**2. Neurological disease classification**

but are proposed to involve cell trafficking across the blood brain barrier. The blood-derived infected macrophages or lymphocytes adhere to the vascular endothelium and then are thought to pass through it by EMPERIPOLESIS [2]. The trafficking-infected cell then transmits the virus to microglial cells or perivascular macrophages on the brain side of the blood brain barrier, a "Trojan horse" type of mechanism. The virus in these infected microglia then undergo productive replication and infects other microglia spreading the infection. Astrocytes are likewise infected but replication within these cells is incomplete or nonproductive and forms a reservoir. Neurons and oligodendrocytes are not directly infected by the virus and damage to these cells occurs by chemokines and cytokines released from the infected microglia and astrocytes [2, 3].

The essential mediators of HIV-related CNS disease are the microglial soluble mediators, including quinolinic acid, TNF-alpha, IL-1 beta (**Figure 1**). Quinolinic acid binds to the NMDA receptor and increases calcium uptake with resultant activation of apoptotic mechanisms. TNF-alpha damages myelin and IL-1 beta stimulates astrocytes. Astrocytes produce nitric

The net result of this inflammatory cascade is an encephalitis, which is pathologically characterized by white matter pallor, neuronal loss, and astroglial reaction. This initiates and is the basis of primary HIV disease or as is commonly referred to as direct HIV infection of the nervous system.

oxide and colony stimulating factors that feed back on microglia [2, 3].

122 Advances in HIV and AIDS Control

**Figure 1.** Neuropathophysiology of HIV infection in the Brain.

The spectrum of HIV related or associated neurological disorders is broad and any part of the neural axis may be affected. Neurological complications of HIV are very *stage-specific* and relate to altered immune responses and deficiencies of cell mediated immunity–*dysregulation of immunity* [1, 2].

*Metabolic diseases* that result from dysfunction of other organ systems and *toxic* complications of drugs used to treat the HIV infection and its complications also cause neurological complications, especially in late stage HIV infection [1–3].

Dysregulation of immunity is caused by:


#### **2.1. Immune dysregulation**

**1.** Autoimmune disease (early and middle phases of HIV infection)

Acute phase encephalitis, neuropathies (AIDP) Subacute and chronic inflammatory neuropathies Acute disseminated encephalomyelitis (ADEM)

**2.** Immunosuppression: opportunistic infections/neoplasms (late phase HIV infection)

Cerebral toxoplasmosis Primary CNS lymphoma (PCNSL) CMV encephalitis Cryptococcal meningitis Progressive multifocal leukoencephalopathy (PML)

**3.** HIV driven

HIV-related neurocognitive disorders (HAND) Distal sensory polyneuropathy

Vacuolar myelopathy HIV myopathy

#### **2.2. Secondary conditions**

**1.** Metabolic

Hypoxic encephalopathies Narcotic overdose Nucleoside neuropathies Zidovudine myopathy

**2.** Psychiatric disorders

Reactive anxiety, depression

**3.** Other

Nutritional and metabolic disorders Drug toxicity

Cerebrovascular complication
