SAN DIEGO—A case of amyotrophic lateral sclerosis (ALS) that appeared with newly diagnosed human immunodeficiency virus (HIV) infection and resolved after antiviral treatment reduced HIV viral loads to undetectable levels has heightened interest in the possible role of retroviruses in ALS. The case was presented by Daniel J. L. MacGowan, MD, MRCPI, at the 52nd Annual Meeting of the American Academy of Neurology. Dr. MacGowan is a specialist in adult neurology at the Hyman–Newman Institute for Neurology and Neurosurgery of Beth Israel Medical Center in New York City. "This represents the first case of viral–associated ALS syndrome with complete response to antiviral therapy," Dr. MacGowan reported.

The patient is a 32–year–old woman who presented with a three–month history of generalized weakness, dysarthria, and a weight loss of 20 lbs. "I first saw her in October of 1997," Dr. MacGowan said. "She had no sensory or sphincter deficits and no known HIV risk factors. Cranial nerve examination was normal except for an atrophic, immobile, and continually fasciculating tongue. The patient had problems with speech, but the gag reflex was intact."

Physical examination revealed mild bilateral facial weakness and widespread pathological hyperreflexia, including pathologic spread, a jaw jerk, extensor plantar, and positive Hoffmann responses bilaterally. At that time, the patient's sensory examination findings were normal.

Dr. MacGowan noted that the patient had some generalized adenopathy with moderate leukopenia and hyperglobulinemia, because of which the referring physicians had done an HIV test. The patient was positive for HIV on ELISA and had a CD4 cell count of 44 cells/µL. "At that point, I saw the patient and checked the blood for HTLV-1 [human T-cell lymphotropic virus type 1], GM-1, Lyme disease, and syphilis antibodies," Dr. MacGowan said. "All were negative."

Cerebrospinal fluid (CSF) examination showed a protein of 134 mg/dL and 17 white cells/µL, primarily lymphocytes. Cytologic findings were negative. A search by polymerase chain reaction (PCR) for opportunistic viral infections such as cytomegalovirus was negative. "At that time, I repeated the spinal tap to measure baseline CSF and plasma HIV viral loads," Dr. MacGowan said. "The Amplicor ultrasensitive PCR technique showed 77,900 HIV copies/cc of CSF and 61,600 copies/cc of plasma."

The results of magnetic resonance imaging (MRI) of the entire spine (including sections of the brainstem), with and without gadolinium, were normal. The electrophysiology of the motor and sensory nerves was normal. Dr. MacGowan said that needle electromyography showed abundant 3 to 4+ fibrillations and positive waves in all muscles, including all limbs, facial muscles, thoracic paraspinals, and tongue—with discrete neurogenic recruitment of normal-appearing units. Fasciculations were seen only in the tongue.

RECOVERY WITH CORRECT TREATMENT

"Within two months, this patient progressed to a bedbound quadriparesis requiring enteral nutrition. She was anarthric and dysphagic. She lost a further 20 pounds of weight and was unable to roll over in bed. Her oxygen saturations remained normal," Dr. MacGowan said. "I then placed her on total daily doses of AZT [zidovudine] 600 mg, lamivudine 300 mg, and nelfinazir 2250 mg. Six months later, she had recovered all of the lost weight, was eating a fully normal oral diet, and was able to walk with the assistance of knee and ankle braces. At that time, the CSF and plasma viral loads had decreased to undetectable levels [<40 copies/mL]."

Dr. MacGowan has followed this patient for three years on this triple-drug therapy and says that she now has minimal weakness in the deltoid muscles, the upper motor neuron signs have disappeared, her tongue has regained normal size and strength, her voice is normal, and the plasma viral load remains undetectable.

"This patient met all the El Escorial clinical criteria for definite ALS. The problem is that the motor neuron morphology was relatively normal in the presence of extensive denervation. I believe this suggests a very rapid motor neuropathy, without reinnervation, rather than typical ALS. The absence of motor changes and generalized fasciculation, along with the rapid response to antiretroviral therapy, suggests some form of HIV-induced arrest of motor neuron functioning rather than cell death," Dr. MacGowan said. "This is the first reported case of viral-associated motor neuron disease with complete sustained response to antiviral therapy. The case resurrects prior controversies on viral causes of ALS, particularly the possibility of transcription of endogenous or exogenous human retroviral DNA sequences."

Viruses other than HIV may be involved. Dr. MacGowan described work (by Michael Westarp and colleagues, in Ulm, Germany) showing Western Blot Reactivity that HIV-2, HTLV-1, HTLV-2, and other human retroviral antigens in the sera of patients with sporadic ALS who are ELISA negative for HIV-1. Dr. MacGowan's suggestion that retroviruses may stun, rather than kill, cells implicated in ALS is expected to incite research into a role for antiretroviral treatments for ALS patients who may have recoverable function.

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