed at controlling symptoms. Surgery can help some NF-1 bone malformations and remove painful or disfiguring tumors; however, there is a chance that the tumors may grow back and in greater numbers. In the rare instances when tumors become malignant (3 to 5 percent of all cases), treatment may include surgery, radiation, or chemotherapy. For NF-2, improved diagnostic technologies, such as an MRI, can reveal tumors as small as a few millimeters in diameter, thus allowing early treatment. Surgery to remove tumors completely is one option but may result in hearing loss. Other options include partial removal of tumors, radiation, and if the tumors are not progressing rapidly, the conservative approach of watchful waiting. Genetic testing is available for families with documented cases of NF-1 and NF-2. New (spontaneous) mutations cannot be confirmed genetically. Prenatal diagnosis of familial NF-1 or NF-2 is also possible utilizing amniocentesis or chorionic villus sampling procedures.
Because symptoms of neurofibromatosis vary, the needs of the patient determine treatment. Doctors try to control symptoms and treat complications as they happen. Patients with neurofibromatosis may require coordinated care from physicians who are medical or surgical specialists. As an example, orthopedic surgeons may help with the management of spinal deformities or limb size discrepancies. A team approach with knowledgeable caregivers and involved patients and families should help to optimize care.
There are some general guidelines.
- Children with neurofibromatosis often need regular medical evaluations to measure growth and blood pressure, and to examine skin, bones, the nervous system, vision, and hearing.
- Adults with neurofibromatosis often need yearly evaluations of the nervous system and hearing.
- Some people with neurofibromatosis have on-going medical issues, such as pain and disability. They may need life-long care from several medical and surgical specialists (i.e., orthopaedic surgeons, neurologists, dermatologists, and radiologists).
- Some people with neurofibromatosis visit multidisciplinary (many different doctors) neurofibromatosis clinics for comprehensive evaluations and management plans. They may receive treatment at the clinic or take a management plan back to their own doctor.
Sometimes, young children with abnormal spots have not yet developed neurofibromas. If this is the case, regular eye examinations and screening tools may help detect optic nerve gliomas for treatment before a child starts to lose his or her sight.
Most tumors caused by neurofibromatosis do not need treatment. But, tumors that are painful, disfiguring, rapidly growing, and impairing the function or compressing other body parts may need treatment. Some neurofibromas grow fast and may be at risk for becoming cancerous (malignant). Bone deformities may also need treatment. The following are some of the treatment options available for abnormal tissue growth.
- Diagnostic Imaging The doctor may use tools such as magnetic resonance imaging (MRI) to see into the body and find tumors when they are still small. Tumors along the nerves of the eyes and ears may be easier to treat when discovered early.
- Biopsy The doctor may check for cancer cells by removing a small part of a tumor.
- Surgery The doctor may remove a tumor by cutting it out of the body. The doctor may also treat bone abnormalities with surgery. To treat severe scoliosis (curvature of the spine) caused by neurofibromatosis, a doctor may need to fuse and use internal instrumentation on part of the spine.
- Radiation The doctor may use beams of energy (radiation) to kill tumors.
- Chemotherapy The doctor may give you drugs (chemotherapy) to kill tumors.
Recommend: Whole plant extracts. Indica x Sativa hybrid. High CBD’s. Use to relieve symptoms. Make your own tinctures (twice a day under the tongue).
Trainwreck, Harlequin, Chemdawg
Cannabidiol —CBD— is a compound in Cannabis that has medical effects but does not make people feel “stoned” and actually counters some of the effects of THC. After decades in which only high-THC Cannabis was available, CBD-rich strains are being grown by and for medical users.
The reduced psychoactivity of CBD-rich Cannabis may make it an appealing treatment option for patients seeking anti-inflammatory, anti-pain, anti-anxiety and/or anti-spasm effects without disconcerting euphoria or lethargy.
Scientific and clinical studies indicate that CBD could be effective in easing symptoms of a wide range of difficult-to-control conditions, including rheumatoid arthritis, diabetes, alcoholism, PTSD, epilepsy, antibiotic-resistant infections and neurological disorders. CBD has demonstrated neuroprotective effects, and its anti-cancer potential is currently being explored at several academic research centers in the U.S. and other countries.
Objectives: To determine whether plant-derived cannabis medicinal extracts (CME) can alleviate neurogenic symptoms unresponsive to standard treatment, and to quantify adverse effects.
Conclusions: Cannabis medicinal extracts can improve neurogenic symptoms unresponsive to standard treatments. Unwanted effects are predictable and generally well tolerated. Larger scale studies are warranted to confirm these findings.
A glioma is a type of tumor that starts in the brain or spine. It is called a glioma because it arises from glial cells. The most common site of gliomas is the brain.
The exact causes of gliomas are not known. Hereditary genetic disorders such as neurofibromatoses (type 1 and type 2) and tuberous sclerosis complex are known to predispose to their development.
Cannabinoids “may represent a new class of anticancer drugs that retard cancer growth; inhibit angiogenesis and the metastic spreading of cancer cells”.
The present invention, in some embodiments thereof, relates to novel quinonoid derivatives of cannabinoids, also referred to herein interchangeably as cannabinoid quinones, to pharmaceutical compositions comprising same and to uses thereof as anti-cancerous agents.
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3. “Are there any prenatal tests for the neurofibromatoses?”
4. Christopher Gillberg (16 October 2003). Clinical Child Neuropsychiatry. Cambridge University Press. pp. 231–. ISBN 9780521543354. Retrieved 20 December 2010.
5. “Neurofibromatosis Type 2: eMedicine Radiology”. Retrieved 2010-12-20.
6. Walter J, Kuhn SA, Brodhun M, Reichart R, Kalff R (June 2009). “Pulmonary meningioma and neurinoma associated with multiple CNS tumours in a patient with neurofibromatosis type 2”. Clin Neurol Neurosurg 111 (5): 454–9. doi:10.1016/j.clineuro.2008.11.018. PMID 19249154.
7. Jean Régis; Pierre-Hugues Roche (2008). Modern Management of Acoustic Neuroma. Karger Publishers. pp. 191–. ISBN 9783805583701. Retrieved 20 December 2010.
10. “Phase II Trial of Sunitinib (SU011248) in Patients With Recurrent or Inoperable Meningioma”
11. “Targeting auditory tumors”, NYU Physician, Winter 2010-2011, page 5