Syringomyelia.

Neurosyphilis. Endarterytis of Brain vessels. Basal meningitis. Meningomyelitis. Meningoradiculitis. Cerebral-Spinal Syphilis. Tabes dorsalis. Dementia Paralytica

Lesion of Nervous system by AIDS

Syringomyelia

The term Syringomyelia connotes a chronic, progressive disorder that most often involves the spinal cord.

Syringomyelia or cavitations of the spinal cord was first described by Esteinne in 1546 in «La Dissection Du Corps Humain». The precise term syringomyelia referring to cavitations of the spinal cord is attributed to Charles P. Ollivier D’Angers in 1827. He attributed the abnormal dilatation of the central canal to a developmental abnormality.

Syringomyelia is quite rare. It occurs more frequently in men then in women. The first sign of the disease appears in the second or third decade of life but sometimes it may begin in childhood or late adulthood.

Etiology

Normally on the 6^th – 8^th week of embryo development as a result of high production of CSF and increased pressure in the neural tube the connection between the ventricular system and subarachnoid space is established and the central canal is obliterated.

The occlusion of drain holes can cause the widening of central canal and creation of cavities.

But this theory has some weak places. That’s why we should pay attention to the others possible reasons of creation of medullar cavity. They are:

· Necrotic myelitis

· Hemorrhage

· Trauma of spinal cord

· After meningitis

In 1971 Grinand supposed that Syringomyelia is one of the slowly progressive infections. According to the pathology there are three types of Syringomyelitic cavities:

• Symmetric central – medullar - the simple wideness of canal
• Central with paracentral expansion. They are usually located in the brain parenchyma and are the result of previous diseases.

Classification

There are several classifications according to the clinical features, expansion, and course of the disease, etiology, pathogenesis and the stage of the disease.

According to the clinical form (Borisova N.A. 1989) there are such forms:

· Posterior horns - 40 – 50 %

· Anterior horns - 10 – 15 %

· Autonomic – trophic – 5 – 10 %

· Mixed - 30 – 40 %

· Bulbar

According to the expansion of pathologic process there are:

• Spinal (cervical - 2 – 4 %, cervical – thoracic – 70 – 80 %, thoracic – 10 %, lumbar – sacral – 1 – 2 %, total - 8 – 10 %)
• Brain stem
• Brain stem – spinal

According to the course of the disease the are:

• Stable – 25 %
• Slowly progressive – 50 %
• Rapid progressive - 25%

According to the etiology and pathogenesis (1998)

I. Idiopathic

II. Secondary

1. As a result of cranio – vertebral abnormality

2. After trauma

3. Associated with hydrocephalus

4. As a result of cervical part of spinal cord stenosis

5. As a result of lumbar myelitis

6. At Pegett disease

7. At cysts of posterior cranial fossa

8. At tumours of occipital large foramen

9. At extramedullar tumours and cysts

10. At brain tumours

11. As a result of arachnoiditis

The risk factors are:

1. Syringomyelia in family members

2. The signs of dysraphic state (facial asymmetry, high palate, eye lids hypertrophy, short neck, shoulders asymmetry, acromehalia, enuresis, scoliosis, shortness)

3. Permanent physical exercises, trauma.

Clinical features and diagnostic criteria:

1.    The first signs of the disease are:

         The loss of pain and temperature sensation on upper extremities (as a result of trauma or burns)

         Pains in the region of shoulders

         Trophic disturbances (ulcers)

         Horner syndrome

30 – 40 % of patients with syringomyelia have subclinical course of the disease and the diagnosis is usually put during the preventive examinations.

2.    At neurologic examination there are:

         Sensory disorders - dissociative loss of pain and temperature sensation “coat like“ and half coat like”. In case of progress of the disease there are signs of loss of deep sensation.

         Motor disorders – segmental (distal one side or bilateral peripheral paresis of upper extremities, seldom – lower extremities), central (spastic mono and paraparesis of lower extremities). In case of pathologic focus in the medulla oblongata we can observe the signs of bulbar palsy.

         Autonomic – trophic disorders – acrocianosis, hyper – anhydrosis, oedema of extremities, neuro – dystrophic lesions of extremities (in 70 % of all patients). There are defects of joints, neuro – osteopathy with the lesion of extremity function. ( Fig ) рис 58 стор 249

In case of clinical features of CSF disturbances at syringomyelia sometimes the signs of limbico – reticular complex are joined.

         AVD

         Neuro – endocrynologic metabolic syndrome

Additional methods of examination

1.    X – ray of cranial cavity, cranio – vertebral part, spinal cord, joints. This method helps to differentiate the disease with inborn defects and secondary pathologic changes

2.    MRI – this method affords us to find out the type of syringomyelia and indications to the surgical treatment

3.    CT – this method doesn’t give us too much information

4.    ENMG – affords us to register pyramidal signs

5.    Esthesiometry helps us to localize the expansion of sensory disorders

Differential diagnosis

1.    Intramedullar tumour (first of all those that are localized in the cervical part of the spinal cord). MRI data helps to put the right diagnosis

2.    Hematomyelia. Differential features are – acute beginning after the trauma, gradual regress of the main symptoms.

3.    ALS at the beginning of the disease in case of anterior horn form. We should pay attention to the rapid progress and additional methods of examination data.

4.    Cervical ischemic myelopathy at anterior horn form, Reino disease and angiopathy at autonomic form.

5.    Compressive - ischemic mononeuropathy (at the beginning of the disease).

Prognosis

In case of slow progress and slight neurologic symptoms the patients preserve working ability up to 6 – 25 years. Rapid progress leads to the loss of working ability during 2 – 5 years. Rapid progress is much more common in persons involved in high physical activity in industry and agriculture.

Treatment

1.    Conservative treatment.

A.   X – ray therapy – at glious forms. The method is based on the fact that X – ray decrease glia proliferation and the progress of the disease. It is used 5 times per week. The dose is – 90 Rad. For the course we use 900 – 1000 Rad. (9 – 11 Gr) . The course is repeated in 1 – 1.5 year.

B.   Radioactive P and J. The mechanism of action is the same as in previous case. J is introduced twice a week in dose 50 – 100 MKuri (150 – 170 MKuri for the whole course. Usually 4 – 5 courses are used every 1 – 1.5 year. P is prescribed in dose 150 – 170 MKuri every 3 – 4 days up to the dose 500 – 450 MKuri. This course is repeated in 3 months.

C.   Symptomatic treatment – Proserinum, Nicotinic acid, vit B, nonsteroid antiinflammatory medicines. At severe pain – analgethics, antidepressants and neuroleptics are used.

D.   Physiotherapy – massage, treating bathes. Hitting procedures are forbidden.

Syringomyelia, Syringobulbia

Definition

Syringomyelia is a cavitation of the spinal cord. It is a rare and destructive condition involving the cord and occasionally the brainstem (syringobulbia).

Etiology and Pathology

Syringomyelia is a syndrome. The common factor is cavitation within the substance of the spinal cord. Three types of cavity can be identified.

1. A tubular dilatation of the central canal of the spinal cord communicates with the fourth ventricle. This abnormality has been termed hydromyelia or communicating syringomyelia and is associated with hydrocephalus and may follow meningitis or subarachnoid hemorrhage, where the aqueduct of Sylvius is obstructed and the outlets from the fourth ventricle occluded by arachnoid adhesions. Other conditions associated with communicating syringomyelia include Chiari type 2 malformation.

The syrinx consists of a dilatation of the central canal lined by ependyma, surrounded by glial tissue. There is no communication with the subarachnoid space, but communicating syringomyelia with Chiari type 2 malformation may be associated with myelomeningocele.

2. The second type of syringomyelia consists of a focal dilatation of the central canal separated from the fourth ventricle by syrinx-free spinal cord. There are Chiari type 1 malformations in about 50 percent of cases, cervical canal stenosis, arachnoiditis, basilar impression, and occipital encephalocele; congenital cysts of the fourth ventricle occur in some cases. This type of syrinx is closed at the upper end by a canal stenosis; the rostral proportion communi cations with a normal or occasionally stenosed central canal. This type of syrinx frequently dissects into the parenchyma of the spinal cord and occasionally communicates with the subarachnoid space. Dissection into the parenchyma of the lower brainstem causing syringobulbia has been described.

3. A third type of syringomyelia consists of a cavity within the parenchyma of the spinal cord, which does not communicate with a central canal. This condition, which is an extracanalicular syrinx, is usually found in central gray matter, dorsal and lateral to the central canal. Etiologic factors include trauma, ischemic infarction, postmeningitic infarction, intramedullary hemorrhage, transverse myelitis, and radiation necrosis. Extracanalicular syringomyelia is associated with as many as 45 percent of intramedullary tumors, with 49 percent presenting above the tumor, 11 percent below the tumor, and 40 percent above and below the tumor. Ependymomas, hemangioblastomas, and astrocytomas, in that order, have the highest association with syringomyelia. Syrinx formation probably results from partial obstruction of the subarachnoid space by arachnoiditis, with passage of pressure waves of CSF through extracellular spaces in the spinal cord, into the parenchyma of the cord, with subsequent cavity formation.

Clinical Features

Syringomyelia occurs most commonly in the cervical area of the cord, and the clinical features can be explained by the anatomic location of the tract of the spinal cord (Fig. 14-3).

Extension of the cavity in an anterolateral direction produces pressure on and destruction of the anterior horn cells, resulting in weakness and wasting of the small muscles of the hand. Fasciculations may be seen. Expansion laterally exerts pressure on the corticospinal tracts, producing spasticity, increased tendon reflexes below the level of the lesion, and extensor plantar responses. Lateral extension involves the lateral spinothalamic tract, with subsequent loss of pain and temperature sensation on the opposite side of the body. When the cavity expands anteriorly, it interrupts the decussating fibers of the lateral spinothalamic tracts and results in bilateral loss of pain and temperature sensation. Loss of pain sensa tion results in undetected injury of the affected areas of the hands and fingers. Infection and joint deformities may result. The presence of Charcot joints in the shoulders is nearly always due to syringomyelia and only occasionally occurs in other conditions such as chronic diabetic peripheral neuropathy. Involvement of the descending sympathetic fibers may result in an ipsilateral Horner syndrome.

In syringobulbia the patient usually presents with weakness and wasting of the tongue or dysphagia and dysarthria due to involvement of the vagal complex. Lateral extension may involve the spinal tract of the trigeminal nerve, producing loss of pain and temperature sensation of the ipsilateral face. If the decussating fibers of the medial lemniscus are involved, ipsilateral loss of touch, vibration, and proprioception may result. Involvement of the medial longitudinal fasciculus may result in nystagmus or internuclear ophthalmoplegia. With more rostral extension, diplopia and ptosis may occur.

Diagnostic Procedures

1. An MRI scan will usually demonstrate the presence of the syrinx within the spinal cord and the extent of the abnormality on sagittal sections (Fig. 14-4). Extracanalicular syringomyelia, including post-traumatic syringomyelia, presents with a centrally located cavity caudally, extending to a rostral cavity, markedly off-center. Extension into the brainstem can be demonstrated in most cases of syringobulbia by MRI scans.

Fig. Arnold-Kiari anomaly

Fig. Syringomyelia

2. Electrophysiologic studies show reduction in hypothenar compound muscle action potentials in the presence of a cervical syrinx, with fibrillations and reduced motor potentials in the small muscles of the hand. Ulnar and median somatosensory evoked potentials are normal in the presence of dissociated sensory loss but abnormal when all sensory modalities are impaired. The tibial nerve somatosensory evoked potentials are usually abnormal.

Differential Diagnosis

1. In hematomyelia, there is a sudden onset of pain in the involved area and a history of trauma. The MRI scan reveals the presence of blood within the substance of the spinal cord.

2. An intermedullary tumor tends to have a more rapid course, and the CSF protein is elevated. However, intermedullary tumors can present as a syrinx or in association with syringomyelia.

3. An extramedullar tumor is more likely to present with root pain and obstruction or block of the subarachnoid space. CSF protein is elevated.

4. Amyotrophic lateral sclerosis. There is no sensory abnormality, and there are generalized increased tendon reflexes in ALS.

5. Cervical spondylosis. The sensory loss is confined to involved nerve roots and cervical spondylosis.

Treatment

A small syrinx with very slow deterioration does not require treatment. However, when there are increasing neurological deficits, a communicating syringomyelia associated with hydrocephalus might benefit from a ventricular drainage procedure, whereas a noncommunicating syrinx or extracanalicular syrinx would require a direct shunting procedure or reconstruction of the subarachnoid space to remove obstruction of the CSF flow and relieve pressure waves passing through the cord parenchyma into the syrinx cavity.

Pain associated with syringomyelia may fail to respond to simple analgesics but may respond to car-bamazepine, amitripityline, gabapentin, or transcutaneous nerve stimulation.

Prognosis Syringomyelia and syringobulbia are usually slowly progressive diseases but can eventually prove to be severely disabling. Some patients show remission with no further deterioration for many years.

Students’ practical Study Program.

Step I. Aim: To put clinical diagnosis. For this in series to solve the following questions:

1.   To inspect a sick (anamnesis, somatic-neurologic status).

2.   To press into the service of data additional methods inspections (EEG, CT, angiography, Roentgenography of the skull)

3. To make the clinical diagnosis.

Step II. Aim: To prescribe the treatment.

The treatment of the brain tumors is surgical extirpation, when possible, followed by radiation therapy when indicated. If the tumor cannot be removed in tote,

Neurosyphilis

Definition

Syphilis is a chronic system infection, which is developed after sexual relations in case of local infections.

Etiology

The etiologic cause of this disease is Treponema pallidum. In 1913 it was identified in the brain by Noguchi and Moore.

Epidemiology

According to the German scientists – Rittr and Prange (1987) the incidence of neurosyphilis is 15 persons per 100 000. Neurosyphilis takes 0.1% of all organic neurological diseases. Significant clinical signs of nervous system involvement are reported in 1- 2% of all patients with neurosyphilis. This disease is much more often observed in men (70%) than in women (30%).

Following the introduction of penicillin the incidence of neurosyphilis declined. One of the very important peculiarities is that among those infected with human immunodeficiency virus (HIV), about 15% have serologic evidence of syphilis and about 1% have neurosyphilis.

Pathogenesis

In early neurosyphilis, lymphocytes and other mononuclear cells infiltrate the meninges. The inflammatory reaction also involves the cranial nerves and provokes axonal degeneration. When the inflammation affects small meningeal vessels, occlusion due to endothelial proliferation may lead to ischemic necrosis of brain and spinal cord. This process may cause demyelination, myelomalacia at the periphery of the cord, or transverse myelitis.

The pathology of dementia paralytica develops slowly. After an inflammatory meningeal reaction, lymphocytes and plasma cells infiltrate small cortical vessels and sometimes extend into the cortex itself. The cortical inflammatory response provokes loss of cortical neurons and glial proliferation. Spirochetes can be demonstrated in the cortex in dementia paralytica, but only rarely in other forms of neurosyphilis.

In tabes dorsalis, the mononuclear inflammation of meninges and blood vessels is followed by insidious degeneration of the posterior roots and posterior fiber columns of the spinal cord, as well as the cranial nerves occasionally.

Classification

Syphilis is divided into:

 Primary – begins with chancre and lasts until it is cured or until the rash appears.

 Secondary – it develops after the appearance of specific pimple rash on skin, condylomas on mucous membrane.

 Latent - early and late. The border between them is 2 years from the moment of infection. The patients do not have clinical signs of the disease but all the serologic reactions are positive. These patients are divided into such groups:

         1/3 of them have no clinical signs of syphilis. Non - treponema blood – tests are negative, but treponema blood – tests are positive.

         1/3 of them have no clinical signs of syphilis. Non - treponema and treponema blood – tests are positive.

         1/3 have tertiary syphilis:

1.    ½ - gummy syphilis

2.    ¼ - cardiovascular syphilis

3.    ¼ - neurosyphilis.

• Tertiary (late) syphilis.

Syphilis is a contagious disease, especially in case of specific changes on skin and mucous membrane. Latent syphilis in case of absence of skin changes and tertiary syphilis aren’t contagious. After the first injections of penicillin the patients become not contagious.

Neurosyphilis is divided into 2 forms:

• Early (mesodermal)
• Late (parechymatous)

Clinical forms:

Early mesodermal syphilis:

1.    Asymptomatic neurosyphilis

2.    Acute syphilitic meningitis

3.    Chronic basal syphilitic meningitis

4.    Early meningovascular syphilis

5.    Syphilitic meningomyelitis

6.    Syphilitic mono – and polyneuropathy

Late mesodermal syphilis:

1.    Late syphilitic meningitis

2.    Late vascular syphilis

3.    Late meningovascular syphilis

4.    Late pupil monosyndrome

5.    Gummy brain and spinal cord

6.    Cerebrospinal syphilis

Late ectodermal (parenchymatous) neurosyphilis:

1.    Tabes dorsalis

2.    Amyotrophic spinal syphilis

3.    Spastic spinal paralysis

4.    Progressive paralysis

Merritt’s classification

1.    Asymptomatic neurosyphilis

2.    Syphilitic meningitis

3. Meningovascular syphilis

        Cerebral (meningitis, stroke)

        Spinal (meningomyelitis, stroke)

4.    Parenchymatous neurosyphilis

        Progressive paralysis

Tabes dorsalis

Taboparalysis

N. opticus atrophy

5.    Gummy neurosyphilis

5.1.         Gummy brain

5.2.         Gummy spinal cord

Clinical features. Diagnosis

Early mesodermal forms of neurosyphilis

Nowadays the most common among all the forms of neurosyphilis is asymptomatic syphilitic meningitis. Usually it is associated with:

1.    General cerebral signs:

         Headache

         Head noise

         Dizziness

         Vomiting

         Painful eyes movements

         General hyperesthesia

2.    Intoxication symptoms (sometimes)

         Weakness

         Nervousness

         Insomnia

         Depression

3.    Focal signs

         Radicular pain

         Transient insufficiency of some cranial nerves

During the 12 – 18 months from the moment of infection there are inflammatory changes in CSF:

• Lymphocyte pleocytosis
• Insignificant increasing of protein content
• Positive Wasserman, Kann reactions

The frequency of asymptomatic neurosyphilis is 30% from all the forms of neurosyphilis.

Acute general syphilitic meningitis

It is very common among the young people in case of inadequate treatment. There are 3 clinical forms:

1.    Acute syphilitic hydrocephalus

2.    Acute basal syphilitic meningitis

3.    Acute syphilitic meningitis with focal neurological signs.

On the background of fever there are:

         Severe headache

         Dizziness

         Nausea, vomiting

         Well –expressed meningeal symptoms

         Pathological reflexes

         Anizoreflexia, paresis

         Seizures

         CN’s lesion

         Consciousness disorders

         Sometimes pelvic disorders and trophic disturbances (such as bed – sores)

CSF:

         Increased pressure up to 300 – 500 mm

         Lymphocyte cytosis

         Protein content - 0.6 – 1.2 g/l

         RW ++++

The course of the disease is favourable. In case of adequate treatment the meningeal syndrome is liquidated in 2 – 3 days, CSF is normalized in 7 – 10 days. Very often this form can be transformed into a chronic one.

Chronic basal syphilitic meningitis

It develops subacutely, sometimes during several weeks. The typical features are:

1.    Early CN’s lesion:

         Oculomotor nerve (cross – eye, ptosis, anisokoria)

         Facial nerve (Bell’s palsy)

         Vestibular-Cochlear nerve

         Optic nerve (chocked discs on eye ground, atrophy, neuritis)

         Trigeminal nerve (pain, sensory disorders)

         Isolated paralysis of certain external or internal eye muscles

2.    General cerebral and meningeal signs

Fig,. Syphilitic inflammation on the basis of the brain.

Rare forms of neurosyphilis:

         Early meningovascular syphilis

         Syphilitic meningomyelitis

         Syphilitic neuropathy and polineuropathy

Early meningovascular syphilis

1.    General cerebral signs

2.    Meningeal signs

3.    Focal symptoms (hemiparesis, aphasia, general seizures)

Syphilitic endarteritis The result of it can be brain and spinal cord infarction. It is characterized by gradual development of focal signs. It is much more common in men than in women. The symptoms of the disease manifest 5 – 30 years after the infection. The progress of the disease is very progressive.

Syphilitic meningomyelitis It is characterized by:

1.    Sudden onset

2.    Acute course of the disease

3.    Rapid development of lower paralysis

4.    Well expressed trophic disturbances

5.    Conductive hyposthesia

6.    Pelvic disorders

Spinal meningovascular syphilis It is an acute infarction in the region of a. spinalis anterior

Clinical features:

1. Lower flaccid paralysis

2. Conductive hyposthesia

3. Pelvis disorders

There are also specific changes in CSF.

Additional methods of neurosyphilis diagnosis

1.    Positive Wasserman test in blood and CSF

2.    Positive serologic tests

3.    Positive Lange reaction in CSF

4.    Lymphocyte pleocytosis and increased protein content in CSF at meningeal forms.

The typical changes in CSF:

1.    Increased protein content from 0.5 to 1.5 g/l

2.    Lymphocyte cytosis (50 – 100 cell in 1 mcl)

3.    Lange reaction of paralytic or meningeal type

4.    Positive reaction of Wasserman

Late mesoderm syphilis

Clinical features appear 7 – 8 years after infection. There are such forms as:

         Late syphilitic meningitis

         Late vascular syphilis

         Late meningovascular syphilis

         Late pupil monosyndrome

To them belong also:

         Gummy brain and spinal cord

         Cerebrospinal syphilis

Late syphilitic meningitis The typical features are:

• Without fever onset
• Gradual development
• Recrudescence chronic course of the disease

Neurological symptoms:

1.    General cerebral symptoms

         Attack – like severe headache

         Vomiting

2.    Meningeal symptoms

         Neck stiffness

         Kernig – sign

3.    CN’s lesion

         Oculomotor nerve

         Argil – Robertson syndrome – myosis, anizokoria, pupils deformation, the absence of pupils reaction at chemical tests

         Optic nerve – decreased vision, hemianopsy, chocked discs on eye ground, atrophy

         V, VI, VIII CN’s

Vascular syphilis

Inflammatory changes are observed in the wall of the vessels. The meninges remain intact. The disease is very similar to brain infarction. As a result of numerous vessels lesion there are repeated brain infarctions associated with new focal signs. Hemorrhages are very rare.

Late meningovascular syphilis Typical focal neurological signs:

• Hemiparesis, hemiplegia
• Sensory disturbances
• Aphasia
• Memory disorders
• Alternating syndromes

The peculiarity of this form is combination of general cerebral and meningeal syndromes.

Late pupil monosyndrome:

• Anizokoria
• Bilateral pupils’ deformation
• Direct Argil – Robertson syndrome

Combination of pupils’ monosyndrome and absence of Achille and knee reflexes, sensory disorders is known as pretabes or pupil – radicular syndrome.

Gummy brain It is a syphilitic without-vessels granuloma. It creates separated focus of lesion. It is a localized form of meningitis. Clinical picture is very similar to brain tumor. The most typical place of its localization is fossa interpeduncularis.

Clinical features:

         Increased brain pressure (headache, vomiting, chocked discs on eye ground, epileptic attacks)

         Focal signs:

  Paralysis

  Sensory disorders

  Aphasia

  Epileptic attacks

  Agnosia

  Chocked discs on eye ground

  Protein – cell dissociation in CSF

Gummy brain is characterized by:

         Pupils deformation

         Slight pupils reactions

         Low Achille and knee reflexes

Cerebrospinal syphilis It is very common disease. Usually cerebral symptoms dominate over the spinal ones.

CSF examination reveals:

• Moderate increasing of protein content (0.5 – 1.0g/l)
• Insignificant mononuclear cytosis (20 – 70 cells in mcl)

There are also positive serologic reactions, such as reaction of immobilization of Treponema pallidum, reaction of immunofluorescention in blood and CSF.

Late ectodermal forms of neurosyphilis

Tabes dorsalis Nowadays it is a rare form of neurosyphilis. Usually it is observed 15 – 25 years after infection. It is the result of posterior columns and posterior roots of spinal cord degeneration. Some of cranial nerves, paravertebral and spinal ganglions can be injured.

There are 3 clinical stages:

         Neuralgic

         Ataxic

         Paralytic

Neuralgic stage

         Parasthesia (numbness, tingling)

         Pain (it has lancinating character. It is very severe and it appears very sudden. Its duration is from 1 – 2 seconds, sometimes longer. Usually it is the first sign of the disease)

         One of the typical features is visceral crisis – the attack of neurological pain in the internal organs with the loss of function of this organ. The most common are stomach crisis, also intestinal crisis, laryngeal crisis, heart crisis, liver, and kidney and urine bladder crisis.

         One of the typical and early sign of tabes dorsalis is Argil – Robertson syndrome –

  Decreased pupils reaction on light at preserved convergence and accomodation

  Anizokoria

  Deformation of pupils

  Myosis

Knee and Achille reflexes are decreasing. There are lesions of n. opticus (primary gray atrophy), VIII CN (dizziness and decreasing of hearing), n. oculomotorius (ptosis, outside cross – eye), n. abducens (inside cross eye), n. trigeminus.

Ataxic stage

The dominating symptoms are disorders of coordination in extremities and unstable standing and walking. These symptoms can be explained by disturbances of deep sensation. Usually the symptoms of lesion dominate in lower extremities. The patients feel the flour badly. It is difficult for him to walk in darkness or with his eyes closed. The muscle tonus is decreased.

Paralytic stage

It is characterized by severe disorders of motor function. There are no true paresis or paralysis. But because of the static and dynamic ataxia the patients are not able to stand and walk. The most common symptoms are:

• Trophic and pelvic disorders
• Retention of urine and feces, sometimes incontinence of urine and feces
• Trophic skin disorders

Psychological disturbances

· Changes of personality

         Memory disturbances

         Consciousness disorders

Sometimes tabes dorsalis is associated with progressive paralysis. The last manifests as memory disturbances, insomnia, and euphoria. There are also speech, writing and reading disorders. This disease is known as taboparalysis.

Diagnosis

         Pupils deformation

         Lancinating pain

         Retention of urine

         Parasthesia

         Back hyperesthesia

         Tabes crisis and ataxic disorders

CSF:

         Insignificant increasing of protein content

         Lymphocyte pleocytosis

         Positive Wasserman test

Progressive paralysis

It is developed 10 – 20 years after syphilis infection. The main clinical features are – memory and personality disturbances, loss of acquired skills, positive Argil – Robertson test, paresis, sensory disturbances, epileptic attacks. There are also increased protein content (0.45 – 0.6 g/l), positive Wasserman test and paralytic Lange curve.

Treatment

The treatment of neurosyphilis begins with the treatment of early syphilis. Usually penicillin is used as standard treatment. It can be introduced in 2 ways:

1.    I/v 12 000 000 – 24 000 000 U per day. 2 – 4 mlns of U every 4 hours. It is used during 10 – 14 days. Then 2 400 U of Retarpen is used once a week during 3 weeks.

2.    I/m 2 400 000 U per day in association with Probenecid (500 mg 4 times per day) during 10 – 14 days. Then 2 400 000 U of Benzatin – Benzylpenicillin is used once a week in a course of next 3 weeks.

The effectiveness of treatment is determined according to the blood tests and CSF examination. That’s why Lumbar puncture is made just after the penicillin treatment and then every 3 months. The result is normal CSF. That means that such patients are observed during several years after the disease.

The patient is considered to be cure only in case of completely normal CSF 2 years after the infection.

Prevention of syphilis:

         Prevention of syphilis infection

         Adequate treatment of early syphilis

         Adequate observation of the patient with control blood tests and CSF – examination.

GRANULOMATOUS INFLAMMATIONS

Syphilis

Syphilis is the result of infection with Treponema pallidum and tends to occur in cycles, with peaks approximately every 10 years. Rates in 1990 were 20.3 per 100,000 and 10.4 per 100,000 by 1993. Primary syphilis is, however, treated effectively in most cases and late symptomatic disease is now unusual, probably because of widespread use of antibiotics with intent to treat syphilis, or inadvertently in treating other infections.⁶¹ This fact should not lead to a complacent attitude toward syphilis. Late symptomatic disease has not been eradicated and may increase once more because there has been a significant increase in syphilis associated with HIV infection.⁶² These patients experience less serological improvement after treatment than do patients with syphilis who are HIV negative. In addition, the combination of syphilis and HIV infection leads to a more rapid development of neurosyphilis.⁶³

The syndrome of neurosyphilis includes a number of conditions: syphilitic meningitis, chronic basal meningitis, syphilitic arteritis, gumma formation, general paresis, syphilitic optic atrophy, congenital neurosyphilis, syphilis of the spinal cord, and tabes dorsalis.

Syphilitic Meningitis

A mild meningeal reaction has been described during the primary stage of syphilis, when T. pallidum is disseminated throughout the body. Acute syphilitic meningitis is an occasional feature of the secondary and tertiary stages of syphilis.

Pathology The presence of T. pallidum leads to an inflammatory response involving the meninges and the superficial areas of the brain and spinal cord. Marked lymphocytic infiltration of the meninges and perivascular cuffing of the blood vessels occur in the superficial areas of the CNS. These vessels are also the site of an endarteritis.

Clinical Features The patient presents with typical signs of acute meningitis, including headache, fever, nuchal rigidity, nausea, vomiting, and cranial nerve palsies.

Diagnostic Procedures

The CSF is under increased pressure and is clear, cloudy, or occasionally xanthochromic. Examination shows a pleocytosis with the presence of 50 to 2000 lymphocytes per cubic millimeter. The protein content is increased and the glucose content is occasionally depressed.

2. There is a positive serological test for syphilitis in the blood and CSF.

Treatment See Table 16-10.

Chronic Basal Meningitis

Chronic basal meningitis is a chronic granulomatous change in the meninges at the base of the brain that occurs in tertiary syphilis.

Pathology The meninges show thickening due to the presence of granulomatous inflammation, particularly around the base of the brain and brainstem. This inflammatory process involves the circle of Willis, the basilar artery, and the upper cranial nerves. There is an extension onto the floor of the fourth ventricle, and obstruction of the foramina of the fourth ventricle may lead to hydrocephalus. Microscopic examination shows the presence of diffuse fibrosis with infiltration of lymphocytes and plasma cells.

Clinical Features The condition usually presents with progressive involvement of the cranial nerves beginning with paralysis of the third and sixth cranial nerves. Extension of this process may lead to involvement of the optic nerves and optic atrophy.

Diagnostic Procedures

1. There is a lymphocytic pleocytosis in the CSF with elevated protein and marked increase in gamma globulin.

2. Serological tests for syphilis are positive in the blood and CSF.

Treatment See Table 16-10. Hydrocephalus may persist despite adequate treatment and may require placement of a ventriculoperitoneal shunt.

Cerebral Syphilitic Arteritis

Syphilitic arteritis is a panarteritis secondary to syphilitic infection involving the cerebral blood vessels.

Pathology Blood vessels in the brainstem and spinal cord show the presence of chronic inflammation, with lymphocytes and plasma cells in all layers of the vessel wall. The internal elastic lamina is preserved but shows reduplication. Endothelial proliferation produces narrowing of the lumina of the affected vessels, with an increased tendency to thrombosis. The penetrating vessels of the brain show a marked perivascular inflammatory response, and there is involvement of the meninges at the base of the brain, with a granulomatous inflammatory change.

Clinical Features Cerebral syphilitic arteritis usually produces symptoms of transient ischemia or cerebral infarction in young individuals. The most common symptom is syphilitic hemiplegia caused by infarction in the distribution of the middle cerebral artery. Vertebral basilar insufficiency or brainstem infarction is probably second in frequency. Involvement of the penetrating vessels of the frontal lobes may produce acute personality change followed by clouding of consciousness, delirium, delusions, and hallucinations. The progressive dementia can be arrested by adequate treatment. Arteritis involving the vessels supplying the brainstem and basal ganglia may result in parkinsonism, dystonia, or ballism.

Diagnostic Procedures

1. Serological tests for syphilis are positive in the blood and CSF.

2. The CSF shows the presence of excessive lymphocytes with increased protein and gamma globulin content.

3. The arteritis can be demonstrated by arteriography. This procedure shows an irregular involvement of blood vessel with segments of narrowing, "beading," and vascular occlusion.

Table 16-10

Current treatment of syphilis

A tabular summary of the current recommended treatment schedules from the Centers for Disease Control and Prevention.

Early syphilis (less than 1 year's duration)	Syphilis of more than 1 year's duration (latent syphilis of indeterminate or more than 1 year's duration, cardiovascular, late benign neurosyphilis)
Benzathine penicillin G 2.4 million units IM at a single session, or aqueous procaine penicillin G 4.8 million units. This should be given 600,000 units IM daily for 8 days. If allergic to penicillin: (1) doxycycline 100 mg orally ql2h for 2 weeks, (2) tetracycline hydrochloride (HC1) 500 mg qid orally for 14 days. Note: Other tetracyclines are not effective. Avoid milk, iron preparations, and antacids with tetracycline because they impair absorption.	Benzathine penicillin G 7.2 million units given as 2.4 million units IM weekly for 3 successive weeks, or aqueous procaine penicillin G 9.0 million units given as 600,000 units IM daily for 15 days. If allergic to penicillin: (1) doxycycline 100 mg orally ql2h for 2 weeks, (2) tetracycline HC1 500 mg qid orally for 30 days. Doxycycline or tetracycline should be administered for 4 weeks if infection has been present for more than 1 year.
Syphilis in pregnancy	Congenital syphilis (infants with abnormal CSF)
Penicillin in dosage schedules appropriate for the stage of syphilis as recommended for nonpregnant patients. If allergic to penicillin, erythromycin will treat mother only because inadequate doses cross placenta. Tetracyclines are contrain-dicated in pregnancy. The only acceptable therapy is penicillin. Therefore, skin testing for penicillin allergy is required (<40 percent of patients who believe they have penicillin allergy are confirmed by skin tests). Patients who are skin test negative are treated with penicillin. Patients with confirmed allergy to penicillin require desensi-tization. This should be carried out by an experienced individual (e.g., an allergist) and should be performed in a health care facility where immediate resuscitative measures are available.	Aqueous penicillin, crystalline penicillin G 100,000-150,000 units/kg IM or IV daily in two divided doses during first 7 days of life and three divided doses thereafter for 10 days or procaine penicillin G 50,000 units/kg IM once daily for 10 days. Infants with normal CSF: benzathine penicillin G 50,000 units/kg IM for one dose. Older infants and children: aqueous penicillin G 50,000 units/kg per day IV or IM q4-6h for 10-14 days.

Treatment See Table 16-10. Although the process is promptly arrested by adequate antibiotic treatment, residual neurological deficits due to infarction are often severe.

Syphilitic Gumma

A syphilitic gumma is a tumor-like mass of granulation tissue occurring in the meninges or brain parenchyma of a patient with tertiary syphilis.

Pathology A gumma is a solitary mass of granulation tissue consisting of epithelioid cells, plasma cells, and giant cells surrounding a central area of necrosis.

Clinical Features Gummas of the CNS are extremely rare and behave as expanding mass lesions.

Diagnostic Procedures

1. Serological tests for syphilis are positive in the blood and CSF.

2. The CSF shows the presence of a lymphocytic pleocytosis, elevated protein content, and elevated gamma globulin.

3. There are focal changes on the electroencephalogram (EEG) compatible with a focal structural lesion.

4. Diagnosis of a mass lesion can be made by MRI or CT scanning.

Treatment See Table 16-10. Gummas presenting as an expanding intracranial mass are often excised and a diagnosis is established postoperatively by a histological examination.

General Paresis

General paresis is a chronic syphilitic encephalitis caused by the presence of T. pallidum in the brain.

Pathology In advanced cases, the brain shows diffuse cortical atrophy and ventricular dilatation. The ependymal lining of the ventricles is thickened and has a granular appearance. This condition has been termed "granular ependymitis." Histological examination shows thickening of the meninges, which are infiltrated with plasma cells and lymphocytes. The gray matter of the brain shows loss of

neurons and proliferation of astrocytes and microglia. The microglia has an atypical rod-shaped appearance often oriented in a perpendicular fashion to the surface of the brain. Blood vessels show the presence of a diffuse syphilitic arteritis. There is marked perivascular cuffing of the vessels penetrating the surface of the brain. Numerous spirochetes may be demonstrated by special staining techniques.

Clinical Features The patient experiences progressive intellectual deterioration beginning with the loss of operational judgment followed by impairment of insight, gradual loss of acceptable social behavior, impairment of recent memory, and personality change. With the passage of time, the affect becomes flat and the patient becomes severely demented and apathetic.

The examination of the patient with established general paresis shows the presence of Argyle Robertson pupils in all cases. A tremor involves the eyelids, lips, tongue, and fingers. The voice is tremulous and rapid alternating movements are impaired because of dyspraxia. Tendon reflexes are symmetrical but diffusely increased. There may be extensor plantar responses.

Diagnostic Procedures

1. Serological tests for syphilis are positive in blood and CSF.

2. The CSF shows the presence of a lymphocytic pleocytosis, increased protein content, and increased gamma globulin.

3. Serial EEGs will show gradual deterioration in the serial records, with a loss of alpha activity and replacement with theta activity and eventually the appearance of delta activity. This activity is symmetrical over both hemispheres. Occasional paroxysmal or epileptic discharges may be recorded.

4. Diffuse cortical atrophy and ventricular dilatation can be demonstrated by MRI or CT scanning of the brain.

Treatment See Table 16-10. Adequate treatment of general paresis in the early stages can arrest the disease before the development of severe dementia. Relapse is rare and requires a second course of treatment.

Syphilitic Optic Atrophy

Syphilitic optic atrophy is optic atrophy caused by, or related to, infection by T. pallidum.

Etiology and Pathology There are two forms of neurosyphilitic optic atrophy. In primary optic atrophy, the condition is a consequence of an inflammatory reaction of the optic nerve. Secondary syphilitic optic atrophy is caused by pressure on the optic nerve due to chronic basal meningitis or increased ICP resulting from hydrocephalus secondary to syphilitic meningitis.

In primary optic atrophy, the optic nerve shows the presence of an inflammatory reaction surrounding the blood vessels that penetrate the nerve (vasa nervorum). This reaction is followed by loss of nerve fibers and demyelination beginning peripherally and gradually involving the center of the optic nerve.

Clinical Features Syphilitic optic atrophy is characterized by progressive restriction of visual fields beginning peripherally and extending toward the center. The visual loss is usually eccentric and the visual loss is total within a 10-year period. Examination shows marked pallor of the optic discs.

Diagnostic Procedures The blood serological test for syphilis is positive in most cases but may be negative in patients with optic atrophy and tabes dor-salis.

Treatment See Table 16-10. Syphilitic optic atrophy is often progressive despite adequate penicillin therapy, and repeated courses of treatment may not prevent the development of blindness.

Congenital Neurosyphilis

Congenital neurosyphilis results when there is transplacental infection of the fetus by T. pallidum.

Pathology The developing fetus is infected during the fourth month of pregnancy; adequate treatment of the mother with active syphilis before the fourth month of pregnancy prevents fetal infection.

The pathological changes are those of syphilis in its early stages.

Clinical Features The child may be stillborn or show signs of congenital syphilis at birth. Untreated infants with congenital syphilis may develop all of the signs of neurosyphilis at a later stage. The condition includes syphilitic meningitis, chronic basal meningitis, optic atrophy, syphilitic arteritis, and juvenile general paresis. General paresis presents during the second decade as a rapidly progressive dementia. Tabes dorsalis has rarely been described in congenital syphilis.

Diagnostic Procedures

1. Infants should be evaluated for congenital syphilis if they were born to seropositive women who have untreated syphilis, were treated during pregnancy with erythromycin, were treated less than 1 month before delivery, were treated with penicillin but nontreponemal antibody titers did not decrease sufficiently following treatment, or were treated appropriately but had insufficient serological testing during follow-up.

2. In evaluation of the infant, a thorough physical examination for congenital syphilis should be performed, and a quantitative serological test for syphilis should be obtained. The CSF should be analyzed for cells, protein, and VDRL. Radiography of the long bones should be performed and pathological examination of the placenta or amniotic cord, using specific antitreponemal antibody staining, should be carried out.

Antibiotic treatment is described in Table 16-10. ,

Syphilis of the Spinal Cord

Syphilitic involvement of the spinal cord is rare and has been virtualh eliminated with penicillin therapy. Acute syphilitic transverse myelitis may occur as an acute infarction i of the spinal cord secondary to syphilitic arteritis of^: the anterior spinal artery or its branches.

Syphilitic meningomyelitis, which is a diffuse granulomatous meningitis involving the spinal cord may produce progressive paraparesis. Pachymeningitis cervicitis hypertrophica is a condition in which marked thickening of the meninges over the cervical area of the spinal cord occurs. This condition is also associated with a progressive paraparesis. In addition, involvement of the motor nerve roots in the cervical area produces wasting of the muscles of the hand and upper limb girdles. Syphilitic amyotrophy resembles amyotrophic lateral sclerosis and is caused by progressive loss of anterior horn cells secondary to ischemia due to an arteritis involving the penetrating branches from the anterior spinal artery. Spinal gummas are rare and may present as a spinal cord tumor.

Diagnostic Procedures

1. The blood serological tests for syphilis will be positive in all cases.

2. Lumbar puncture may show evidence of occlusion of the subarachnoid space with low opening pressure, positive Queckenstedt test, xanthochromic CSF, lymphocytic pleocytosis, and elevated protein content. The serological tests for syphilis will be positive in the CSF.

3. Areas of spinal cord compression can be demonstrated by MRI scanning or CT scan with myelography.

Treatment Most patients respond to adequate penicillin therapy. Cord compression must be relieved surgically by removal of a gumma or excision of thickened meninges.

Tabes Dorsalis

This slowly progressive degenerative condition is a rare complication of syphilis but was common in hospital clinics 40 years ago. The pathological changes, which were the result of T. pallidum, began in the posterior nerve roots of the site of penetration of the pia, proximal to the nerve root entry into the spinal cord. Degenerative changes in the nerve root spread into the posterior columns with progressive loss of axons and myelin culminating in total bilateral destruction of the posterior columns.

Clinical Features The earliest symptoms consisted of lightning pains—paroxysmal lancinating pains in the lower limbs eventually spreading to the trunk. Several years later, the patient developed progressive ataxia due to the loss of proprioception with a typical wide-based, slapping gait. Autonomic involvement resulted in a painless distention of the bladder, with retention of urine, and overflow incontinence. Other autonomic defects produced loss of libido in both sexes and a tendency to postural hypotension.

Loss of joint sensation in the lower limbs resulted in Charcot joints—painless, swollen, hyper-mobile joints. Syphilitic optic atrophy was not uncommon, often progressing to total blindness. Impaired sensation in the feet resulted in trophic ulcers over the heads of the metatarsal bones or the heels.

Clinical examination showed Argyll Robertson pupils, optic atrophy in some cases, bilateral ptosis, and a prominent nasolabial fold, giving a typical facial appearance. There was generalized hypotonia and a wide-based, ataxic gait with a positive Romberg test.

Diagnostic Procedures

1. The blood serological test for syphilis was positive in about 50 percent of cases of tabes dorsalis.

2. The CSF examination revealed a clear fluid under normal pressure. In some cases, there was a slight increase in lymphocytic content with normal or slightly elevated protein content and an increased gamma globulin.

Treatment The treatment of tabes dorsalis is outlined in Table 16-10. Lightning pains respond to the use of carbamazepine (Tegretol) in some cases, phenytoin (Dilantin), or gabapentin. Charcot joints may require bracing or orthopedic fusion. A patient with bladder involvement should, if possible, use self-catheterization. Men might benefit from transurethral resection of the prostate. Trophic ulcers of the feet should be treated with extra care to avoid infection which leads to bony necrosis.

Syphilis in HIV Infection

The manifestation, therapy, and response to treatment of syphilis in patients coinfected with HIV is the subject of controversy. Atypical presentation of syphilis, rapid progression to neurosyphilis, erratic serological findings, and failure of recommended doses of penicillin G benzathine to cure infection have been documented. However, similar problems were described before the advent of HIV infection and have also been described in treatment of syphilis in intravenous drug users in the absence of HIV infection.

A diagnosis of neurosyphilis in HIV-infected patients is complicated by the frequency of abnormalities in the CSF—pleocytosis and elevated protein levels—resulting from HIV infection itself. However, at this time, HIV-infected patients with evidence of syphilis and unexplained CSF pleocytosis or elevated protein levels, as well as those with a positive CSF-VDRL test should be treated with a regimen appropriate for neurosyphilis. Any patient with a lack of decline of nontreponemal antibody titers 6 months after treatment or persistence of symptoms and signs of syphilis requires assessment of the CSF and probably retreatment.

Latent Syphilis

This condition may be denned as periods after acquisition of T. pallidum infection when untreated individuals are seroreactive but have no other signs of infection. Data are limited in such cases but suggest that penicillin is effective in preventing progression to clinical neurosyphilis. Lumbar puncture may reveal pleocytosis and elevated protein levels, but these results are nonspecific and unreliable, often representing other comorbidities other than active neurosyphilis. Consequently, treatment of latent syphilis should be instituted in those who show new clinical symptoms or signs of syphilis, particularly neurosyphilis, and in those who show a fourfold increase in serum VDRL titers or a positive serum treponemal antibody absorption test (FTA-ABS).

Students’ practical Study Program.

Step I. Aim: To put clinical diagnosis. For this purpose it is necessary:

1.    To determine the clinical form of the neurosyphilis according to algorithm of differential diagnosis (look to references).

2.    To analyze specific serological tests (VDRL, RPR, ART, FTA-ABS, MHA-TP, and TPI).

3.    To consider the specific AIDS tests.

4.    To find out clinical stages of poliomyelitis according to algorithm of differential diagnosis (look to references).

5.    To localized pathological focus.

6.    To formulate clinical diagnosis, for example:

a)    Tabes dorsalis, algae stage with paroxysmal visceral episodes.

b)    Poliomyelitis, residual stage, with deep flaccid palsy of the right foot.

The clinical presentation of symptomatic neurosyphilis are protean (“stroke”, “dementia”, CNS mass lesion, meningitis, hydrocephalus); for this reason the CSF test for syphilis must be done on every patient undergoing a lumbar puncture; the diagnosis is most often made in this serendipitous manner.

The serologic tests for syphilis are:

1.    VDRL, rapid plasma reagin test (RPR), ART – nontreponemal tests

2.    FTA-ABS – fluorescent treponemal antibody absorption test

3.    MHA-TP – microhemagglutination -Treponema pallidum test

4.    TPI – Treponema pallidum immobilization test

- Nontreponemal cardiolipin antibody tests (VDRL, RPR) are useful for screening.

- Treponemal tests confirm the diagnosis.

- A decrease in nontreponemal titres documents adequate therapy.

Patients with a past history of syphilis or who have a positive serum test for syphilis should have a lumbar puncture to rule out asymptomatic neurosyphilis.

In active neurosyphilis there is a high CSF Ig M.

Step II. Aim: To prescribe the treatment.

Neurosyphilis is a treatable disease; progression may be stopped in all cases, and most patients will show improvement.

1.    Aqueous penicillin G 2 to 4 million units IV q4h for 10 days, followed by penicillin G Benzanthine 2.4 million units IM weekly, for three doses.

2.    Amoxicillin 3 g/day PO plus probenecid 1 g/day for ten days or aqueous procaine penicillin G IM 2.4 million units/day plus probenecid 500 mg qid for ten days followed by penicillin G Benzanthine 2.4 million units IM weekly for three doses.

3.    For penicillin allergy, chloramphenicol 2 g/day for 15 to 30 days.

4.    Patients with neurosyphilis must be followed with periodic serologic testing and repeat CSF exam for 3 years.

Step III. Aid: to study preventive measures.

Lesion of Nervous system by AIDS

Human immunodeficiency virus infection / acquired immunodeficiency syndrome (HIV/AIDS) is a disease of the human immune system caused by infection with human immunodeficiency virus (HIV). During the initial infection, a person may experience a brief period of influenza-like illness. This is typically followed by a prolonged period without symptoms. As the illness progresses, it interferes more and more with the immune system, making the person much more likely to get infections, including opportunistic infections and tumors that do not usually affect people who have working immune systems.

HIV is transmitted primarily via unprotected sexual intercourse (including anal and even oral sex), contaminated blood transfusions, hypodermic needles, and from mother to child during pregnancy, delivery, or breastfeeding. Some bodily fluids, such as saliva and tears, do not transmit HIV. Prevention of HIV infection, primarily through safe sex and needle-exchange programs, is a key strategy to control the spread of the disease. There is no cure or vaccine; however, antiretroviral treatment can slow the course of the disease and may lead to a near-normal life expectancy. While antiretroviral treatment reduces the risk of death and complications from the disease, these medications are expensive and may be associated with side effects.

Diagnosis

A generalized graph of the relationship between HIV copies (viral load) and CD4⁺ T cell counts over the average course of untreated HIV infection.                      CD4⁺ T Lymphocyte count (cells/mm³)                     HIV RNA copies per mL of plasma

HIV/AIDS is diagnosed via laboratory testing and then staged based on the presence of certain signs or symptoms. HIV screening is recommended by the United States Preventive Services Task Force for all people 15 years to 65 years of age including all pregnant women. Additionally testing is recommended for all those at high risk, which includes anyone diagnosed with a sexually transmitted illness.^[15] In many areas of the world a third of HIV carriers only discover they are infected at an advanced stage of the disease when AIDS or severe immunodeficiency has become apparent.

HIV testing

Most people infected with HIV develop specific antibodies (i.e. seroconvert) within three to twelve weeks of the initial infection. Diagnosis of primary HIV before seroconversion is done by measuring HIV-RNA or p24 antigen. Positive results obtained by antibody or PCR testing are confirmed either by a different antibody or by PCR.

Antibody tests in children younger than 18 months are typically inaccurate due to the continued presence of maternal antibodies. Thus HIV infection can only be diagnosed by PCR testing for HIV RNA or DNA, or via testing for the p24 antigen.^[12] Much of the world lacks access to reliable PCR testing and many places simply wait until either symptoms develop or the child is old enough for accurate antibody testing.^[78] In sub-Saharan Africa as of 2007–2009 between 30 and 70% of the population was aware of their HIV status.^[79] In 2009, between 3.6 and 42% of men and women in Sub-Saharan countries were tested^[79] which represented a significant increase compared to previous years.^[79]

Classifications of HIV infection

Two main clinical staging systems are used to classify HIV and HIV-related disease for surveillance purposes: the WHO disease staging system for HIV infection and disease,^[12] and the CDC classification system for HIV infection. The CDC's classification system is more frequently adopted in developed countries. Since the WHO's staging system does not require laboratory tests, it is suited to the resource-restricted conditions encountered in developing countries, where it can also be used to help guide clinical management. Despite their differences, the two systems allow comparison for statistical purposes.

The World Health Organization first proposed a definition for AIDS in 1986. Since then, the WHO classification has been updated and expanded several times, with the most recent version being published in 2007. The WHO system uses the following categories:

• Primary HIV infection: May be either asymptomatic or associated with acute retroviral syndrome.
• Stage I: HIV infection is asymptomatic with a CD4⁺ T cell count (also known as CD4 count) greater than 500 per microlitre (µl or cubic mm) of blood.^[12] May include generalized lymph node enlargement.
• Stage II: Mild symptoms which may include minor mucocutaneous manifestations and recurrent upper respiratory tract infections. A CD4 count of less than 500/µl.
• Stage III: Advanced symptoms which may include unexplained chronic diarrhea for longer than a month, severe bacterial infections including tuberculosis of the lung, and a CD4 count of less than 350/µl.
• Stage IV or AIDS: severe symptoms which include toxoplasmosis of the brain, candidiasis of the esophagus, trachea, bronchi or lungs and Kaposi's sarcoma. A CD4 count of less than 200/µl.

The United States Center for Disease Control and Prevention also created a classification system for HIV, and updated it in 2008. This system classifies HIV infections based on CD4 count and clinical symptoms, and describes the infection in three stages:

• Stage 1: CD4 count ≥ 500 cells/µl and no AIDS defining conditions
• Stage 2: CD4 count 200 to 500 cells/µl and no AIDS defining conditions
• Stage 3: CD4 count ≤ 200 cells/µl or AIDS defining conditions
• Unknown: if insufficient information is available to make any of the above classifications

For surveillance purposes, the AIDS diagnosis still stands even if, after treatment, the CD4⁺ T cell count rises to above 200 per µL of blood or other AIDS-defining illnesses are cured.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the CNS characterized by widespread lesions due to infection of oligodendrocytes by a human papovavirus. The virus was identified as the etiological agent in 1967 and is named JC virus in 1971 after John Cunningham, from whom it was first isolated. It occurs almost exclusively in immunosuppressed individuals, such as patients with AIDS, hematological and lymphoreticular malignancies, autoimmune rheumatological diseases, or those undergoing organ transplantation. PML has also been reported in patients receiving immune therapy with monoclonal antibodies (eg, natalizumab, rituximab) and various other immunosuppressants, including prednisone, cyclophosphamide, methotrexate, and cyclosporine.

PML is associated with both HIV-1 and HIV-2.^{[2, 3]} HIV infection accounts for almost 85% of the total cases, and its prevalence in this population is around 4-5%. It is currently one of the AIDS-defining illnesses in HIV-infected patients.

HIV-associated PML also occurs during immune recovery following the initiation of highly active antiretroviral therapy (HAART). Such cases are associated with an inflammatory reaction in brain lesions and contrast enhancement on neuroimaging studies. The outcome of inflammatory PML is more variable than that of PML in end-stage AIDS.

Most patients with HIV infection develop PML in the setting of a poor immunological status expressed by a low CD4 cell count (< 200/µL). Very few reports have described of PML in HIV-infected patients in the setting of better immunological function (ie, CD4 counts >500/µL).

Clinical Presentation

Patients with progressive multifocal leukoencephalopathy (PML) typically experience insidious onset and steady progression of focal symptoms that include behavioral, speech, cognitive, motor (eg, head tremorjavascript:showrefcontent('refrenceslayer');), and visual impairment. Though the neuropathological evaluation reveals the multifocal nature of the disease, its presentation is typically unifocal; however, MRI may demonstrate multifocal pathology. Unlike other major opportunistic disorders that produce focal brain lesions (eg, cerebral toxoplasmosis, primary CNS lymphoma), which characteristically progress over the course of hours or a few days, PML evolves over several weeks. However, PML demonstrates more rapid progression than AIDS dementia complex (ADC). Involvement of the brainstem is more commonly seen in PML associated with AIDS than with other entities.As individual lesions expand, either concentrically or along white matter tracts, manifestations may worsen and involve a larger territory. For example, initial weakness of one leg may progress to hemiparesis.^[21] Patients with more preserved immune status may show a slower progression of the disease than those with a immunocompromised state.

Although seizures have been considered a rare manifestation of PML, Lima et al found that seizures occurred in 18% of PML patients. Many of the PML patients presenting with seizures had demyelinating lesions immediately adjacent to the cortex. Seizures usually responded well to treatment and did not affect survival.

In PML related to immune reconstitution, onset may occur weeks to months after the initiation of antiretroviral therapy.

Physical examination

Focal neurologic signs include aphasia, hemiparesis, ataxia, cortical blindness, limb apraxia, brainstem symptoms and, less frequently, head tremor. Focal signs tend to be related to posterior brain (eg, occipital lobes). Gait abnormalities occur in up to 65% patients, and cognitive dysfunction is seen at the time of presentation in up to 30% people.

Conjugate gaze abnormalities are common. This is the initial presentation in more than 30% of patients. Abnormalities may progress to quadriparesis and coma. Occasionally, neurologic signs are diffuse rather than focal.

Workup

In a patient with steadily progressive focal neurologic deficits consistent with progressive multifocal leukoencephalopathy (PML), neuroimaging is indicated. The combination of a characteristic clinical picture and typical imaging findings supports a confident presumptive diagnosis of PML.^[21]

Computed tomography or magnetic resonance imaging

With CT scan or MRI of the brain, single or multiple confluent lesions without mass effects are seen, most frequently in the parieto-occipital white matter. Occasional infratentorial lesions are usually asymmetrical. The demyelinating plaques involve subcortical U fibers but tend to spare the cortical ribbons and deep gray matter structures; however, cases have been described that have involvement of deep gray matter. Subcortical gray matter or the spinal cord may be involved, but rarely. Gray matter involvement has a scalloped appearance.

PML sometimes can resemble lymphoma, toxoplasmosis, or HIV encephalitis. However, the absence of a mass effect or displacement of normal structures is more consistent with PML than these other disorders. Rarely, PML can also present as a mass lesion with enhancement on postcontrast MRI scans. Magnetization transfer ratio (MTR) is typically low in PML cases compared with normal white matter and that of HIV-infected white matter without PML.

CT scan may show hypodense lesions. On MRI, PML lesions characteristically are hypointense on T1-weighted images; this finding may be subtle but can help distinguish PML lesions from those of other diseases (eg, white matter lesions of HIV encephalitis). On T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences, PML lesions are characteristically hyperintense (see the image below).^[21]

T2-weighted MRI shows left occipital hyperintense white matter changes with the lesion margin reaching the cortex.

Neuroimaging in patients with inflammatory PML may demonstrate atypical features, including a mass effect of the PML lesions with surrounding edema. Contrast enhancement, which is uncommon in classic PML and tends to be sparse when it does occur, may be striking in patients with inflammatory PML. Any area of the white matter can be affected but is usually in the cerebellum.

Lumbar puncture

Cerebrospinal fluid (CSF) is usually normal, but protein levels may be elevated slightly. Normal CSF findings serve to rule out other etiologies. CSF pleocytosis can sometimes occur, but the cell count is usually less than 20/µL. JC virus culture in the CSF is usually unrevealing.

Polymerase chain reaction (PCR) of the CSF has been shown to be highly specific (92-99%) and sensitive (74-93%) for the detection of JC virus in patients with PML. False negatives may be due to the low viral DNA in the CSF, storage of the specimen, low volume of the specimen, and loss of DNA during concentration. The false-positive rate has been reported to be around 2%. Measuring CSF JC virus DNA load is a reliable marker of disease activity in patients receiving HAART and has a potential use in drug trials. Conceivably, this test could eliminate the need for brain biopsy. However, the detection of JC virus in CSF may be less likely in patients with inflammatory PML. If PML is suspected, even though the initial JC virus PCR is negative, the recommendation is to repeat the spinal fluid analysis.

Prevention

Sexual contact

Consistent condom use reduces the risk of HIV transmission by approximately 80% over the long term. When condoms are used consistently by a couple in which one person is infected, the rate of HIV infection is less than 1% per year.^[82] There is some evidence to suggest that female condoms may provide an equivalent level of protection.^[83] Application of a vaginal gel containing tenofovir (a reverse transcriptase inhibitor) immediately before sex seems to reduce infection rates by approximately 40% among African women. By contrast, use of the spermicide nonoxynol-9 may increase the risk of transmission due to its tendency to cause vaginal and rectal irritation. Circumcision in Sub-Saharan Africa "reduces the acquisition of HIV by heterosexual men by between 38% and 66% over 24 months". Based on these studies, the World Health Organization and UNAIDS both recommended male circumcision as a method of preventing female-to-male HIV transmission in 2007. Whether it protects against male-to-female transmission is disputed and whether it is of benefit in developed countries and among men who have sex with men is undetermined. Some experts fear that a lower perception of vulnerability among circumcised men may cause more sexual risk-taking behavior, thus negating its preventive effects.

Programs encouraging sexual abstinence do not appear to affect subsequent HIV risk. Evidence for a benefit from peer education is equally poor. Comprehensive sexual education provided at school may decrease high risk behavior. A substantial minority of young people continues to engage in high-risk practices despite knowing about HIV/AIDS, underestimating their own risk of becoming infected with HIV.^[97] It is not known whether treating other sexually transmitted infections is effective in preventing HIV.

Pre-exposure

Treating people with HIV whose CD4 count ≥ 350cells/µL with antiretrovirals protects 96% of their partners from infection. This is about a 10 to 20 fold reduction in transmission risk.http://en.wikipedia.org/wiki/HIV/AIDS - cite_note-Chou2012-99 Pre-exposure prophylaxis with a daily dose of the medications tenofovir, with or without emtricitabine, is effective in a number of groups including men who have sex with men, couples where one is HIV positive, and young heterosexuals in Africa. It may also be effective in intravenous drug users with a study finding a decrease in risk of 0.7 to 0.4 per 100 person years.

Universal precautions within the health care environment are believed to be effective in decreasing the risk of HIV. Intravenous drug use is an important risk factor and harm reduction strategies such as needle-exchange programmes and opioid substitution therapy appear effective in decreasing this risk.^[102][103]

Post-exposure

A course of antiretrovirals administered within 48 to 72 hours after exposure to HIV-positive blood or genital secretions is referred to as post-exposure prophylaxis (PEP).^[104] The use of the single agent zidovudine reduces the risk of a HIV infection five-fold following a needle-stick injury.^[104] As of 2013, the prevention regime recommended in the United States consists of three medications—tenofovir, emtricitabine and raltegravir—as this may reduce the risk further.^[105]

PEP treatment is recommended after a sexual assault when the perpetrator is known to be HIV positive, but is controversial when their HIV status is unknown.^[106] The duration of treatment is usually four weeks^[107] and is frequently associated with adverse effects—where zidovudine is used, about 70% of cases result in adverse effects such as nausea (24%), fatigue (22%), emotional distress (13%) and headaches (9%).^[29]

Mother-to-child

Programs to prevent the vertical transmission of HIV (from mothers to children) can reduce rates of transmission by 92–99%. This primarily involves the use of a combination of antiviral medications during pregnancy and after birth in the infant and potentially includes bottle feeding rather than breastfeeding. If replacement feeding is acceptable, feasible, affordable, sustainable, and safe, mothers should avoid breastfeeding their infants; however exclusive breastfeeding is recommended during the first months of life if this is not the case. If exclusive breastfeeding is carried out, the provision of extended antiretroviral prophylaxis to the infant decreases the risk of transmission.

Vaccination

As of 2012 there is no effective vaccine for HIV or AIDS. A single trial of the vaccine RV 144 published in 2009 found a partial reduction in the risk of transmission of roughly 30%, stimulating some hope in the research community of developing a truly effective vaccine. Further trials of the RV 144 vaccine are ongoing.

Management

There is currently no cure or effective HIV vaccine. Treatment consists of high active antiretroviral therapy (HAART) which slows progression of the disease and as of 2010 more than 6.6 million people were taking them in low and middle income countries. Treatment also includes preventive and active treatment of opportunistic infections.

Antiviral therapy

Abacavir – a nucleoside analog reverse transcriptase inhibitor (NARTI or NRTI)

Current HAART options are combinations (or "cocktails") consisting of at least three medications belonging to at least two types, or "classes," of antiretroviral agents.^[116] Initially treatment is typically a non-nucleoside reverse transcriptase inhibitor (NNRTI) plus two nucleoside analogue reverse transcriptase inhibitors (NRTIs). Typical NRTIs include: zidovudine (AZT) or tenofovir (TDF) and lamivudine (3TC) or emtricitabine (FTC). Combinations of agents which include a protease inhibitors (PI) are used if the above regime loses effectiveness.

When to start antiretroviral therapy is subject to debate. The World Health Organization, European guidelines and the United States recommends antiretrovirals in all adolescents, adults and pregnant women with a CD4 count less than 350/µl or those with symptoms regardless of CD4 count. This is supported by the fact that beginning treatment at this level reduces the risk of death. The United States in addition recommends them for all HIV-infected people regardless of CD4 count or symptoms; however it makes this recommendation with less confidence for those with higher counts. While the WHO also recommends treatment in those who are co-infected with tuberculosis and those with chronic active hepatitis B. Once treatment is begun it is recommended that it is continued without breaks or "holidays". Many people are diagnosed only after treatment ideally should have begun. The desired outcome of treatment is a long term plasma HIV-RNA count below 50 copies/mL. Levels to determine if treatment is effective are initially recommended after four weeks and once levels fall below 50 copies/mL checks every three to six months are typically adequate.^[15] Inadequate control is deemed to be greater than 400 copies/mL. Based on these criteria treatment is effective in more than 95% of people during the first year.

Benefits of treatment include a decreased risk of progression to AIDS and a decreased risk of death. In the developing world treatment also improves physical and mental health. With treatment there is a 70% reduced risk of acquiring tuberculosis. Additional benefits include a decreased risk of transmission of the disease to sexual partners and a decrease in mother-to-child transmission. The effectiveness of treatment depends to a large part on compliance. Reasons for non-adherence include poor access to medical care, inadequate social supports, mental illness and drug abuse. The complexity of treatment regimens (due to pill numbers and dosing frequency) and adverse effects may reduce adherence. Even though cost is an important issue with some medications, 47% of those who needed them were taking them in low and middle income countries as of 2010 and the rate of adherence is similar in low-income and high-income countries.

Specific adverse events are related to the agent taken. Some relatively common ones include: lipodystrophy syndrome, dyslipidemia, and diabetes mellitus especially with protease inhibitors. Other common symptoms include diarrhea, and an increased risk of cardiovascular disease. Newer recommended treatments are associated with fewer adverse effects. Certain medications may be associated with birth defects and therefore may be unsuitable for women hoping to have children.

Treatment recommendations for children are slightly different from those for adults. In the developing world, as of 2010, 23% of children who were in need of treatment had access. Both the World Health Organization and the United States recommend treatment for all children less than twelve months of age. The United States recommends in those between one year and five years of age treatment in those with HIV RNA counts of greater than 100,000 copies/mL, and in those more than five years treatments when CD4 counts are less than 500/µl.

Opportunistic infections

Measures to prevent opportunistic infections are effective in many people with HIV/AIDS. In addition to improving current disease, treatment with antiretrovirals reduces the risk of developing additional opportunistic infections. Vaccination against hepatitis A and B is advised for all people at risk of HIV before they become infected; however it may also be given after infection. Trimethoprim/sulfamethoxazole prophylaxis between four and six weeks of age and ceasing breastfeeding in infants born to HIV positive mothers is recommended in resource limited settings.^[130] It is also recommended to prevent PCP when a person's CD4 count is below 200 cells/uL and in those who have or have previously had PCP. People with substantial immunosuppression are also advised to receive prophylactic therapy for toxoplasmosis and Cryptococcus meningitis. Appropriate preventive measures have reduced the rate of these infections by 50% between 1992 and 1997.