Alteration of the Serotoninergic System in Fatal Familial Insomnia Pietro Cortelli, 1 Ronald Polinsky, 2 Pasquale Montagna, 3 and Elio Lugaresi 3 We read with interest that Wanschitz and colleagues 1 found a substantial increase in tryptophan hydroxylase-immunoreactive neurons in the pons (superior central nucleus) and medulla (raphe obscurus nucleus) of fatal familial insomnia (FFI) pa- tients, suggesting that a serotoninergic system impairment rep- resents the functional substrate of some typical FFI symptoms. We report the lumbar cerebrospinal fluid (CSF) concen- trations of monoamine metabolites in 3 FFI subjects (1 fe- male) of 2 unrelated Italian families already described. 2 We measured 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) by a gas chromatographic, mass spectroscopic method previ- ously described. 3,4 The central component of MHPG was calculated according to the formula [total CSF MHPG] - 0.9 [free plasma MHPG]. 4 FFI patients had the typical point mutation at codon 178 of the prion protein gene combined with methionine at codon 129 of the mutated allele. Lumbar puncture was performed in a standardized fashion 3 13 (in 1 case) and 6 (in 2 cases) months after disease onset. Average ages ( standard error of the mean) at the time of CSF collection for the 3 FFI patients and 24 controls were 55  2 and 47  3 years. The CSF level of 5-HIAA in FFI pa- tients (37.63  4.13ng/ml) was significantly higher ( p  0.0001) than that in controls (18.72  1.95ng/ml). There were no significant differences between controls and FFI pa- tients with respect to lumbar CSF levels of HVA (FFI 44  1.2ng/ml, controls 42  2.3ng/ml) and corrected CSF MHPG (FFI 6.46  0.8ng/ml, controls 5.34  0.2ng/ml). Our results in FFI patients are consistent with increased central serotonin [5-hydroxytryptophan (5-HT)] turnover and with the findings of Wanschitz et al., 1 attended by normal dopaminergic activity and a slight increase in central norad- renergic function. However, we caution against an oversimpli- fied explanation of an altered serotoninergic system as the only functional substrate for all symptoms of FFI. The hallmark of FFI is selective degeneration of anteroventral (AV) and me- diodorsal (MD) thalamic nuclei, which constitute an impor- tant control station in the so-called central autonomic net- work, including several areas of the telencephalon, hypo- thalamus, and brain stem interconnected via parallel, function- ally specific, and neurochemically complex pathways. 5 The 5-HT system is one of these pathways and has been implicated in the regulation of the sleep–wake cycle and cardiovascular system, but its effects are subordinate to the control of higher diencephalic centers and the subtype of 5-HT receptors in- volved. 5 The crucial role of the AV and MD thalamic nuclei in regulating sleep and integrating autonomic and endocrine responses critical for homeostasis has been confirmed by stud- ies showing that wake–sleep and autonomic features compara- ble to FFI may be reproduced in experimental animals by kainic acid injection into the MD and the reticular nucleus of the thalamus. 2 Lesions to the thalamus disrupt the cortical– limbic circuitry with a cascade effect on the functions of many systems. For instance, there is pharmacological evidence of GABAergic system involvement in FFI patients. 6 Thus, while confirming increased activity of the serotoninergic system in FFI, we believe that it represents just one of the many bio- chemical systems involved. 1 University of Modena and Reggio Emilia, Bologna, Italy; 2 AstraZeneca Pharmaceuticals, Wilmington, DE; and 3 University of Bologna, Bologna, Italy References 1. Wanschitz J, Kloppel S, Jarius C, et al. Alteration of the seroto- nergic system in fatal familial insomnia. Ann Neurol 2000;48: 788 –791. 2. Montagna P, Cortelli P, Avoni P, et al. Clinical features of fatal familial insomnia: phenotypic variability in relation to a poly- morphism at codon 129 of the prion protein gene. Brain Pathol 1998;8:515–520. 3. Polinsky RJ, Brown RT, Burns RS, et al. Low lumbar CSF levels of homovanillic acid and 5-hydroxyindoleacetic acid in multiple system atrophy with autonomic failure. J Neurol Neurosurg Psy- chiatry 1988;51:914 –919. 4. Polinsky RJ, Jimerson DC, Kopin IJ. Chronic autonomic failure: CSF and plasma 3-methoxy-4-hydroxyphenylglycol. Neurology 1984;34:979 –983. 5. Benarroch EE. Central autonomic network: functional organiza- tion and clinical correlations. Armonk, NY: Futura, 1997. 6. Lugaresi E, Medori R, Montagna P, et al. Fatal familial insomnia and dysautonomia with selective degeneration of thalamic nuclei. N Engl J Med 1986;315:997–1003. Reply Julia Wanschitz, MD, 1 Marin Guentchev, MD, 1 and Herbert Budka, MD 1,2 We thank Cortelli and colleagues for their attention to our article. Their report of high cerebrospinal fluid (CSF) levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in 3 patients with fatal familial insomnia (FFI) confirms in- creased activity of the serotoninergic [5-hydroxytryptophan (5-HT)] system in FFI patients as indicated by our obser- vation of an increased number of tryptophan hydroxylase- immunoreactive (TH + ) neurons in median raphe nuclei. 1 As Cortelli and colleagues stated, these results must be in- terpreted with caution. We did not postulate a trivial expla- nation of the complex and unique clinical features of FFI as simply a serotonin-related disorder. We hypothesized that enhanced serotoninergic neurotransmission might contribute to the profound disturbance of control of autonomic ho- meostasis in FFI in accordance with the current knowledge about serotoninergic function on sleep, circadian rhythmicity, 2 and cardiovascular responses, 3 based on the dense innerva- tion of the limbic anteroventral and mediodorsal thalamic nuclei by serotoninergic fibers. The critical role of thalamic nuclei in the pathophysiology of central dysautonomia characteristic of FFI is well estab- lished. 4 Despite the paucicity of classical histopathological le- sions in other areas involved in the control of autonomic functions, such as the hypothalamus and several regions of the brain stem, the importance of subtle changes recorded in these areas 5 remained unclear. The changes in the ratio of TH + to TH - neurons in median raphe nuclei of the brain stem in FFI patients most likely represents an impaired neu- ronal function of the 5-HT system as one of the pathways LETTERS © 2001 Wiley-Liss, Inc. 421