Indistinguishable clinically from AIDP and CIDP in non-HIV-infected states
Most common HIV-l-related form of neuropathy
Prominent lower extremity syndrome resembling spinal cord compression
Laryngeal nerve involvement can ocour and lead to hoarseness with vocal cord paralysis
Modified from So YT Holtzman DM Abrams Dl Olney RK Penpheral neuropathy assoeiated with acquired immunodeflciency syndrome; prevalence and clinical features from a population-based survey Arch Neurol 1988;45:945 948. AIDP Acute inflammatory demyelinating polyrleuropathy; CIDP, chronic inflammatory demyelinating polyneuropathy; Bx, biopsy.
Clinical features of AIDP are similar to that of patients without HIV-1 infection (see Chapter 49 ). Patients present with progressive, symmetrical weakness of the upper and lower extremities. Although sensory symptoms may be present, the examination commonly shows sensory deficits that are mild in comparison to degree of weakness. The CSF protein may be elevated, and a majority of patients have a lymphocytic pleocytosis of up to 50 cells/mm3 . As in non-HIV-1-infected patients with AIDP, the pathophysiological mechanism is thought to be on an immune-mediated basis ("autoimmune"). AIDP is a monophasic illness which responds well to treatment but can also remit without therapy. At present, plasmapheresis is the treatment of choice. The natural history of HIV-1-associated CIDP is unknown. As in treatment of CIDP in non-HIV-1 patients, prednisone or plasmapheresis are reported to be efficacious (see Chapter^.).
Pathophysiological mechanisms of this form of HIV-associated polyneuropathy remain unclear. Several hypotheses have been proposed: (1) direct effects of HIV-1 M , [1401 [1411 [1421 ; (2) HIV-1-mediated effects of activated macrophages and the production of cytokines (tumor necrosis factor (TNF)- alpha, interleukin-1 (IL-1) and (IL-6) y^ ; (3) nutritional deficiencies; and (4) toxins. Further studies are needed to clarify the role of these agents in the pathogenesis of distal symmetrical polyneuropathy (DSP) in AIDS. Infectious etiologies (mainly CMV) have also been implicated; however, some investigators believe that infection-related distal symmetrical polyneuropathy should be considered as a separate and distinct category. y
Pathological examination of nerve biopsies shows degeneration of myelinated and unmyelinated axons,  , yi with mild epineurial and endoneurial perivascular mononuclear inflammation. The inflammatory cells are characterized as T lymphocytes and activated macrophages. In the endoneurium, suppressor/cytotoxic cells (CD8+) predominate over helper/inducer (CD4+) cells. A more equal ratio is seen in the epineurium and perineurium. Immunoglobulin, complement, or fibrin is not seen. Associated demyelinationy1 may be present but does not appear to be macrophage mediated or segmental.^1 Distal axonal degeneration is noted in both central and peripheral projections of dorsal root ganglion cells and is a frequent autopsy finding in AIDS patients. Gracile tract degeneration in the upper thoracic and cervical segments may also be seen.y?1 Loss of dorsal root ganglion cells and mononuclear infiltration is usually mild in comparison with the degree of axonal degeneration and inflammation of distal nerves.
Characteristically, sensory symptoms in the form of neuropathic pain far exceed motor dysfunction in DSP. Typical symptoms are burning pain, numbness, or tingling of the toes or over the soles. Some patients develop contact hyperalgesia. Upper extremity involvement occurs somewhat later in the course of the neuropathy. Muscle weakness is not a prominent symptom. The most common signs are those typical of a predominantly sensory length-dependent neuropathy with depressed or absent ankle tendon reflexes, elevated sensory threshold, increased vibratory thresholds, decreased pinprick and temperature, in a stocking-and- glove distribution. Joint position sensation is relatively normal. y^ , ^ If present, weakness is minimal and is generally restricted to intrinsic foot muscles. yj , W1
DSP is the most frequent type of HIV-associated neuropathy. A 2.81 percent overall incidence is estimated in HIV-1-infected persons; however, it can be detected clinically in 10 to 35 percent of patients with AIDS. [ 1 , [ 1 , [ 1
Differential diagnosis of HIV-1-associated DSP includes toxic neuropathies attributable to chemotherapeutic agents (e.g., vincristine isoniazid 2 ,3
-dideoxycytidine [ddC1, and 2 ,3
-dideoxyinosine [ddI1, d4T [stavudine!)^1 and tarsal tunnel syndrome. Electrodiagnostic studies do not differentiate between toxic neuropathies and other causes of DSP. The diagnosis of toxic neuropathy is based on the temporal association of the peripheral neuropathy with drug treatment and improvement after the suspected agent is removed. Co-morbid conditions such as diabetes or excessive alcohol intake may exacerbate, unmask, or predispose HIV- 1 patients to develop this neuropathy sooner than expected.
The electrodiagnostic features of DSP in AIDS are consistent with distal and symmetrical degeneration of sensory and motor axons, in a pattern similar to other forms of DSP (absent or low-amplitude sural nerve action potentials). y?1 Nerve conduction velocities are usually in the low range of normal or mildly reduced. yj Late responses are also delayed in a pattern consistent with axonal neuropathy. Reduction in the amplitudes of the peroneal or tibial compound muscle action potential is less common. Electromyography (EMG) may demonstrate signs of active or chronic partial denervation with re-innervation in distal leg muscles. y? , ^ Serum vitamin B12 levels, folate, erythrocyte sedimentation rate, antinuclear antibodies, fasting blood glucose, liver enzymes, creatinine, thyroid function tests, and serum protein electrophoresis are usually normal. ^ Cerebrospinal fluid examination is nonspecific and often shows mild abnormalities in cell count and protein level (as is common in HIV-1-infected patients).^1
DSP is often a disabling condition owing to severe pain. The main treatment is symptomatic and includes those agents used in the treatment of painful non-AIDS peripheral neuropathies (analgesics, tricyclic, antidepressants, and membrane stabilizing drugs) (see Chapt§.L20 ).
Two forms of mononeuritis multiplex (MM), both relatively rare, have been recognized as a complication of HIV- 1 infection and AIDS. The first form affects patients in early stages of HIV-1 infection (CD4+ cell counts greater than 200 cell/mm 3 ), and the second affects those individuals with advanced disease. yj , W Patients in early HIV-1 stages have a more benign disease, the extent of nerve involvement is more restricted, and the course is self- limited. Motor and sensory deficits have an asymmetrical pattern in the distribution of discrete peripheral nerves that usually develops over the course of a few weeks. As in non-AIDS mononeuritis multiplex, an autoimmune vasculitis is proposed (see Chapter 50 ). This form of mononeuritis neuropathy should be differentiated from compressive neuropathies of the ulna or peroneal nerves seen particularly in patients who are bed-bound with profound weight loss.
In contrast, more widespread, multifocal weakness is characteristic of the second type, which affects patients with low CD4+ counts. The clinical presentation is typically subacute with progression over several weeks or a few months. Asymmetrical, multifocal sensory and motor deficits in the distribution of several major peripheral nerves or spinal roots are characteristic of this neuropathy. Significant motor deficits are present, and deep tendon reflexes mediated by the affected nerves are diminished or absent. Cranial neuropathy is common, and '144] some patients have hypophonia, hoarseness, and vocal cord paresis. The asymmetric weakness in discrete distributions of peripheral nerves and occasional laryngeal nerve involvement help distinguish these patients from those with the more frequently encountered CIDP.
Electrodiagnostic studies show multifocal neuropathy with mixed demyelination and axonal loss. Compressive or entrapment neuropathies are excluded by these studies. Early disease stage HIV-1-associated MM, as is non-HIV- 1-related MM, is thought to be due to a vasculitis. yi , yi Pathological specimens from patients with advanced AIDS show polymorphonuclear infiltrates, with mixed axonal and demyelinative lesions as well as evidence of CMV. yi , yi
This syndrome develops primarily in patients with very low CD4+ counts and advanced HIV-1 disease. It is generally considered to be due to secondary viral, infectious, or tumerous processes in the immune-compromised host and not directly related to HIV infection. Presenting features of progressive lumbar polyneuropathy include an acute cauda equina syndrome with rapid progression of bilateral leg weakness and urinary/fecal incontinence. Back pain is a prominent feature in some patients. Initially, weakness is restricted to the lower extremities as is areflexia. Paresthesias are common, but sensory deficits are rarely marked. Perineal or perianal sensory changes are characteristic but not always present. Areflexia and sensory disturbance (albeit mild) help differentiate this syndrome from weakness due to myopathy or the wasting syndrome (see later). Sphincteric disturbances and sparing of the upper extremities separate this disorder from AIDP,
CIDP, and mononeuritis multiplex. Electromyography demonstrates denervation in clinically weak muscles. Nerve conduction velocity abnormalities may be present in up to one third of patients and indicates a co-existing polyneuropathy. Cerebrospinal fluid examination is the most important confirmatory study. Elevated protein content and hypoglycorrhachia are common. About half of patients have a marked pleocytosis, with cell counts in excess of 500 cells/mm 3 . The other half have a less striking mononuclear cell count.
CMV infection is the most important infectious cause of this syndrome W and may be detected by CSF culture and the use of CMV PCR testing. This disorder should be treated with ganciclovir and foscarnet (see Chapter.41 ). A polyradiculopathy syndrome may also be caused by pathogens other than CMV (e.g., herpes zoster infections, Treponema pallidum, Mycobacterium tuberculosis, toxoplasmosis of the conus medullaris and by leptomeningeal lymphoma).^1 Therefore, CSF studies should include viral cultures, VDRL titer, and cytological studies. A lumbarsacral spine MRI excludes a compressive or mass lesion and may show enhancement of nerve roots. When herpes zoster radiculitis is present, lesions are improved and the incidence of neuralgia reduced by acyclovir. Parenteral acyclovir (30 mg/kg/d) should be used when cervical or lumbar dermatones are involved in an attempt to prevent a severe myeloradiculitis. Amitriptyline, carbamazepine, and capsaicin can be used in the setting of postherpetic neuralgia.
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