Von Hippel–Lindau disease

The von Hippel -Lindau syndrome ( VHL), sometimes referred to as Retino - cerebellar angiomatosis, is a rare, hereditary tumor disease in the form of so-called circle phakomatoses. The patients develop benign, tumor- like tissue changes ( Angioma ) primarily in the area of the retina of the eye and the cerebellum. In the central nervous system may also home to the brainstem and the spinal cord, cerebrum rarely be affected. It is characteristic of the VHL syndrome that develop tumors from preforms of connective tissue, consisting of glomeruli. Many patients also have tissue changes in the area of the kidney ( renal cell carcinoma), adrenal gland ( pheochromocytoma ), and pancreas. In men, the epididymis may be affected. These tissue changes can be harmless, but also develop into malignant tumors. The cause of the disease is a genetic mutation. As products in the VHL syndrome is a genetic disorder, no cure is possible. The treatment of patients is based upon the location and severity of tissue changes. In the eye, the retinal tumors are destroyed by laser beams. Malignant tumors occur primarily in the kidney and be treated according to the guidelines of the management of this disease. The tissue changes in the central nervous system surgery, may occur if dangerous consequences for the patient by their location and size. Since the disease can be detected early, regular check-ups are recommended.

History

The namesake of the disease are the Göttingen ophthalmologist Eugen von Hippel (1867-1939) and the Swedish pathologist Arvid Lindau ( 1892-1958 ). 1904 Von Hippel first described Angioma of the eye, Lindau 1926, the angioma in the spinal cord.

Incidence, Inheritance, epidemiology

A familial context, the disease was first suspected in 1894 in the study of siblings. In 1929 it was found that the VHL syndrome an autosomal dominant inheritance obeyed. With increasing age, the risk increases to form tumors. In this case, the maximum of the genetic penetrance is reached at the age of 65 years. The incidence is between 1:36.000 - 1:45.000 specified. The possible forms of the disease can vary greatly based drugs. Depending on the study, the spontaneous mutation rate is up to 50%. Men and women are equally affected.

Pathogenesis, molecular and pathophysiological mechanisms

The gene for von Hippel- Lindau disease was localized p25/26 in the area of chromosome 3, band. It is involved in the cell cycle, and the formation of new vessels. HL gene has three exons and encodes a nuclear protein which binds to the proteins elongin group. In patients with a disease, HL a variety of mutations was found, all of which are distributed substantially uniformly throughout the batt. Was found in various studies that 35 % of the mutations are missense mutations and about 75 % of patients have a germline mutation.

Pathology

The angiomas of the HL- syndrome is predominantly capillary hemangiomas and hemangioblastomas. As hemangioma is called benign tumor- like growths with a specification as blood glomeruli. They usually occur as hamartomas, so there are no tumors in the strict sense. The hemangiomas do not arise, as the name suggests, from blood vessels, but from Bindegewebsvorläufern and they develop into structures that are easiest to describe as a blood vessel clusters or hemangiomas. The hemangiomas, which are found in the cerebellum, brain stem and spinal cord of VHL patients are hemangioblastomas. This term refers to true neoplasms composed of proliferated capillary buds.

• The retinal hemangiomas may have a more angiomatous or more fibrosing expression. This is very important for the prognosis of the disease in relation to the eye. For more angiomatous hemangiomas of the vascular portion of the tissue change, which can often lead to massive bleeding into the eye with a sudden complete blindness predominates. Fibrosing hemangiomas make more of a traction change in the retina. If the hemangiomas are located in the periphery of the retina, they often make no complaints. If they are, however, central vision loss may occur soon a. When the glomeruli develop short circuits between veins and arteries, it can lead to leakage of tissue fluid in the eye come with consequences ( pressure increase ).

• Hemangioblastomas manifest preferentially in the cerebellum and become symptomatic during slow growth through disruption of Liquorabflusses. Since they also educate erythropoietin, in some cases, polycythemia is observed. Under the microscope there is the capillary hemangioblastoma is extremely well vascularized tumor with CD31/CD34-positivem vascular endothelium and NSE expression of the stroma dar.

Disease

The core or cardinal symptoms of VHL syndrome is the occurrence of hemangiomas of the retina and hemangioblastomas of the cerebellum.

The clinical spectrum of disease includes not only the affections of the eyes and cerebellum, the occurrence of hemangioblastomas in the brainstem and spinal cord. Then, renal cell carcinoma ( disease risk is 25 - 45 %, usually from the age of 50 ), pancreatic cysts, pheochromocytomas, epididymal cysts and polycythemia observed.

The hemangioblastomas of the CNS present in approximately 60% of cases in the cerebellum, in 13 % of cases in the spinal cord and in 4% of cases in the brainstem. Rare <1% in the cerebrum. The lesions in the cerebellum are on average in patients aged 29 years and clinically apparent in the case of spinal cord lesions at the age of 34 years.

As a diagnostic criterion is the demonstration of bilateral or multiple retinal hemangiomas or the detection of multiple hemangioblastomas of the posterior fossa.

Because clinical histories and differences in the phenotype - genotype correlation there are two forms of the VHL syndrome. Patients without pheochromocytoma assigns you the VHL Type I, patients with pheochromocytoma, VHL type II

The Course of the disease very different precautions. Retinal angiomas are revealed, on average, in patients at the age of 25. The retinal changes, if they are discovered in time to be treated well. The intracerebral and spinal hemangioblastomas can cause dangerous bleeding, especially in the area of the brain stem.

Genotype-phenotype correlation

In the HL- I type of cases investigated microdeletions and nonsense mutations were detected in over 50 %. When HL type II were found in almost 100 % of the patients studied missense mutations.

Diagnosis

The diagnosis of VHL syndrome is found in the presence of capillary hemangioblastomas ( hypervascular tumors) in the CNS or the retina of the eye. More to the VHL complex associated tumors ( pheochromocytoma, renal cell carcinoma) or a family history are emerging. In magnetic resonance imaging to ask the hemangioblastomas as a contrast medium Participating nodules dar.

Therapy

The choice of therapy depends on the size, location and the clinical picture. Only early diagnosis and effective therapy may allow for preservation of visual acuity. In some rare cases, spontaneous regressions have been described without treatment of retinal angiomas.

Laser photocoagulation

The laser photocoagulation is currently being used in smaller retinal hemangiomas. In this case, argon, krypton, dye and diode lasers, formerly xenon coagulator used. The advantage of the method is the targeted destruction with extreme accuracy, the healthy tissue is spared. Frequent applications of the method to show success in retinal hemangiomas up to a size of 4.5 mm, but the therapy is most effective in sizes up to 1.5 mm (equivalent to a disc diameter ) or smaller. Angiomas, which are larger than a disc diameter, show in the laser photocoagulation only unsatisfactory results and should therefore be treated with other methods. The laser coagulation can be performed directly on the Angioma, at the same time on the feeding vessels of the angioma, or both. The response rate in the direct photocoagulation in the use of argon Lasor is 91-100 %. Hemangiomas with the size of a papilla need an average of three applications until complete obliteration, while a session is usually sufficient for Mikroangiomen. Some authors recommend a combination of laser photocoagulation with other methods to treat Angioma, which could not be adequately treated by the sole Laserkoagultion.

The use of the yellow laser krypton laser has a theoretical advantage over other laser method, since the oxidized and reduced hemoglobin absorbs more yellow wavelengths, as a green or blue as in the argon laser. Thus, the feeding vessels should be more strongly irradiated.

The most common side effects of laser photocoagulation may vitreous hemorrhage or exudative retinal detachments, especially by lipid deposits in the macula with a lasting loss of vision may occur. This degenerative process can occur within one day after treatment. The complications occur most frequently when the Angioma has already caused structural changes. In the indirect laser photocoagulation may, after a few months of treatment, come to reperfusion of the afferent vessels of the angioma. Whereby post treatments may be necessary. The occlusion of a feeding artery can lead to a heart attack the serving of their retina by itself. The result is visual field defects.

In spite of treatment with the direct or indirect laser photocoagulation later new hemangiomas may develop. Relapses of the treated angioma can occur. In histological examinations were seen in treatment with laser beams only a superficial destruction of tumor cells with large hemangiomas. In the depth unchanged tumor tissue could be found. In contrast, a complete destruction could be detected in small hemangiomas.

Cryotherapy

When cryotherapy are angiomas, which are greater than two disc diameters and are far peripherally treated. Even with subretinal exudates angiomas can be treated. This method was used in 1967 for the first time by Lincoff and examined. In this case, the retinal angioma is iced at temperatures from -60 ° C to -80 ° C. In a long- term study showed the best results in angiomas, which were smaller than 3.75 mm. For larger angiomas cryotherapy was no more successful than the laser coagulation, but showed fewer complications than with treatment with laser beams.

Even with cryotherapy post-treatments are often necessary, but a minimum of two months between treatments should be respected. Complications exudative retinal detachment and proliferative vitreoretinopathy one may occur.

Brachytherapy

In angiomas of a size of 4 mm ruthenium -106 applicators can be used as episkeral sewn steel beams. After the irradiation, it is, in comparison with the treatment with laser beams, to the slower formation of the back angiomas. The average regression period is 5 to 14 months. After irradiation arise almost always chorioretinal scars, which were larger than the tumor. The biggest danger is the injury of the optic nerve by the radioactive rays.

Also in brachytherapy exudative retinal detachment and vitreous hemorrhage may occur, but less frequent than in the conventional treatment methods. Rarely, epiretinal membrane formation occur, which makes surgical therapy necessary. In one existing before the treatment, retinal detachment, the risk of complications after brachytherapy is greatly increased.

Transpupillary thermotherapy

The transpupillary thermal therapy can be tried in the treatment of choroidal melanoma, retinoblastoma and choroidal hemangiomas. This local heating generated at the tumor by means of infrared diode laser. Histology showed marked necrosis of the tumor in the choroidal melanoma after treatment. In the treatment of retinal hemangiomas on the one hand showed success, on the other hand, other studies showed no effectiveness of the method.

Photodynamic therapy

For larger angiomas the effectiveness of photodynamic therapy with verteporfin in clinical trials is currently under investigation. This improvement in visual acuity by an average of 0.5 were observed after two years. As a side effect of macular edema can occur, which in turn can lead to visual loss. This method can also be combined with photocoagulation.

Radiotherapy

Treatment with radiation therapy has been tried as all first method for retinal angiomas by Houwer 1919. It noted, however, no efficacy, which was confirmed by other authors. The therapy was successful at a dose of 12 Gray in individual cases. In a long-term study of 11 radiation therapy was successful with an average dose of 38 Gray in only one case. In a recent study from 2004 showed an improvement of visual acuity from 0.28 to 0.44, with an average tumor reduction by approximately 40 %, but not all tumors equally reduced. The greatest reduction was seen in smaller angiomas. Patients were treated with a total dose of 2160 Gray fractionated over twelve days irradiated. As a side effect occurred in a patient cataract.

Proton Therapy

In this treatment method is the advantage of high precision of tissue destruction, with non-diseased tissue components are protected. Therefore, this method is applied when Angioma grow near sensitive tissue areas. These protons are used, which can penetrate several centimeters into the tissue with great energy.

Drug treatment

The treatment of angiomas with VEGF inhibitors such as pegaptanib or SU 5416 has been studied in clinical trials. In this case, no change in tumor size were observed. However Visusverbesserungen occurred through the reduction of macular edema. As a serious side effect that can occur anaphylaxis. Currently, the drug therapy as adjunctive therapy in addition to conventional therapy methods is discussed.

Enucleation

The indication for enucleation is rarely asked. Most in pain during blind eye due to secondary glaucoma.

Other

Therapy is the surgical removal of tumors.