Sunday, October 31, 2010

Central Nervous System Vasculitis

Necrotizing vasculitis may affect the central and peripheral nervous system. The vasculitides may become life threatening due to ischemic ulceration of the gut, kidney failure, and myocarditis; but it may also primarily involve the nervous system.

Although mild cases have been reported, a fulminant course is much more common. Therefore, its early recognition is paramount to secure a good outcome. Unfortunately, its perplexing initial presentation in many patients makes it very challenging to diagnose. This is also partly because this disorder may affect the central nervous system alone. Not uncommonly a major localizing deficit has occurred at the time of diagnosis. Angiitis of the central nervous system can be part of the systemic disorder which has to be uncovered before treatment is initiated. Three primary CNS vasculitides have been identified, many others are secondary to systemic vasculitis, connective tissue disease, malignancy, infections, and drugs. This section summarizes the most important clinical findings, the differential diagnosis, neuroimaging, and pathological characteristics. It also provides a recommendation for treatment.

Pathology and Classification
Vasculitis (or angiitis) on histologic analysis is characterized by inflammation involving layers of polymorphonuclear cells, mononuclear cells, and giant cells destroying the vessel wall resulting in fibrinoid necrosis, aneurysm formation, and possibly hemorrhage.

The pathological mechanisms that lead to vasculitis have not been elucidated. There is some evidence of cell-mediated immunity and when infiltrates are examined closely, they consist particularly of CD4 lymphocytes. Circulating immunocomplexes or a marked decrease in complement is not a typical feature in isolated CNS angiitis. When pathology is available either at autopsy or from a brain biopsy specimen, angiitis typically involves smaller blood vessels. The criteria for vasculitis have been outlined by Kolodny. These criteria include the following: a) intimal swelling and hyperplasia in arteries, b) adventitial lymphocytes infiltration in veins, c) subintimal and intimal fibrinoid change with adventitial accumulation of histiocytes, d) necrosis and fibrinoid change in media, e) fragmentation of internal elastic lamina, f) panmural infiltration of lymphocytes and histiocytes, g) and the presence of granulomas replacing all or part of the vessel wall.

These lesions involve a cluster of lymphocytes, large monocular cells, fibroblasts, multinucleated giant cells, and plasma cells. Inflammation of the small arteries and veins preferably involve the vessels of the leptomeninges and the branches that penetrate the cortex. (This characteristic is useful when performing a brain biopsy). Most notable is a panangiitis in a longitudinal and circumferential direction. In some patients, the abnormality involves the spinal cord arteries and arterioles, but this is an extremely uncommon cause of a myelopathy. Pathology involving the eye vasculature is uncommon and more widespread not only leading to retinal vasculitis but also uveitis or epiduritis.

The necrosis of the vessel wall results in occlusion and ischemia. A vessel wall rupture commonly leads to subarachnoid hemorrhage often involving the sulci and not the basal cisterns as in rupture from aneurysms located at the circle of Willis. Generally a brain biopsy is done at the time of diagnosis and should ideally involve the area that is abnormal on MRI scan. Although several series claim a sensitivity of 70%, a random brain biopsy has a much lower yield. If a brain biopsy is done, the specimen should include dura, leptomeninges, cortex, and white matter and fixated in 10% buffered formalin for light microscopy. Additional specimen can be frozen or stored with dry ice to be further examined by electron microscopy. Isolated angiitis of the central nervous system has been also termed granulomatous angiitis, but this connotation has been deleted because granulomatous changes are absent in 50% of the cases. When an underlying disorder is absent, central nervous system vasculitis is quite rare with only 300 cases or so reported. Related disorders are Eales disease, seen in India and the Middle East, with predominant retinal artery and vein involvement. Retinal hemorrhages and peripheral scotomas are common, but ischemic strokes have been reported.

Another disorder confined to the central nervous system is radiation angiitis due to carcinoma of the larynx, optic glioma, or pituitary tumor. A marked delay (often decades) is typical, but the effects can be devastating and the arteritis is not responsive to immunosuppression.

Clinical Diagnosis
Isolated CNS angiitis is typically seen in younger (30-50 years) individuals with some predilection for females. It may present as an encephalopathy or dementia, multiple cranial neuropathies or recurrent transient ischemic attacks. Many reviews have noted the predominance of headache at presentation. Biller and Adam’s review claim that diffuse encephalopathy signs are present in up to 80% of the patients, but other reviews have predominantly highlighted the presence of behavioral changes. Obviously, a psychiatric presentation can make the diagnosis extremely challenging. This presentation may involve emotional lability but also at times histrionic behavior, confusional states mimicking dementia, suicidal depression, and acute psychotic exacerbations with visual hallucinations particularly when the occipital lobes have become infarcted. Localizing neurologic findings such as aphasia, apraxia, or hemiparesis often emerge. These neurologic signs and symptoms may be associated not only with infarction but also associated with lobar hemorrhages.

Because vasculitis of the central nervous system more likely can be seen in a setting of other disorders, a comprehensive medical examination is needed. For example, CNS angiitis can be seen in Behcet’s disease in which oral and genital ulcers and many other skin manifestations such as erythema nodosa and multiple pustules are present. Pustules may form 24 hours after a sterile needle prick (Pathergy) and may clinch the diagnosis. However when fever, weight loss and malaise, nondeforming arthritis, abdominal pain, as well as proteinuria and progressive renal failure occurs, polyarteritis nodosa or a more systemic necrotizing vasculitis should be considered. CNS vasculitis has been linked to drug abuse (e.g. amphetamine). However, histopathology available in the reported cases is scanty leading some investigators to conclude that the relationship between amphetamine and vasculitis is tentative at best. The proof of vasculitis due to cocaine is also weak. Many reported cases do show a vasculopathy, but inflammation is rarely impressive. We have noted a very severe occlusive vasculopathy (with a moyamoya pattern) but no evidence of vasculitis on biopsy. Other signs are absent peripheral pulses and difficulty recording blood pressure (Takayasu’s arteritis), uveitis (sarcoidosis), and recent asthma (Churg-Strauss).

The classification of the vasculitides is shown in Table 1.

Table 1 – Classification of angiitis

Isolated CNS vasculitis

Isolated angiitis (granulomatous)
Eales Disease
Radiation vasculitis
CNS vasculitis due to secondary causes

Polyarteritis nodosa
Giant cell arteritis
Takayasu’s arteritis
Wegener’s granulomatosis
Churg-Strauss
Behcet’s disease
Sarcoidosis
SLE, RA
Sjörgen’s disease
Malignancies (lymphoma)
Infections (herpes zoster, syphilis)
Cocaine, amphetamine
Moore’s clinical criteria for the diagnosis of CNS vasculitis are shown here in table 2 for reference. However it remains difficult to define a perfect set of criteria in this rare disorder (more experts than patients) and diagnostic tests, particularly interpretation of brain biopsy may not resolve uncertainties.

Table 2 – Moore’s clinical criteria for diagnosis of isolated angiitis of the CNS

Recent severe onset of headaches, confusion, or multifocal neurologic deficits that are recurrent of progressive
Typical angiographic findings
Exclusion of systemic disease or infection
Leptomeningeal or parenchymal biopsy findings confirming vascular inflammation with exclusion of infection, neoplasia, and non-inflammatory vascular disease
Diagnostic tests
Central nervous system vasculitis is first suggested after routine neuroimaging. The CT scan may show cerebral infarcts in multiple territories but typically involving cortical structures. Although at times, a CT scan may be helpful in diagnosing Wegener’s granulomatosis in which bone thickening focal erosive changes of the natal septum and typical soft tissue mass in the sinuses are seen. The MRI scan more likely will document abnormalities in multiple and cortical structures but may also may be limited to scattered lesions in the white matter as well. Meningeal enhancement due to involvement of the meningeal vessels has been noted. Conversely, one may make an argument that a completely normal MRI scan including diffusion-weighted images would make the diagnosis of fulminant angiitis of the central nervous system highly unlikely. Obviously multiple cerebral infarcts on MRI are nonspecific findings and many disorders (although equally uncommon) may produce similar findings. They are listed in Table 3 and should be excluded before invasive tests (e.g. brain biopsy) are performed.

Table 3 – Differential diagnosis of multiple cerebral infarctions

Generalized atherosclerosis
Endocarditis
Cardiac tumor (myxoma)
Antiphospholipid antibody syndrome
Cholesterol embolization syndrome
Thrombotic thrombocytopenia purpura
Coagulopathy (inherited)
Paraproteinemia
MR angiogram should be considered inferior to a conventional cerebral angiogram and current sequencing techniques may not visualized involvement of smaller arteries. Cerebral angiogram remains an important diagnostic test; but again, the findings are nonspecific and may be mimicked by many other disorders (Table 4).

Table 4 – Disorders with angiographic findings that can simulate vasculitis

Neoplastic angioendotheliosis
Cerebral vasospasm following aneurysmal or traumatic subarachnoid hemorrhage
Advanced atherosclerosis
Multiple arterial dissections
Acute migraine (thunderclap) attack
Fibromuscular dyplasia
Radiation angiopathy
Moyamoya disease
However, many of the angiographic findings can be very suggestive of vasculitis particularly when there is alternating constrictions and obliterations ("cutoffs"), irregularities, and dilations in a beading pattern. These abnormalities are typically in the smaller blood vessels and careful viewing of the smaller branches is necessary to find these abnormalities.

The utility of cerebrospinal fluid in the diagnosis of central nervous system angiitis is very questionable. Cerebrospinal fluid examination may show entirely normal protein and cell count including at the time of flare-up. However, mildly increased protein can be seen, and some patients have only a mild pleocytosis with less than 20 lymphocytes per cubic mm. CSF is needed to exclude infectious causes of cerebral arteritis and might be found in cultures and serology. Fungi, tuberculosis, and syphilis may all cause a cerebral arteritis that has to be excluded by CSF and other diagnostic tests and is treated differently.

Blood and serology tests are necessary to exclude a connective tissue disorder. This should include antinuclear antibody, rheumatoid factor, antineutrophil cytoplasmic antibodies, sedimentation rate and serology against an immunodeficiency virus, herpes zoster virus, cytomegalovirus, syphilis, and toxoplasma. A drug screen is essential to exclude the recent use of cocaine or amphetamines. Ideally, the diagnosis is confirmed by a brain biopsy. Diagnostic evaluation are shown in Table 5.

Table 5 – Diagnostic tests in CNS vasculitis

· CBC with platelets

· Chemistry

· ESR

· C3/C4, CH-50

· ANCA

· ANA, ds DNA

· Rheumatoid factor

· VDRL

· Hepatitis serology

· Viral serology (HZV, HIV)

· Urine analysis for glomerular red cells

· Cerebrospinal fluid

· Neurophthalmologic evaluation

· MRI with gadolinium

· Cerebral angiogram

· Brain and meningeal biopsy

False negative brain biopsies remain a major problem in its diagnosis; and in some cases, the diagnosis remains probable on the basis of multiple infarction, cerebral angiographic findings, involvement of other arterial territories, and exclusion of an infectious trigger. Generally, temporal artery biopsy is negative in isolated CNS vasculitis.

The diagnostic evaluation of CNS vasculitis should take into account the presence of systemic signs. If present it may be more practical and safe to obtain a less invasive biopsy such as skin, muscle and kidney. It is useful to perform an MRA in a patient with multiple hyperintensity in cortical areas indicating vasculitis. The MRA may show in some instances fibromuscular dysplasia, atheromatous disease and intracranial stenosis or dissections. MRA should be followed by a cerebral angiogram and a meningeal or brain biopsy. In fulminant cases aggressive immuno-suppressive agents should be started before invasive diagnostic tests.

Management
Many experts prefer a combination of corticosteroids and cyclophosphamide. There is good evidence that aggressive therapy with corticosteroids using 1–2 mg/kg per day in two divided doses and cyclophosphamide, 2 mg/kg per day orally may reverse isolated CNS vasculitis. Typically, corticosteroids are given for at least one month at a high dose and then start gradually tapering with alternate-day and morning dose. The side effects of corticosteroids are significant and involve cushingoid stigmata, delirium, paroxysmal myopathy, hypertension and rarely epidural lipomatosis with cord compression, hyperosmolar nonketotic hyperglycemia, and herpes zoster infections. Osteoporosis is uncommon with a comparatively short treatment, but supplemental calcium should be considered. Cyclophosphamide is probably needed in patients who have a fulminant form and there is some initial evidence that the corticosteroids alone may not reverse vasculitis. Cyclophosphamide is an alkylating agent and is used in an oral dose but has major toxicity including myelosuppression, increased risk of later malignancy particularly leukemia and lymphomas, and a risk of infertility. Egg and sperm harvesting should offered to young patients. The white blood cell count should be carefully monitored (>3000/mm3). Urinalysis may indicate the development of hemorrhagic cystitis. Cyclophosphamide can be tapered after one year. A follow-up cerebral angiogram may not be useful because scar tissue may result in persistent abnormal findings. MRI follow-up documenting absence of further infarction is probably a better monitoring tool. Recurrence is very uncommon.

VASCULITIS OF THE PERPHERAL NERVOUS SYSTEM

The peripheral nervous system may become involved in a variety of acute vasculitis syndromes but may occur isolated. It is present in up to 70 percent in vasculitic syndromes. It may be the first manifestation but features of a more generalized vasculitis become more obvious soon after presentation. Most commonly it is observed in polyarteritis nodosa, Churg-Strauss syndrome, and Wegener’s granulomatosis.

Clinical Diagnosis
Commonly peripheral nerves are an innocent bystander and the ravaging organ involvement is apparent. Acute mode of onset is not very common (although expected when infarction is the presumed causation) and progression over weeks is typical.

In many connective tissue disorders it may take months to develop a functional disturbance. Transitory shooting pain and paresthesias, foot and wrist drop, and diminished sensation over large skin patches is typical. A "sock-glove" distal sensory-motor polyneuropathy is most common; however, cranial nerves may become involved as well (III, V,VI). Pain and a rapid crippling state are typical if untreated. An ascending paralysis resulting in a quadriparesis may occur, but the marked asymmetry makes a confusion with Guillain-Barré syndrome less likely. Cramping and burning sensation with inability to walk and constant sensation of "rock in a shoe" or "tight band in calves" are common complaints. Examination often shows some skin involvement (purpura, erythema multiforme). Radial, ulnar, and femoral nerves are commonly involved.

Diagnostic tests
Nerve conduction studies will confirm nerve involvement. General observations in axonal damage are poor recruitement of motor units with voluntary effort, reduced amplitude of the motor response and mild slowing of the nerve conduction velocity. Over time reinnervation will produce long duration-high amplitude- motor unit potentials.

The diagnosis hinges on confirmation by sural nerve biopsy but biopsy may also include muscle (30% positive result), rectum (15% positive result), and liver (7% positive result).

The diagnosis of vasculitis is highly probable with transmural inflammatory cell infiltration but other features are very suggestive such as vascular thickening and sclerosis in combination with Wallerian degeneration, obliteration of vessel lumen, periadventitial hemosiderin and epineural capillary proliferation. A recent study found that biopsy of the superficial peroneal and peroneus brevis muscle resulted in a higher yield. Additional iron stains and immune staining for immunoglobulin could further increase the sensitivity.

Treatment
Both cyclophosphamide (1–2 mg/kg orally) and prednisone (1 mg/kg/day) for 2 months followed by a tapering schedule can reduce damage and lead to improvement. Plasma exchange or azathioprine may be useful. Neuropathic pain can be treated with gabapentin, 900 to 3600 mg/day or low dose of prednisone, 10 mg/day after initial high-dose therapy of nortriptyline or amitriptyline. A recent report of a necrotizing vasculitis associated with cold agglutinins suggest improvement with plasma exchange.

Central Nervous System Vasculitis

Necrotizing vasculitis may affect the central and peripheral nervous system. The vasculitides may become life threatening due to ischemic ulceration of the gut, kidney failure, and myocarditis; but it may also primarily involve the nervous system.

Although mild cases have been reported, a fulminant course is much more common. Therefore, its early recognition is paramount to secure a good outcome. Unfortunately, its perplexing initial presentation in many patients makes it very challenging to diagnose. This is also partly because this disorder may affect the central nervous system alone. Not uncommonly a major localizing deficit has occurred at the time of diagnosis. Angiitis of the central nervous system can be part of the systemic disorder which has to be uncovered before treatment is initiated. Three primary CNS vasculitides have been identified, many others are secondary to systemic vasculitis, connective tissue disease, malignancy, infections, and drugs. This section summarizes the most important clinical findings, the differential diagnosis, neuroimaging, and pathological characteristics. It also provides a recommendation for treatment.

Pathology and Classification
Vasculitis (or angiitis) on histologic analysis is characterized by inflammation involving layers of polymorphonuclear cells, mononuclear cells, and giant cells destroying the vessel wall resulting in fibrinoid necrosis, aneurysm formation, and possibly hemorrhage.

The pathological mechanisms that lead to vasculitis have not been elucidated. There is some evidence of cell-mediated immunity and when infiltrates are examined closely, they consist particularly of CD4 lymphocytes. Circulating immunocomplexes or a marked decrease in complement is not a typical feature in isolated CNS angiitis. When pathology is available either at autopsy or from a brain biopsy specimen, angiitis typically involves smaller blood vessels. The criteria for vasculitis have been outlined by Kolodny. These criteria include the following: a) intimal swelling and hyperplasia in arteries, b) adventitial lymphocytes infiltration in veins, c) subintimal and intimal fibrinoid change with adventitial accumulation of histiocytes, d) necrosis and fibrinoid change in media, e) fragmentation of internal elastic lamina, f) panmural infiltration of lymphocytes and histiocytes, g) and the presence of granulomas replacing all or part of the vessel wall.

These lesions involve a cluster of lymphocytes, large monocular cells, fibroblasts, multinucleated giant cells, and plasma cells. Inflammation of the small arteries and veins preferably involve the vessels of the leptomeninges and the branches that penetrate the cortex. (This characteristic is useful when performing a brain biopsy). Most notable is a panangiitis in a longitudinal and circumferential direction. In some patients, the abnormality involves the spinal cord arteries and arterioles, but this is an extremely uncommon cause of a myelopathy. Pathology involving the eye vasculature is uncommon and more widespread not only leading to retinal vasculitis but also uveitis or epiduritis.

The necrosis of the vessel wall results in occlusion and ischemia. A vessel wall rupture commonly leads to subarachnoid hemorrhage often involving the sulci and not the basal cisterns as in rupture from aneurysms located at the circle of Willis. Generally a brain biopsy is done at the time of diagnosis and should ideally involve the area that is abnormal on MRI scan. Although several series claim a sensitivity of 70%, a random brain biopsy has a much lower yield. If a brain biopsy is done, the specimen should include dura, leptomeninges, cortex, and white matter and fixated in 10% buffered formalin for light microscopy. Additional specimen can be frozen or stored with dry ice to be further examined by electron microscopy. Isolated angiitis of the central nervous system has been also termed granulomatous angiitis, but this connotation has been deleted because granulomatous changes are absent in 50% of the cases. When an underlying disorder is absent, central nervous system vasculitis is quite rare with only 300 cases or so reported. Related disorders are Eales disease, seen in India and the Middle East, with predominant retinal artery and vein involvement. Retinal hemorrhages and peripheral scotomas are common, but ischemic strokes have been reported.

Another disorder confined to the central nervous system is radiation angiitis due to carcinoma of the larynx, optic glioma, or pituitary tumor. A marked delay (often decades) is typical, but the effects can be devastating and the arteritis is not responsive to immunosuppression.

Clinical Diagnosis
Isolated CNS angiitis is typically seen in younger (30-50 years) individuals with some predilection for females. It may present as an encephalopathy or dementia, multiple cranial neuropathies or recurrent transient ischemic attacks. Many reviews have noted the predominance of headache at presentation. Biller and Adam’s review claim that diffuse encephalopathy signs are present in up to 80% of the patients, but other reviews have predominantly highlighted the presence of behavioral changes. Obviously, a psychiatric presentation can make the diagnosis extremely challenging. This presentation may involve emotional lability but also at times histrionic behavior, confusional states mimicking dementia, suicidal depression, and acute psychotic exacerbations with visual hallucinations particularly when the occipital lobes have become infarcted. Localizing neurologic findings such as aphasia, apraxia, or hemiparesis often emerge. These neurologic signs and symptoms may be associated not only with infarction but also associated with lobar hemorrhages.

Because vasculitis of the central nervous system more likely can be seen in a setting of other disorders, a comprehensive medical examination is needed. For example, CNS angiitis can be seen in Behcet’s disease in which oral and genital ulcers and many other skin manifestations such as erythema nodosa and multiple pustules are present. Pustules may form 24 hours after a sterile needle prick (Pathergy) and may clinch the diagnosis. However when fever, weight loss and malaise, nondeforming arthritis, abdominal pain, as well as proteinuria and progressive renal failure occurs, polyarteritis nodosa or a more systemic necrotizing vasculitis should be considered. CNS vasculitis has been linked to drug abuse (e.g. amphetamine). However, histopathology available in the reported cases is scanty leading some investigators to conclude that the relationship between amphetamine and vasculitis is tentative at best. The proof of vasculitis due to cocaine is also weak. Many reported cases do show a vasculopathy, but inflammation is rarely impressive. We have noted a very severe occlusive vasculopathy (with a moyamoya pattern) but no evidence of vasculitis on biopsy. Other signs are absent peripheral pulses and difficulty recording blood pressure (Takayasu’s arteritis), uveitis (sarcoidosis), and recent asthma (Churg-Strauss).

The classification of the vasculitides is shown in Table 1.

Table 1 – Classification of angiitis

Isolated CNS vasculitis

Isolated angiitis (granulomatous)
Eales Disease
Radiation vasculitis
CNS vasculitis due to secondary causes

Polyarteritis nodosa
Giant cell arteritis
Takayasu’s arteritis
Wegener’s granulomatosis
Churg-Strauss
Behcet’s disease
Sarcoidosis
SLE, RA
Sjörgen’s disease
Malignancies (lymphoma)
Infections (herpes zoster, syphilis)
Cocaine, amphetamine
Moore’s clinical criteria for the diagnosis of CNS vasculitis are shown here in table 2 for reference. However it remains difficult to define a perfect set of criteria in this rare disorder (more experts than patients) and diagnostic tests, particularly interpretation of brain biopsy may not resolve uncertainties.

Table 2 – Moore’s clinical criteria for diagnosis of isolated angiitis of the CNS

Recent severe onset of headaches, confusion, or multifocal neurologic deficits that are recurrent of progressive
Typical angiographic findings
Exclusion of systemic disease or infection
Leptomeningeal or parenchymal biopsy findings confirming vascular inflammation with exclusion of infection, neoplasia, and non-inflammatory vascular disease
Diagnostic tests
Central nervous system vasculitis is first suggested after routine neuroimaging. The CT scan may show cerebral infarcts in multiple territories but typically involving cortical structures. Although at times, a CT scan may be helpful in diagnosing Wegener’s granulomatosis in which bone thickening focal erosive changes of the natal septum and typical soft tissue mass in the sinuses are seen. The MRI scan more likely will document abnormalities in multiple and cortical structures but may also may be limited to scattered lesions in the white matter as well. Meningeal enhancement due to involvement of the meningeal vessels has been noted. Conversely, one may make an argument that a completely normal MRI scan including diffusion-weighted images would make the diagnosis of fulminant angiitis of the central nervous system highly unlikely. Obviously multiple cerebral infarcts on MRI are nonspecific findings and many disorders (although equally uncommon) may produce similar findings. They are listed in Table 3 and should be excluded before invasive tests (e.g. brain biopsy) are performed.

Table 3 – Differential diagnosis of multiple cerebral infarctions

Generalized atherosclerosis
Endocarditis
Cardiac tumor (myxoma)
Antiphospholipid antibody syndrome
Cholesterol embolization syndrome
Thrombotic thrombocytopenia purpura
Coagulopathy (inherited)
Paraproteinemia
MR angiogram should be considered inferior to a conventional cerebral angiogram and current sequencing techniques may not visualized involvement of smaller arteries. Cerebral angiogram remains an important diagnostic test; but again, the findings are nonspecific and may be mimicked by many other disorders (Table 4).

Table 4 – Disorders with angiographic findings that can simulate vasculitis

Neoplastic angioendotheliosis
Cerebral vasospasm following aneurysmal or traumatic subarachnoid hemorrhage
Advanced atherosclerosis
Multiple arterial dissections
Acute migraine (thunderclap) attack
Fibromuscular dyplasia
Radiation angiopathy
Moyamoya disease
However, many of the angiographic findings can be very suggestive of vasculitis particularly when there is alternating constrictions and obliterations ("cutoffs"), irregularities, and dilations in a beading pattern. These abnormalities are typically in the smaller blood vessels and careful viewing of the smaller branches is necessary to find these abnormalities.

The utility of cerebrospinal fluid in the diagnosis of central nervous system angiitis is very questionable. Cerebrospinal fluid examination may show entirely normal protein and cell count including at the time of flare-up. However, mildly increased protein can be seen, and some patients have only a mild pleocytosis with less than 20 lymphocytes per cubic mm. CSF is needed to exclude infectious causes of cerebral arteritis and might be found in cultures and serology. Fungi, tuberculosis, and syphilis may all cause a cerebral arteritis that has to be excluded by CSF and other diagnostic tests and is treated differently.

Blood and serology tests are necessary to exclude a connective tissue disorder. This should include antinuclear antibody, rheumatoid factor, antineutrophil cytoplasmic antibodies, sedimentation rate and serology against an immunodeficiency virus, herpes zoster virus, cytomegalovirus, syphilis, and toxoplasma. A drug screen is essential to exclude the recent use of cocaine or amphetamines. Ideally, the diagnosis is confirmed by a brain biopsy. Diagnostic evaluation are shown in Table 5.

Table 5 – Diagnostic tests in CNS vasculitis

· CBC with platelets

· Chemistry

· ESR

· C3/C4, CH-50

· ANCA

· ANA, ds DNA

· Rheumatoid factor

· VDRL

· Hepatitis serology

· Viral serology (HZV, HIV)

· Urine analysis for glomerular red cells

· Cerebrospinal fluid

· Neurophthalmologic evaluation

· MRI with gadolinium

· Cerebral angiogram

· Brain and meningeal biopsy

False negative brain biopsies remain a major problem in its diagnosis; and in some cases, the diagnosis remains probable on the basis of multiple infarction, cerebral angiographic findings, involvement of other arterial territories, and exclusion of an infectious trigger. Generally, temporal artery biopsy is negative in isolated CNS vasculitis.

The diagnostic evaluation of CNS vasculitis should take into account the presence of systemic signs. If present it may be more practical and safe to obtain a less invasive biopsy such as skin, muscle and kidney. It is useful to perform an MRA in a patient with multiple hyperintensity in cortical areas indicating vasculitis. The MRA may show in some instances fibromuscular dysplasia, atheromatous disease and intracranial stenosis or dissections. MRA should be followed by a cerebral angiogram and a meningeal or brain biopsy. In fulminant cases aggressive immuno-suppressive agents should be started before invasive diagnostic tests.

Management
Many experts prefer a combination of corticosteroids and cyclophosphamide. There is good evidence that aggressive therapy with corticosteroids using 1–2 mg/kg per day in two divided doses and cyclophosphamide, 2 mg/kg per day orally may reverse isolated CNS vasculitis. Typically, corticosteroids are given for at least one month at a high dose and then start gradually tapering with alternate-day and morning dose. The side effects of corticosteroids are significant and involve cushingoid stigmata, delirium, paroxysmal myopathy, hypertension and rarely epidural lipomatosis with cord compression, hyperosmolar nonketotic hyperglycemia, and herpes zoster infections. Osteoporosis is uncommon with a comparatively short treatment, but supplemental calcium should be considered. Cyclophosphamide is probably needed in patients who have a fulminant form and there is some initial evidence that the corticosteroids alone may not reverse vasculitis. Cyclophosphamide is an alkylating agent and is used in an oral dose but has major toxicity including myelosuppression, increased risk of later malignancy particularly leukemia and lymphomas, and a risk of infertility. Egg and sperm harvesting should offered to young patients. The white blood cell count should be carefully monitored (>3000/mm3). Urinalysis may indicate the development of hemorrhagic cystitis. Cyclophosphamide can be tapered after one year. A follow-up cerebral angiogram may not be useful because scar tissue may result in persistent abnormal findings. MRI follow-up documenting absence of further infarction is probably a better monitoring tool. Recurrence is very uncommon.

VASCULITIS OF THE PERPHERAL NERVOUS SYSTEM

The peripheral nervous system may become involved in a variety of acute vasculitis syndromes but may occur isolated. It is present in up to 70 percent in vasculitic syndromes. It may be the first manifestation but features of a more generalized vasculitis become more obvious soon after presentation. Most commonly it is observed in polyarteritis nodosa, Churg-Strauss syndrome, and Wegener’s granulomatosis.

Clinical Diagnosis
Commonly peripheral nerves are an innocent bystander and the ravaging organ involvement is apparent. Acute mode of onset is not very common (although expected when infarction is the presumed causation) and progression over weeks is typical.

In many connective tissue disorders it may take months to develop a functional disturbance. Transitory shooting pain and paresthesias, foot and wrist drop, and diminished sensation over large skin patches is typical. A "sock-glove" distal sensory-motor polyneuropathy is most common; however, cranial nerves may become involved as well (III, V,VI). Pain and a rapid crippling state are typical if untreated. An ascending paralysis resulting in a quadriparesis may occur, but the marked asymmetry makes a confusion with Guillain-Barré syndrome less likely. Cramping and burning sensation with inability to walk and constant sensation of "rock in a shoe" or "tight band in calves" are common complaints. Examination often shows some skin involvement (purpura, erythema multiforme). Radial, ulnar, and femoral nerves are commonly involved.

Diagnostic tests
Nerve conduction studies will confirm nerve involvement. General observations in axonal damage are poor recruitement of motor units with voluntary effort, reduced amplitude of the motor response and mild slowing of the nerve conduction velocity. Over time reinnervation will produce long duration-high amplitude- motor unit potentials.

The diagnosis hinges on confirmation by sural nerve biopsy but biopsy may also include muscle (30% positive result), rectum (15% positive result), and liver (7% positive result).

The diagnosis of vasculitis is highly probable with transmural inflammatory cell infiltration but other features are very suggestive such as vascular thickening and sclerosis in combination with Wallerian degeneration, obliteration of vessel lumen, periadventitial hemosiderin and epineural capillary proliferation. A recent study found that biopsy of the superficial peroneal and peroneus brevis muscle resulted in a higher yield. Additional iron stains and immune staining for immunoglobulin could further increase the sensitivity.

Treatment
Both cyclophosphamide (1–2 mg/kg orally) and prednisone (1 mg/kg/day) for 2 months followed by a tapering schedule can reduce damage and lead to improvement. Plasma exchange or azathioprine may be useful. Neuropathic pain can be treated with gabapentin, 900 to 3600 mg/day or low dose of prednisone, 10 mg/day after initial high-dose therapy of nortriptyline or amitriptyline. A recent report of a necrotizing vasculitis associated with cold agglutinins suggest improvement with plasma exchange.

Saturday, October 30, 2010

Inflammatory Bowel Disease and Male Fertility

Men treated for inflammatory bowel disease with Sulfazalazine have drug related impairment in sperm quality that often persists after cessation of the drug. This had prompted pharmaceutical companies to develop other “sperm friendly” treatment options. The most frequent age of onset of the inflammatory bowel diseases including idiopathic chronic inflammatory bowel disease (IBD), Crohn’s disease (CD) and Ulcerative Colitis (UC) is between 15 to 30 years of age. This range, of course, coincides with the peak reproductive years. Therefore, it makes good sense that the effect on male fertility of any drug treatment should be known. Azathioprine and 6-Mercaptopurine (6-MP) are effective immunosuppressive agents commonly used for the long term control of UC and CD in the steroid dependent patient and are focus of this article.

Azathioprine is converted to 6-mercaptopurine which acts to decrease cell metabolism and DNA biosynthesis. A study by Russell and Hunsicker (Study of the base analog 6-mercaptopurine in the mouse specific-locus test., Mutat Res. 1987 Jan;176(1):47-52.) found that in mice 6-Mercaptopurine caused chromosomal damage (both structural and numerical) in all stages of development of the male germ-cell. This data was again confirmed by Witt and Bishop (Mutagenicity of anticancer drugs in mammalian germ cells., Mutat Res. 1996 Aug 17;355(1-2):209 34). In a study in rats, a dose dependent decrease in sperm concentration, damage to the seminiferous tubules and a lowering of testosterone was found with Azathioprine therapy (Iwasaki M, Fuse H, Katayama T., The effects of cyclosporine azathioprine and mizoribine on male reproduction in rats, Nippon Hinyokika Gakkai Zasshi. 1996 Jan;87(1):42-9). In addition, in a study in mice, spermatogenesis and fertility was also decreased (Sykora I. Dominant-lethal test of 6-mercaptopurine: dependence on dosage, duration and route of administration. Neoplasma. 1981;28(6):739-46).

There is some, but unfortunately not much, data available on the effect of these agents on sperm production and sperm function in man. A study by Dejaco et al suggested that men treated with Azathioprine have no change in semen quality and
implied that fertility was also unaffected (Gastroenterology. 2001 Nov;121(5):1048 53. Azathioprine treatment and male fertility in inflammatory bowel disease. Comment in: Inflamm Bowel Dis. 2002 May;8(3):234-5). In this study, paired data wasn’t examined. In contrast, a case study by Sills and Tucker found markedly impaired semen parameters in a single patient who had conceived twice with his partner prior to three months of therapy with 6-MP (First experience with intracytoplasmic sperm injection for extreme oligozoospermia associated with Crohn’s disease and 6-mercaptopurine chemotherapy. Asian J Androl. 2003 Mar;5(1):76-8).

Much more data is needed in humans. Many questions remain unanswered; Are the effects of these drugs in man similar to those found in rodents? Is it the medication used or the underlying disease that has a greater effect on sperm? Are the effects seen reversible, and if so over what time period? Additional research is needed to define the effect of these (and other) drugs used in the treatment of inflammatory bowel disease in reproductive-aged men. Until these studies are done, I feel it is advisable to discuss the potential for impairment in fertility and offer sperm banking to reproductive aged men prior to long term treatment with Azathioprine or 6-Mercaptopurine.

Friday, October 29, 2010

Women On Meds That Can Cause Birth Defects Still Skip Birth Control Pills

Despite the risks, women who take medications that can cause birth defects don’t always take their contraceptive pills, a new study suggests.

The study, in the American Journal of Medicine, is the latest addition to a growing genre of medical research based on the giant databases of drug claims assembled by pharmacy-benefit managers. In this case, Medco Health Solutions Inc. looked at 26,136 women among its enrollees who were between the ages of 18 to 44 and were prescribed both an oral contraceptive and a medication that poses a risk to a fetus. Those included statins, sedatives, cancer drugs and anti-acne medications.

Of those women, around 60% appeared to take their contraceptives very reliably, measured as filling prescriptions often enough to have the pills on hand at least 95% of the time. About 22% were moderately adherent, with their contraceptive available 80% to 94% of the time, and another 19% or so appeared to have the pills less than 80% of the time. Those rates barely differed from those for women who weren’t taking drugs that posed fetal dangers.

The researchers said certain groups of women were less adherent to their contraceptive regimens, including those who were taking a large number of different prescription drugs, members of ethnic minorities and those who reported lower levels of education. They suggested that some patients aren’t counseled effectively by doctors or pharmacists, and may not understand information they receive from medication labels and other sources about possible birth-defect risks posed by their drugs.

“This is one of those discussions that can be awkward for patients as well as physicians and pharmacists,” Amy Steinkellner, the study’s lead author and national practice leader for women’s health and family medicine at Medco, tells the Health Blog.

PBMs are getting increasingly aggressive about research and services that push medication compliance, which isn’t a big surprise because they make money partly based on prescriptions being filled. Though patients’ failure to take drugs generally is seen as a significant public-health issue, some ethics researchers have questioned whether PBM and health-insurer enrollees should get a chance to give specific consent before their information is used for research and other purposes. Medco said it analyzed data without names attached and got permission from its clients, which are mostly employers, to use the anonymous information.
go to:
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Thursday, October 28, 2010

The Medical Loss Ratio MLR and Disease Management: Can the Notes Be Cut?

          In the movie Amadeus, Emperor Joseph II criticizes young Wolfgang's "quality" music with the observation that "....there are simply too many notes, that's all. Just cut a few and it will be perfect!"
The same kind of logic has been applied by the same kind political class to the health insurers' medical loss ratio or "MLR." According to the Patient Protection and Affordability Care Act (PPACA), "standard" health plans must now, depending on the type of business line, have a MLR of at least 80% or 85%. This is interpreted to mean that of every dollar in insurance premiums collected by insurers, at least 80 or 85 cents has to be spent on medical care. The remainder (15 to 20 cents) goes to insurance functions, such as marketing, investing, actuarial activities, underwriting, claims processing, associated overhead and profit or surplus. A low MLR could suggest skimping on medical services, bloated administrative overhead or excessive shareholder returns. Therefore, a high MLR is good, right?

Not exactly. Check out this still timely and well written piece on the MLR by James Robinson appearing in a 1997 issue of Health Affairs. He points out that the line that separates money spent for medical services from the money spent for insurance services is very blurred. Insurers are increasingly using premium to administratively promote efficient and high quality medical care, while providers are assuming varieties of insurance-like risk-based arrangements such as capitation, upside shared savings and pay for performance.

Accordingly, says Dr. Robinson, it's easy for a MLR to become "skewed." Being in a market with small number of providers, a large amount of capitated arrangements, a limited number of insurance products, a lot of large customers or government contracts and little attention to quality all require less administrative support and will therefore have a higher MLR. On the other hand, health insurers with large networks that insure significant numbers individuals and small businesses, pay claims on a fee for service basis and have NCQA accreditation are likely to have a lower MLR.

What's more, the MLR is not necessarily a good gauge of insurer efficiency. The MLR was originally developed to help regulators and investors assess health insurer solvency, creditworthiness and profitability. That's because a rising MLR could herald a looming inability of an insurer to pay its debt obligations. The converse assumption - that the MLR measures health plan quality or waste - is more uncertain. In addition, there are no studies that have shown that there is a correlation between the MLR and a) the health status of or b) the total administrative expense per managed care enrollee.

These inconvenient truths haven't stopped a hostile Congress from piling on insurers even after PPACA was passed. Much like Emperor Joseph, Senator Rockefeller prefers that health insurers not have "too many notes" in their administrative expenses and simply solve the problem by eliminating some of them. The good news is that PPACA requires that the National Association of Insurance Commissioners (NAIC) figure out just what "notes" belong among the legitimate administrative expenses of a health insurer and which ones can be assigned to the MLR.

It won't be an easy task. For example, the U.S. Senate report linked above decries the expensing of nurse "hotlines, health and wellness, including disease management and medical management and clinical health policy” in the MLR and cites them as examples of insurer shenanigans aimed at putting profits over patients. Fortunately, the DMAA The Care Continuum Alliance has come out with a more common sense position that reflects the realities described in the Robinson paper linked above.

The DMCB recalls that it helped lead a disease management program that was, in an abundance of regulatory caution, 'expensed' as an health plan administrative cost. The nurses took care of patients. We worried about blood glucose control among persons with diabetes, made sure asthmatics used their inhalers properly and worked hard to keep patients with heart failure from being unnecessarily admitted to the hospital. Based on Robinson's insights about the MLR and a common sense interpretation of what's going on in the trenches of disease management, it's silly to categorize population-based care as an "administrative" function.

Back then, the expensing of population-based care was a local and minor issue. Thanks to this now being the subject of an inflexible, clumsy and one-size-fits-all act of Congress, it's become far more important. The DMCB hopes that the NAIC will recognize that disease management makes beautiful music and that notes cannot be simply cut.

Wednesday, October 27, 2010

Medical Loss Ratios & Health Insurance: Are You A "Constructionist" or an "Activist?"

        As readers may recall from a prior Disease Management Care Blog posting on the topic of medical loss ratios (MLR), the ratio of health insurer medical costs to total costs is conceptually simple, yet administratively complicated. One reason is because providers of medical services - such as hospitals and physicians - are accepting various forms of risk transfer such as capitation, gain sharing and risk contracting that behave like insurance. Health insurers, in turn, have been taking on clinical roles that look and feel like traditional provider services. Examples of the latter include quality assurance, patient reminders and wellness initiatives.

Will the Patient Protection and Affordable Care Act's (PPACA) 80% to 85% MLR requirement make this mash-up "better?"

Opinions seem to fall into two camps:

1) The MLR requirement limits administrative costs and maximizes the spend on health care services and is evidence of an enlightened civilization at work that, by the way, is also providing a target rich environment for health policy bloggers

2) The MLR floor is a clumsy, ill-fated, if well meaning, intrusion into the business operations of insurers that will assure the perpetual employment of a host of health lawyer-regulators which, by the way, provides a target rich environment for bloggers.

The DMCB really thinks that the two points of view above embody a much bigger debate about the role of health insurance in reform between the

1. Constructionists, who view insurance as a means of monetizing and pooling risk in a way that enables the payment of needed health care services, or ...

2) Activists, who favor using the monetizing and pooling of risk to enable the betterment of needed health care services.

Interestingly, despite Senator Rockefeller's apparent constuctionism, the PPACA seems to favor activism. While the DMCB finds the legislative language as murky as a Gulf of Mexico oil plume, it appears to require that health insurers improve health care quality including "effective case management, care coordination, chronic disease management and medication and care compliance initiatives including through use of the medical home model.... activities to prevent hospital readmissions... including patient centered education ...(and).... activities to improve patient safety and reduce medical errors." By the way, the activist view of Medicare may underlie the nomination of Dr. Berwick to lead the Agency.

Unfortunately, since the law is flawed by being both ambiguous and ambivalent, we're in for an interesting time on this issue. Stay tuned.

Monday, October 11, 2010

Light Alcohol Use Related To Reduced Sudden Death In Women

In the October issue of Heart Rhythm, investigators from the Nurses' Health Study report that light to moderate alcohol use is associated with a reduced risk of sudden death in women.

The Nurses' Health Study enrolled over 85,000 women in 1980 (back in those primitive days when "nurses" and "women" were considered synonymous terms), and has followed them for 30 years. Investigators now report that women who consumed one-half to one alcoholic beverage per day had, over a 25 year period, a significantly reduced incidence of sudden cardiac death than did abstainers.

Women who drank more than this, however, had an increased risk of atrial fibrillation, stroke and cancer.

A reduced incidence of sudden death in men who consume light to moderate amounts of alcohol has been reported in previous studies. This is the first large study which examined the question in women.

There are now a number of studies that strongly suggest a cardiovascular benefit from consuming small amounts of alcohol. However, physicians have to weigh such findings against the more massive and far more definitive evidence that consuming larger amounts of alcohol greatly increases not only cardiac risk, but the risk of many other types of medical problems. Added to this is the inherently addictive nature of alcohol, and the great difficulty many people have in limiting their consumption to small amounts.

In consideration of these factors, so far most doctors have refrained from recommending that patients adopt light alcohol consumption, and indeed, have generally decided not to discuss with their patients the evidence that small amounts of alcohol may be beneficial.

Sunday, October 10, 2010

Medical Problems during Pregnancy

Millions of women become pregnant every year and a significant proportion of these pregnancies are complicated by one or more of the medical disorders that can occur during pregnancy. Some of the medical disorders during pregnancy are common and some are less common and some of the medical disorders during pregnancy are rare. The pattern of medical disorders during is also changing. Medical science is advancing rapidly and many medical disorders which were considered contraindications of pregnancy few decades ago are no more considered contraindication of pregnancy. Due to advancement of obstetrics, neonatology, obstetric anesthesiology, and medicine, the expectation of happy outcome of pregnancy for the mother as well as the fetus has also increased to a great extent.

Marked physiological changes occur during pregnancy (e.g. marked increase in cardiac output and workload of heart, which is as much as 40% increase) and the mother’s body need to adapt to these physiological changes appropriately to have a good outcome of pregnancy. Medical disorders which interfere with physiological adaptations of pregnancy can increase the risk of a poor outcome of pregnancy and pregnancy may sometimes aggravate the preexisting medical disorder in a woman.

The medical disorders which can occur during pregnancy are preeclampsia (development of hypertension and presence of protein in urine after 20 weeks of pregnancy or gestation) which occurs in approximately 5-7% of all pregnancies, eclampsia, gestational hypertension, aggravation of existing essential hypertension, cardiovascular disorders (like mitral stenosis, mitral and aortic regurgitation etc.), renal disorders, pulmonary hypertension, pulmonary embolism, deep vein thrombosis, hormonal disorders (like diabetes, gestational diabetes, hypothyroidism or hyperthyroidism), blood disorders, neurological disorders, gastrointestinal disorders and liver diseases. The pregnant women are also prone to develop certain bacterial (urinary tract infection, which is very common medical problem during pregnancy) and viral infections (cytomegalovirus infection, rubella, herpes, HIV infection etc.).

Saturday, October 9, 2010

Treatments For Hyperacidity Problems

Hyperacidity is conventionally treated with antacid tablets. Antacids provide temporary relief especially during an acute, painful attack of hyperacidity. Nonetheless, some antacids have side effects such as hypersensitivity, headache, confusion and dryness. Though the side effects may be considered normal and not to be a cause of concern, they can be very annoying.

To date, there are many medicines for hyperacidity, each with their own way of reducing or preventing excess acid in the stomach. The common and known anti-acidity drugs are Zantac, Prevacid and Prilosec. Studies pitting them against placebo test cases show favorable results.

Nowadays, however, homeopathic treatment is also used to treat hyperacidity. Acidity of the stomach is said to be caused not just by physiological factors but by emotional and psychological factors, too. The homeopathic treatment of hyperacidity is safe and convenient for it focuses on treating the condition by understanding the the mind and body interrelationship. Remedies, however, may also include natural medicines that are not habit-forming. Part of a homeopathy therapy are doing Yoga exercises. These Yoga exercises aims to strengthen digestive power. It also has a relaxing effect to the digestive organs resulting to a more controlled digestion.

On the other hand, self-help treatment can also be done simply by avoiding food and drinks that can lead to hyperacidity. Food and drinks that can cause too much acidity in the stomach includes fried, fatty & spicy foods, as well as caffeinated and alcoholic drinks. Also, eating the food properly will help in proper digestion. A personal regimen to treat hyperacidity can also include regular exercise, losing weight, and a balanced diet.

Tuesday, October 5, 2010

Rheumatic Fever (Acute Rheumatic Fever or ARF)

What is rheumatic fever?
Rheumatic fever (acute rheumatic fever or ARF) is an autoimmune disease that may occur after a group A streptococcal throat infection that causes inflammatory lesions in connective tissue, especially that of the heart, joints, blood vessels, and subcutaneous tissue. The disease has been described since the 1500s, but the association between a throat infection and rheumatic fever symptom development was not described until the 1880s. It was associated with scarlet fever (rash caused by streptococcal exotoxins) in the 1900s. Prior to the broad availability of penicillin, rheumatic fever was a leading cause of death in children and one of the leading causes of acquired heart disease in adults। The disease has many symptoms and can affect different parts of the body, including the heart, joints, skin, and brain. There is no simple diagnostic test for rheumatic fever, so the American Heart Association's modified Jones criteria (first published in 1944 and listed below) are used to assist the physician in making the proper diagnosis.

What are the Jones criteria?
Jones criteria are guidelines decided on by the American Heart Association to help doctors clinically diagnose rheumatic fever. Two major criteria or one major and two minor plus a history of a streptococcal throat infection are required to make the diagnosis of rheumatic fever.

The major criteria for diagnosis include

arthritis in several joints (polyarthritis),
heart inflammation (carditis),
nodules under the skin (subcutaneous nodules or Aschoff bodies),
rapid, jerky movements (Sydenham's chorea), and
skin rash (erythema marginatum).
The minor criteria include
fever,
high ESR (erythrocyte sedimentation rate, an laboratory sign of inflammation),
joint pain (arthralgia),
EKG changes (electrocardiogram), and
other laboratory findings (elevated C-reactive protein, elevated or rising streptococcal antigen test)

What causes rheumatic fever?
There is a direct and well described connection between certain streptococcal infections and rheumatic fever. Most commonly, rheumatic fever is preceded by a throat infection with group A beta-hemolytic Streptococcus (strep throat, GABHS, or GAS). The bacterium causes an autoimmune (antibodies that attack the host's own cells) inflammatory response in some people which leads to the myriad of signs and symptoms described by the Jones criteria. Streptococcal throat infections are contagious, but rheumatic fever is not. The symptoms of rheumatic fever generally develop within two to three weeks of an infection with streptococcal bacteria, and usually the first symptoms are painful joints or arthritis.

Stroke

What is a stroke?
Brain cell function requires a constant delivery of oxygen and glucose from the bloodstream. A stroke, or cerebrovascular accident (CVA), occurs when blood supply to part of the brain is disrupted, causing brain cells to die. Blood flow can be compromised by a variety of mechanisms.

 
Blockage of an artery

Narrowing of the small arteries within the brain can cause a lacunar stroke, (lacune means "empty space"). Blockage of a single arteriole can affect a tiny area of brain causing that tissue to die (infarct).

Hardening of the arteries (atherosclerosis) leading to the brain. There are four major blood vessels that supply the brain with blood. The anterior circulation of the brain that controls most motor activity, sensation, thought, speech, and emotion is supplied by the carotid arteries. The posterior circulation, which supplies the brainstem and the cerebellum, controlling the automatic parts of brain function and coordination, is supplied by the vertebrobasilar arteries.
Embolism to the brain from the heart. In some instances blood clots can form within the heart and the potential exists for them to break off and travel (embolize) to the arteries in the brain and cause a stroke.
Rupture of an artery (hemorrhage)

Cerebral hemorrhage (bleeding within the brain substance). The most common reason to have bleeding within the brain is uncontrolled high blood pressure. Other situations include aneurysms that leak or rupture or arteriovenous malformations (AVM) in which there is an abnormal collection of blood vessels that are fragile and can bleed.

What causes a stroke?
Blockage of an artery

The blockage of an artery in the brain by a clot (thrombosis) is the most common cause of a stroke. The part of the brain that is supplied by the clotted blood vessel is then deprived of blood and oxygen. As a result of the deprived blood and oxygen, the cells of that part of the brain die and the part of the body that it controls stops working. Typically, a cholesterol plaque in a small blood vessel within the brain that has gradually caused blood vessel narrowing ruptures and starts the process of forming a small blood clot.

Risk factors for narrowed blood vessels in the brain are the same as those that cause narrowing blood vessels in the heart and heart attack (myocardial infarction). These risk factors include:

high blood pressure (hypertension),
high cholesterol,
diabetes, and
smoking.
Embolic stroke

Another type of stroke may occur when a blood clot or a piece of atherosclerotic plaque (cholesterol and calcium deposits on the wall of the inside of the heart or artery) breaks loose, travels through the bloodstream and lodges in an artery in the brain. When blood flow stops, brain cells do not receive the oxygen and glucose they require to function and a stroke occurs. This type of stroke is referred to as an embolic stroke. For example, a blood clot might originally form in the heart chamber as a result of an irregular heart rhythm, such as occurs in atrial fibrillation. Usually, these clots remain attached to the inner lining of the heart, but occasionally they can break off, travel through the blood stream, form a plug (embolism) in a brain artery, and cause a stroke.

Cerebral hemorrhage

A cerebral hemorrhage occurs when a blood vessel in the brain ruptures and bleeds into the surrounding brain tissue. A cerebral hemorrhage (bleeding in the brain) causes stroke symptoms by depriving blood and oxygen to parts of the brain in a variety of ways. Blood flow is lost to some cells. As well, blood is very irritating and can cause swelling of brain tissue (cerebral edema). Edema and the accumulation of blood from a cerebral hemorrhage increases pressure within the skull and causes further damage by squeezing the brain against the bony skull further decreasing blood flow to brain tissue and cells.

Subarachnoid hemorrhage


In a subarachnoid hemorrhage, blood accumulates in the space beneath the arachnoid membrane that lines the brain. The blood originates from an abnormal blood vessel that leaks or ruptures. Often this is from an aneurysm (an abnormal ballooning out of the wall of the vessel). Subarachnoid hemorrhages usually cause a sudden, severe headache, nausea, vomiting, light intolerance, and a stiff neck. If not recognized and treated, major neurological consequences, such as coma, and brain death may occur.

Vasculitis

Another rare cause of stroke is vasculitis, a condition in which the blood vessels become inflamed causing decreased blood flow to brain tissue.

Migraine headache


There appears to be a very slight increased occurrence of stroke in people with migraine headache. The mechanism for migraine or vascular headaches includes narrowing of the brain blood vessels.

What are the risk factors for stroke?
Overall, the most common risk factors for stroke are:

high blood pressure,
high cholesterol,
smoking,
diabetes and
increasing age.
Heart rhythm disturbances like atrial fibrillation, patent foramen ovale, and heart valve disease can also be the cause.

An example of a genetic predisposition to stroke occurs in a rare condition called homocystinuria, in which there are excessive levels of the chemical homocystine in the body. Scientists are trying to determine whether the non-hereditary occurrence of high levels of homocystine at any age can predispose to stroke.

Syphilis

Syphilis:
A sexually transmitted disease caused by Treponema pallidum.

Syphilis is a major health problem. About 12 million new cases of syphilis occur every year. More than 90% of them are in developing nations where congenital syphilis remains a leading cause of stillbirths and newborn deaths. In North America and Western Europe, syphilis is disproportionately common and rising among men who have sex with men and among persons who use cocaine or other illicit drugs.


There are three stages of syphilis:

The first (primary) stage (1-5 weeks): This involves the formation of the chancre,a classic painless ulcer of syphilis. At this stage, syphilis is highly contagious.
The second (secondary) stage (4-6 weeks): However, 25 percent of cases will proceed to the secondary stage of syphilis.
This phase can include hair loss; a sore throat; white patches in the nose, mouth, and vagina; fever; headaches; and a skin rash. There can be lesions on the genitals that look like genital warts, but are caused by spirochetes rather than the wart virus. These wart-like lesions, as well as the skin rash, are highly contagious. The rash can occur on the palms of the hands, and the infection can be transmitted by casual contact.
The third (tertiary) stage: This final stage of the disease involves the brain and heart, and is usually no longer contagious. At this point, however, the infection can cause extensive damage to the internal organs and the brain, and can lead to death.
Diagnosis :
Is by following blood tests
Rapid plasma reagin (RPR)
Venereal Disease Research Laboratory (VDRL) test.
Fluorescent treponemal antibody absorbed (FTA-ABS) test.
Treatment : Syphilis is treated with penicillin, administered by injection.
Other antibiotics can be used for patients allergic to penicillin.
A small percentage of patients do not respond to the usual doses of penicillin. Therefore, it is important that patients have periodic repeat blood tests to make sure that the infectious agent has been completely destroyed and there is no further evidence of the disease.
In all stages of syphilis, proper treatment will cure the disease, but in late syphilis, damage already done to body organs cannot be reversed.

Prevention of Syphilis:
Patients with infectious syphilis should abstain from sexual activity until rendered noninfectious by antibiotic therapy.
Talk openly with your partner about STDs, HIV, and hepatitis B infection, and the use of contraception. All sexually active persons should consider using latex condoms to prevent STDs and HIV infection, even if they are using another form of contraception.
Latex condoms used consistently and correctly are an effective means for preventing disease (and pregnancy). Since latent condoms protect covered parts only, the exposed parts should be washed with soap and water as soon after contact as possible. This applies to men and women.

Gonorrhea

What is Gonorrhea?
Also called the "clap" or "drip," gonorrhea is a contagious disease transmitted most often through sexual contact with an infected person. Gonorrhea may also be spread by contact with infected bodily fluids, so that a mother could pass on the infection to her newborn during childbirth. Both men and women can get gonorrhea. The infection is easily spread and occurs most often in people who have many sex partners.

What Causes Gonorrhea?
Gonorrhea is caused by Neisseria gonorrhoeae, a bacterium that can grow and multiply easily in mucus membranes of the body. Gonorrhea bacteria can grow in the warm, moist areas of the reproductive tract, including the cervix (opening to the womb), uterus (womb), and fallopian tubes (egg canals) in women, and in the urethra (the tube that carries urine from the bladder to outside the body) in women and men. The bacteria can also grow in the mouth, throat, and anus.

How Common Is Gonorrhea?
Gonorrhea is the second most common infectious disease in the U.S. There were almost 337,000 reported cases of gonorrhea in the U.S. in 2008, a slight decline from the previous year. The largest number of reported cases that year was among girls between the ages of 15 and 19.

How Do I Know If I Have Gonorrhea?
Not all people infected with gonorrhea have symptoms, so knowing when to seek treatment can be tricky. When symptoms do occur, they are often within two to 10 days after exposure, but can take up to 30 days and include the following:


Gonorrhea symptoms in women

Greenish yellow or whitish discharge from the vagina
Lower ab dominal or pelvic pain
Burning when urinating
Conjunctivitis (red, itchy eyes)
Bleeding between periods
Spotting after intercourse
Swelling of the vulva (vulvitis)
Burning in the throat (due to oral sex)
Swollen glands in the throat (due to oral sex)
In some women, symptoms are so mild that they escape unnoticed.

Many women with gonorrhea discharge think they have a yeast infection and self-treat with over-the-counter yeast infection drug. Because vaginal discharge can be a sign of a number of different problems, it is best to always seek the advice of a doctor to ensure proper diagnosis and treatment.

kidney stone

What is a kidney stone?

A kidney stone is a hard, crystalline mineral material formed within the kidney or urinary tract. Kidney stones are a common cause of blood in the urine and often severe pain in the abdomen, flank, or groin. Kidney stones are sometimes called renal calculi. One in every 20 people develops a kidney stone at some point in their life.

The condition of having kidney stones is termed nephrolithiasis. Having stones at any location in the urinary tract is referred to as urolithiasis.

What causes kidney stones?

Kidney stones form when there is a decrease in urine volume and/or an excess of stone-forming substances in the urine. The most common type of kidney stone contains calcium in combination with either oxalate or phosphate. Other chemical compounds that can form stones in the urinary tract include uric acid and the amino acid cystine.

Dehydration from reduced fluid intake or strenuous exercise without adequate fluid replacement increases the risk of kidney stones. Obstruction to the flow of urine can also lead to stone formation. Kidney stones can also result from infection in the urinary tract; these are known as struvite or infection stones.

Men are especially likely to develop kidney stones, and Caucasians are more often affected than blacks. The prevalence of kidney stones begins to rise when men reach their 40s, and it continues to climb into their 70s. People who have already had more than one kidney stone are prone to develop more stones. A family history of kidney stones is also a risk factor for developing kidney stones.

A number of different medical conditions can lead to an increased risk for developing kidney stones:

* Gout results in an increased amount of uric acid in the urine and can lead to the formation of uric acid stones.


* Hypercalciuria (high calcium in the urine), another inherited condition, causes stones in more than half of cases. In this condition, too much calcium is absorbed from food and excreted into the urine, where it may form calcium phosphate or calcium oxalate stones.


* Other conditions associated with an increased risk of kidney stones include hyperparathyroidism, kidney diseases such as renal tubular acidosis, and some inherited metabolic conditions including cystinuria and hyperoxaluria. Chronic diseases such as diabetes and high blood pressure (hypertension) are also associated with an increased risk of developing kidney stones.


* People with inflammatory bowel disease or who have had an intestinal bypass or ostomy surgery are also more likely to develop kidney stones.


* Some medications also raise the risk of kidney stones. These medications include some diuretics, calcium-containing antacids, and the protease inhibitor indinavir (Crixivan), a drug used to treat HIV infection.

What are kidney stones symptoms?

While some kidney stones may not produce symptoms (known as "silent" stones), people who have kidney stones often report the sudden onset of excruciating, cramping pain in their low back and/or side, groin, or abdomen. Changes in body position do not relieve this pain. The pain typically waxes and wanes in severity, characteristic of colicky pain (the pain is sometimes referred to as renal colic). It may be so severe that it is often accompanied by nausea and vomiting. Kidney stones also characteristically cause blood in the urine. If infection is present in the urinary tract along with the stones, there may be fever and chills. Sometimes, symptoms such as difficulty urinating, urinary urgency, penile pain, or testicular pain may occur due to kidney stones.


How are kidney stones diagnosed?

The diagnosis of kidney stones is suspected by the typical pattern of symptoms when other possible causes of the abdominal or flank pain are excluded. Imaging tests are usually done to confirm the diagnosis. A helical CT scan without contrast material is the most common test to detect stones or obstruction within the urinary tract. Formerly, an intravenous pyelogram (IVP; an X-ray of the abdomen along with the administration of contrast dye into the bloodstream) was the test most commonly used to detect urinary tract stones, but this test has a greater risk of complications, takes longer, and involves higher radiation exposure than the non-contrasted helical CT scan. Helical CT scans have been shown to be a significantly more effective diagnostic tool than the IVP in the diagnosis of kidney or urinary tract stones.

In pregnant women or those who should avoid radiation exposure, an ultrasound examination may be done to help establish the diagnosis.

Hematuria

What is blood in urine (hematuria)?
Hematuria, or blood in the urine, can be either gross (visible) or microscopic (as defined by more than three to five red blood cells per high power field when viewed under magnification). Gross hematuria can vary widely in appearance, from light pink to deep red with clots. Despite the quantity of blood in the urine being different, the types of conditions that can cause the problem are the same, and the workup or evaluation that is needed is identical.

People with gross hematuria usually present to their doctor with this as a primary complaint. Microscopic hematuria, on the other hand, is most commonly detected as part of a periodic checkup by a primary-care physician.


What are the causes of blood in urine?
The causes of gross and microscopic hematuria are similar and may result from bleeding anywhere along the urinary tract. One cannot readily distinguish between blood originating in the kidneys, ureters (the tubes that transport urine from the kidneys to the bladder), bladder, or urethra. Any degree of blood in the urine should be fully evaluated by a physician, even if it resolves spontaneously.

Infection of the urine, stemming either from the kidneys or bladder, is a common cause of microscopic hematuria. Kidney and bladder stones can cause irritation and abrasion of the urinary tract, leading to microscopic or gross hematuria. Trauma affecting any of the components of the urinary tract or the prostate can lead to bloody urine. Hematuria can also be associated with renal (or kidney) disease, as well as hematologic disorders involving the body's clotting system. Medications that increase the risk of bleeding, such as aspirin, warfarin (Coumadin), or clopidogrel (Plavix), may also lead to bloody urine. Lastly, cancer anywhere along the urinary tract can present with hematuria.

Scabies

What is scabies?
Human scabies is caused by an infestation of the skin by the human itch mite (Sarcoptes scabiei var. hominis). The microscopic scabies mite burrows into the upper layer of the skin where it lives and lays its eggs. The most common symptoms of scabies are intense itching and a pimple-like skin rash. The scabies mite usually is spread by direct, prolonged, skin-to-skin contact with a person who has scabies.

Scabies occurs worldwide and affects people of all races and social classes. Scabies can spread rapidly under crowded conditions where close body contact is frequent. Institutions such as nursing homes, extended-care facilities, and prisons are often sites of scabies outbreaks.

Transmission
Human scabies is caused by an infestation of the skin by the human itch mite (Sarcoptes scabiei var. hominis). The adult female scabies mites burrow into the upper layer of the skin (epidermis) where they live and deposit their eggs. The microscopic scabies mite almost always is passed by direct, prolonged, skin-to-skin contact with a person who already is infested. An infested person can spread scabies even if he or she has no symptoms. Humans are the source of infestation; animals do not spread human scabies.

Persons At Risk
Scabies can be passed easily by an infested person to his or her household members and sexual partners. Scabies in adults frequently is sexually acquired.

Scabies is a common condition found worldwide; it affects people of all races and social classes. Scabies can spread easily under crowded conditions where close body and skin contact is common. Institutions such as nursing homes, extended-care facilities, and prisons are often sites of scabies outbreaks. Child care facilities also are a common site of scabies infestations.

Eczema

What is eczema?
Eczema is a general term for many types of skin inflammation, also known as dermatitis. The most common form of eczema is atopic dermatitis (some people use these two terms interchangeably). However, there are many different forms of eczema.

Eczema can affect people of any age, although the condition is most common in infants, and about 85% of people have an onset prior to 5 years of age. Eczema will permanently resolve by age 3 in about half of affected infants. In others, the condition tends to recur throughout life. People with eczema often have a family history of the condition or a family history of other allergic conditions, such as asthma or hay fever. Up to 20% of children and 1%-2% of adults are believed to have eczema. Eczema is slightly more common in girls than in boys. It occurs in people of all races.

Eczema is not contagious, but since it is believed to be at least partially inherited, it is not uncommon to find members of the same family affected.


What are the causes of eczema?
Doctors do not know the exact cause of eczema, but a defect of the skin that impairs its function as a barrier, possibly combined with an abnormal function of the immune system, are believed to be an important factors. Studies have shown that in people with atopic dermatitis, there are gene defects that lead to abnormalities in certain proteins (such as filaggrin) that are important in maintaining the barrier of normal skin.

Some forms of eczema can be triggered by substances that come in contact with the skin, such as soaps, cosmetics, clothing, detergents, jewelry, or sweat. Environmental allergens (substances that cause allergic reactions) may also cause outbreaks of eczema. Changes in temperature or humidity, or even psychological stress, can lead to outbreaks of eczema in some people.


What are the symptoms of eczema?
Eczema most commonly causes dry, reddened skin that itches or burns, although the appearance of eczema varies from person to person and varies according to the specific type of eczema. Intense itching is generally the first symptom in most people with eczema. Sometimes, eczema may lead to blisters and oozing lesions, but eczema can also result in dry and scaly skin. Repeated scratching may lead to thickened, crusty skin.

While any region of the body may be affected by eczema, in children and adults, eczema typically occurs on the face, neck, and the insides of the elbows, knees, and ankles. In infants, eczema typically occurs on the forehead, cheeks, forearms, legs, scalp, and neck.


What are the different types of eczema?
Atopic dermatitis is the most common of the many types of eczema, and sometimes people use the two terms interchangeably. But there are many terms used to describe specific forms of eczema that may have very similar symptoms to atopic dermatitis. These are listed and briefly described below.

Dandruff (Seborrhea)

What is dandruff (seborrhea)?
It is a common form of skin eczema that occurs in parts of the body with high oil (sebum) production. Body areas that are commonly affected include the scalp, ears, face, chest, and folds of skin, such as the underarms or the skin below breasts or overhanging abdominal folds. The cause of seborrhea is unknown, although a yeast that often lives on the skin, Malassezia furfur, may play a role.

One common manifestation of seborrhea that affects the scalp is dandruff. Scalp seborrhea can also present as thick, flaky, localized patches of scale. On the face, seborrhea produces reddish-brown, dry-looking, or thick, greasy scales on the eyebrows, sides of the nose, and behind the ears. Reddish, scaly patches may also appear in the folds of skin mentioned above. Although skin affected by seborrhea may feel "dry," moisturizing only makes them redder.

Scalp seborrhea and dandruff do not cause permanent hair loss. Often, scalp seborrhea doesn't even itch significantly. Seborrhea can appear during infancy, starting shortly after birth and lasting several months. It may affect the scalp ("cradle cap") or produce scaly patches on the body. Adults of all ages may develop seborrhea, too, especially on the scalp and face.

What treatments are available for dandruff?
Treatment of seborrhea (dandruff) is directed at fighting the skin inflammation. This is done either directly, by using cortisone-based creams and lotions (which reduce inflammation), or by reducing the yeast that builds up on scaly areas and adds to the problem. Note, though, that seborrhea is not a yeast infection.


What doesn't help dandruff?
Moisturizing: Moisturizing lotions don't do much more than smooth out scales and make patches look redder.
Switching brands of shampoo: Shampoo doesn't cause dandruff. However, medicated shampoos (see below) can help.
Changing hair-care routines: There is no "right" shampoo or conditioner, nor is there a "correct" number of times to shampoo per week; seborrhea and dandruff are not caused by excessive shampooing "drying out the scalp." Hair dyes and conditioners do not cause or aggravate dandruff.
Switching antiperspirants: When underarms are red from seborrhea, almost anything will make them redder, including antiperspirants, even though they are only aggravating the seborrhea and not causing it.