CNS Whipple Disease with Insomnia

Abstract & Commentary

Source: Lieb K, et al. Insomnia for 5 years. Lancet 1999; 354:1966.

This one-page report underscores the protean symptoms, difficult diagnosis, and treatment of CNS Whipple’s disease. A 45-year-old man had been accurately identified and treated for the intestinal form of the disease from 1989 to 1996. Gradually increasing insomnia began in 1994, at which time polysomnographic records showed a sleep duration of 265 minutes. Physical examination, EEG, and CT scan were normal. Hypnotics had little effect. Memory and mood deteriorated by 1999 and examination identified an isolated supranuclear defect in upward gaze. Monitoring showed nocturnal sleep activity to be less than 60 minutes per 24 hours. Only sleep patterns 1 and 2 appeared, leaving absent sleep patterns 3, 4, and REM. Brain MRI disclosed nonspecific white matter patches, EEG patterns slowed to 7-8 seconds, and PCR testing of CSF identified Whipple’s disease. Among several drug trials, only carbamazepine brought sleep behavior back to approximately four hours per day.

Commentary

Whipple’s disease is rare and its brain involvement even more so. Thus, the long comment over the short index report. Early systemic symptoms consist of migratory polyarthralgia, chronic diarrhea, and unexplained fever. Progress may be slow in the non-neurologic portion of the illness but accumulates rapidly once central nervous system abnormalities express clinical symptoms. Whipple, a Johns Hopkins surgeon, identified the disease as the result of microorganisms in the gut (Whipple GH. Johns Hopkins Hosp Bull 1907; 18:382-391). The illness is uncommon, and clinically expressed central nervous system invasion is even less frequent (about 5%). Neither transmission nor independent development of the illness is as yet understood. The organism has resisted culturing, but can be identified by electron microscopy or PCR testing of tissue. Using PAS stain, Sieracki and colleagues (J Neuropathol Exp Neurol 1960;19:70-75) first identified the bacillus within a single macrophage in CSF. Subsequently, Cohen and colleagues (Lancet 1996;347:329) detected it in the CSF using PCR. Mistaken diagnoses since 1963 often have identified the disease as ’chronic encephalitis.” According to Louis and associates, important clues to brain intrusion of the organism include gradual functional evidence of supranuclear ophthalmoplegia, dementia, somnolence, insomnia, cranial-facial myoclonus, and hypothalamic dysfunction (Louis ED, et al. Ann Neurol 1996;40:561-568). Myorhythmia and masticatory movements that synchronize with pendular vergent oscillations were considered pathognomonic by Louis et al. About half of affected persons suffer from gradually advancing impaired cognitive functions. Brain imaging to date has shown only nonspecific changes. Treatment has limited success; tetracycline appears best but nothing has yet been effective in the late stage of the illness.

Of interest is the severe insomnia suffered by this unfortunate man and others described in Louis et al’s survey, cited above. One can also note similar examples of pathological insomnia associated with other brainstem illness (Aldrich MS, et al. Ann Neurol 1989;25:577-581). Aldrich and associates described 10 patients with progressive supranuclear palsy (PSP) whose nocturnal sleep ranged from 163-352 minutes (mean, 234 min). Patients with brain trauma, acute ischemia, or hemorrhage affecting the pontine midline tegmental structures often undergo severe reductions of sleep of less than 2.5 hours. Some suffer from no sleep at all and many of the others have reduced or absent REM. Many such persons retain their awareness, but may become confused or severely delirious. Markand and Dyken (Neurology 1976;26:769-776), for example, described two such ’locked-in” examples of this stroke syndrome. Both displayed no sleep at all when twice monitored for 24 hours. Both died, and post-mortem examination confirmed the pontine tegmental abnormalities. Other examples in the pre-1990s literature demonstrate similar structural damage to the medial pontine tegmentum. Most famous of present conditions causing malignant sleeplessness, of course, is the prion disease of fatal familial insomnia in which widespread spongiform changes are found diffusely in the cerebrum. —fp